Drugs List

Therapeutic Indications

Uses

Treatment of symptomatic anaemia associated with chronic kidney disease in adults.

Administration

For intravenous or subcutaneous injection. Subcutaneous injection is preferred for patients not receiving haemodialysis to avoid puncture of peripheral veins.

Subcutaneously, the injection may be given in the abdomen, arm or thigh.

Handling

Do not shake

Allow the solution for injection to reach room temperature before administration.

Incompatibilities

Methoxy polyethylene glycol-epoetin beta should not be mixed with any other medicinal product.

Contraindications

Children under 18 years

Uncontrolled hypertension

Pure red cell aplasia (PRCA) following previous erythropoietin therapy

Precautions and Warnings

Therapy should be supervised by physicians experienced in the treatment of patients with renal impairment.

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.

Haemoglobin should be monitored every 2 weeks until stabilised, and periodically thereafter.

Use with caution when escalating doses in patients with chronic renal failure 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.

All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies) should be excluded and corrected if necessary, before instituting therapy with methoxy polyethylene glycol-epoetin beta.

Experience is limited in patients receiving peritoneal dialysis. Regular haemoglobin monitoring and strict adherence to dose adjustment recommendations are required in these patients.

Monitor iron status before and during treatment in all patients.

An oral iron supplement is recommended in all patients with serum ferritin values below 100 micrograms/l, transferrin saturation below 20%, or where there are other signs of iron deficiency.

If the patients does not respond to therapy, causative factors should be investigated (such as iron, folic acid or vitamin B12 deficiency; aluminium intoxication; intercurrent infections; inflammatory or traumatic episodes; occult blood loss; haemolysis, underlying haematological disease, and bone marrow fibrosis). Evaluation of reticulocyte count should also be considered. If these conditions are excluded and the patient experiences a sudden drop of haemoglobin associated with reticulocytopenia and anti-erythropoietin antibodies, the bone marrow should be examined for evidence of pure red cell aplasia (PRCA). If PRCA is diagnosed, therapy should be discontinued and the patients should not receive another erythropoiesis stimulating agent.

Antibody-mediated Pure red cell aplasia (PRCA) has been reported in association with erythropoiesis stimulating agents. Patients suspected or confirmed to have antibodies to erythropoietin should not be switched to methoxy polyethylene glycol-epoetin beta.

In all patients receiving methoxy polyethylene glycol-epoetin beta, blood pressure should be closely monitored before and during therapy and should be controlled as necessary. Methoxy polyethylene glycol-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 high blood pressure cannot be controlled by medical treatment or diet, the dose should be reduced or therapy discontinued.

Patients should be monitored closely to ensure that the lowest approved dose is used to provide adequate control of the symptoms of anaemia whilst maintaining a haemoglobin concentration below or at 12 g/dl (7.45 mmol/l).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

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

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

Misuse by healthy persons may lead to an excessive increase in haemoglobin. This may be associated with life threatening complications of the cardiovascular system.

Methoxy polyethylene glycol-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.

Use with caution in the following patients as safety and efficacy has not been established:
Haemoglobinopathies
Epilepsy
Bleeding
Recent history of bleeding requiring a transfusion
Platelet levels exceeding 500 x 10 to the power of 9 / litre

Use with caution in patients with the following conditions:
Ischaemic vascular disease
Malignant disease.

Record the trade name of the administered ESA on the patient's file in order to improve traceability.

PRCA has been known to develop in patients with hepatitis C receiving interferon and ribavirin and treated with ESAs. Epoetins are not approved in the management of anaemia associated with hepatitis C.

Pregnancy - see 'Pregnancy' section

Breastfeeding - see 'Lactation' section

CSM Warnings

There have been very rare reports of pure red cell aplasia in patients treated with epoetin alfa. The MHRA/CHM has advised that in patients developing epoetin alfa failure with a diagnosis of pure red cell aplasia, treatment with epoetin alfa must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another form of erythropoietin.

Overcorrection of haemoglobin concentrations 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.
CSM advice is that:
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 haemoglobin concentration should be maintained within the range 10 - 12 g/100ml.
Haemoglobin concentrations higher than 12g/100ml should be avoided.
The aim of treatment is to relieve symptoms of anaemia, and in patients with chronic kidney 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).

Pregnancy and Lactation

Pregnancy

Use with caution during pregnancy.

There is no data from the use of methoxy polyethylene glycol-epoetin beta during human pregnancy.

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. However, studies do indicate a class-related reduction in foetal weight.

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 at ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Lactation

Use with caution.

It is not known if methoxy polyethylene glycol-epoetin beta is excreted in human breast milk. Animal studies have demonstrated that methoxy polyethylene glycol-epoetin beta is excreted in 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 the 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 appear 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

Side Effects

Hypertension
Headache
Hypertensive encephalopathy
Rash
Maculopapular rash
Vascular access thrombosis
Hot flush
Hypersensitivity reaction
Decreased platelets
Stroke
Anaphylactic reaction
Thrombosis
Thrombocytopenia
Pulmonary embolism
Pure red cell aplasia
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Vascular access thrombosis

Presentation

Solution for injection containing 30micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 50micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 75micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 100micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 120micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 150micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 200micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 250micrograms/0.3ml of methoxy polyethylene glycol-epoetin beta
Solution for injection containing 360micrograms/0.6ml of methoxy polyethylene glycol-epoetin beta

Methoxy polyethylene glycol-epoetin beta is a covalent conjugate of a protein produced by recombinant DNA technology in Chinese Hamster Ovarian cells and conjugated to a linear methoxy-polyethylene glycol (PEG).

Drugs List

Therapeutic Indications

Uses

Treatment of symptomatic anaemia associated with chronic kidney disease in adults.

Dosage

Therapy should be supervised by physicians experienced in the treatment of patients with renal impairment.

Haemoglobin should be monitored every 2 weeks until stabilised, and periodically thereafter.

Adults

Elderly

Children

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For intravenous or subcutaneous injection. Subcutaneous injection is preferred for patients not receiving haemodialysis to avoid puncture of peripheral veins.

Subcutaneously, the injection may be given in the abdomen, arm or thigh.

Handling

Do not shake

Allow the solution for injection to reach room temperature before administration.

Incompatibilities

Methoxy polyethylene glycol-epoetin beta should not be mixed with any other medicinal product.

Contraindications

Children under 18 years

Uncontrolled hypertension

Pure red cell aplasia (PRCA) following previous erythropoietin therapy

Precautions and Warnings

Therapy should be supervised by physicians experienced in the treatment of patients with renal impairment.

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.

Haemoglobin should be monitored every 2 weeks until stabilised, and periodically thereafter.

Use with caution when escalating doses in patients with chronic renal failure 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.

All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies) should be excluded and corrected if necessary, before instituting therapy with methoxy polyethylene glycol-epoetin beta.

Experience is limited in patients receiving peritoneal dialysis. Regular haemoglobin monitoring and strict adherence to dose adjustment recommendations are required in these patients.

Monitor iron status before and during treatment in all patients.

An oral iron supplement is recommended in all patients with serum ferritin values below 100 micrograms/l, transferrin saturation below 20%, or where there are other signs of iron deficiency.

If the patients does not respond to therapy, causative factors should be investigated (such as iron, folic acid or vitamin B12 deficiency; aluminium intoxication; intercurrent infections; inflammatory or traumatic episodes; occult blood loss; haemolysis, underlying haematological disease, and bone marrow fibrosis). Evaluation of reticulocyte count should also be considered. If these conditions are excluded and the patient experiences a sudden drop of haemoglobin associated with reticulocytopenia and anti-erythropoietin antibodies, the bone marrow should be examined for evidence of pure red cell aplasia (PRCA). If PRCA is diagnosed, therapy should be discontinued and the patients should not receive another erythropoiesis stimulating agent.

Antibody-mediated Pure red cell aplasia (PRCA) has been reported in association with erythropoiesis stimulating agents. Patients suspected or confirmed to have antibodies to erythropoietin should not be switched to methoxy polyethylene glycol-epoetin beta.

In all patients receiving methoxy polyethylene glycol-epoetin beta, blood pressure should be closely monitored before and during therapy and should be controlled as necessary. Methoxy polyethylene glycol-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 high blood pressure cannot be controlled by medical treatment or diet, the dose should be reduced or therapy discontinued.

Patients should be monitored closely to ensure that the lowest approved dose is used to provide adequate control of the symptoms of anaemia whilst maintaining a haemoglobin concentration below or at 12 g/dl (7.45 mmol/l).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

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

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

Misuse by healthy persons may lead to an excessive increase in haemoglobin. This may be associated with life threatening complications of the cardiovascular system.

Methoxy polyethylene glycol-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.

Use with caution in the following patients as safety and efficacy has not been established:
Haemoglobinopathies
Epilepsy
Bleeding
Recent history of bleeding requiring a transfusion
Platelet levels exceeding 500 x 10 to the power of 9 / litre

Use with caution in patients with the following conditions:
Ischaemic vascular disease
Malignant disease.

Record the trade name of the administered ESA on the patient's file in order to improve traceability.

PRCA has been known to develop in patients with hepatitis C receiving interferon and ribavirin and treated with ESAs. Epoetins are not approved in the management of anaemia associated with hepatitis C.

Pregnancy - see 'Pregnancy' section

Breastfeeding - see 'Lactation' section

CSM Warnings

There have been very rare reports of pure red cell aplasia in patients treated with epoetin alfa. The MHRA/CHM has advised that in patients developing epoetin alfa failure with a diagnosis of pure red cell aplasia, treatment with epoetin alfa must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another form of erythropoietin.

Overcorrection of haemoglobin concentrations 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.
CSM advice is that:
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 haemoglobin concentration should be maintained within the range 10 - 12 g/100ml.
Haemoglobin concentrations higher than 12g/100ml should be avoided.
The aim of treatment is to relieve symptoms of anaemia, and in patients with chronic kidney 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).

Pregnancy and Lactation

Pregnancy

Use with caution during pregnancy.

There is no data from the use of methoxy polyethylene glycol-epoetin beta during human pregnancy.

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. However, studies do indicate a class-related reduction in foetal weight.

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 at ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Lactation

Use with caution.

It is not known if methoxy polyethylene glycol-epoetin beta is excreted in human breast milk. Animal studies have demonstrated that methoxy polyethylene glycol-epoetin beta is excreted in 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 the 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 appear 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

Effects on Ability to Drive and Operate Machinery

There are no effects on the ability to drive or operate machinery.

Side Effects

Hypertension
Headache
Hypertensive encephalopathy
Rash
Maculopapular rash
Vascular access thrombosis
Hot flush
Hypersensitivity reaction
Decreased platelets
Stroke
Anaphylactic reaction
Thrombosis
Thrombocytopenia
Pulmonary embolism
Pure red cell aplasia
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Vascular access thrombosis

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 ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Shelf Life and Storage

Store at 2-8 degrees C
Do not freeze
Keep the syringe in the outer carton to protect from light
Do not shake

The patient may store the product at room temperature (below 30 degrees C) for a single period of 1 month. Once removed from the refrigerator, the product must be used within this one month period.

Further Information

Last Full Review Date: August 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.

Summary of Product Characteristics: Mircera solution for injection in pre-filled syringe. Roche Products Ltd. Revised September 2017.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 25 September 2015

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: 1st March 2012
Last Accessed: 21st August 2012