Epoetins
Description. Erythropoietin is a glycosylated protein hormone
and a haematopoietic growth factor produced primarily in the
kidneys.
Erythropoietin for clinical use is produced by recombinant DNA
technology and the name epoetin is often applied to such material.
Epoetin alfa, epoetin beta, epoetin gamma, epoetin omega,
and epoetin zeta are recombinant human erythropoietins derived
from a cloned human erythropoietin gene. All have the same 165
amino acid sequence but differ in the glycosylation pattern. Epoetin
delta is a recombinant human erythropoietin derived from a
genetically engineered continuous human cell line. It has the
same amino acid sequence and glycosylation pattern as human
erythropoietin.
Epoetins
Description. Erythropoietin is a glycosylated protein hormone
and a haematopoietic growth factor produced primarily in the
kidneys.
Erythropoietin for clinical use is produced by recombinant DNA
technology and the name epoetin is often applied to such material.
Epoetin alfa, epoetin beta, epoetin gamma, epoetin omega,
and epoetin zeta are recombinant human erythropoietins derived
from a cloned human erythropoietin gene. All have the same 165
amino acid sequence but differ in the glycosylation pattern. Epoetin
delta is a recombinant human erythropoietin derived from a
genetically engineered continuous human cell line. It has the
same amino acid sequence and glycosylation pattern as human
erythropoietin.
Adverse Effects and Treatment
Adverse effects of epoetins include flu-like symptoms such as fever, chills, headache, arthralgias, myalgias, asthenia, dizziness, and tiredness, which occur especially at the start of treatment. Other effects include rashes, urticaria, nausea and vomiting, diarrhoea, hyperkalaemia, and reactions at the injection site. Severe hypersensitivity reactions have been reported rarely. Pure red cell aplasia associated with neutralising antibodies has also been reported rarely in patients with chronic renal failure. Modest increases in the platelet count within the normal range may occur during epoetin therapy.
Hypertension is common with the use of epoetins, particularly in patients with renal failure, and is associated with a rapid rise in haematocrit. Hypertensive crisis with encephalopathy and seizures has been reported, even in patients with initially normal or low blood pressure.
Reports of thromboembolism include myocardial ischaemia and infarction, transient ischaemic attacks and cerebrovascular accidents, deep-vein thrombosis, and pulmonary embolism. Shunt thromboses may occur in the arteriovenous fistulae of dialysis patients, and occlusion of the dialysis system is possible, due to an increased haematocrit.
Effects on the blood.
The use of recombinant human erythropoietin has been associated with an increase in thrombotic events, including vascular access thrombosis in haemodialysis patients. A number of mechanisms have been proposed for this increase such as increased blood viscosity, effects on proteins involved in coagulation, activation of platelets and the endothelium, and a vasoconstrictor effect on vascular smooth muscle.
Pure red cell aplasia has been reported rarely in patients with chronic renal failure after months to years of treatment with epoetin alfa; most patients have been found to have antibodies to epoetins.There have also been a few cases in patients treated with epoetin beta. A review of cases reported between January 1988 and April 2004 found that the number peaked in 2001 and 2002, and decreased rapidly when changes were made to recommendations for storage, handling, and use of epoetin alfa preparations. The effect appeared to be brand specifi and associated particularly with the subcutaneous use of preparations containing polysorbate 80 as a stabiliser. Other possible causes have been proposed including contamination with silicone lubricant used in pre-filled syringes or release of organic compounds from rubber plungers. Subsequently, manufacturers have reported that cases of red cell aplasia with neutralising antibodies have also occurred in chronic renal failure patients treated with subcutaneous darbepoetin alfa. They also warn that because of cross-reactivity, patients who develop antibody-mediated anaemia with either an epoetin or darbepoetin alfa should not be swapped to another erythropoietic protein.
Epoetin-induced red cell aplasia has been managed with withdrawal of the epoetin and treatment with immunosuppressants including corticosteroids, cyclophosphamide, and ciclosporin. Intravenous normal immunoglobulin has also been used. Kidney transplantation is reported to bring about a rapid recovery.
Effects on electrolytes.
Hyperkalaemia and hyperphosphataemia may occur in patients receiving recombinant human erythropoietin. However, hypophosphataemia has also been reported in cirrhotic patients given erythropoietin before autologous blood donation.
Effects on mental function.
Visual hallucinations occurred in 4 patients during treatment with recombinant human erythropoietin, stopped when treatment was withdrawn, and recurred in 2 patients when erythropoietin was reinstituted. Commenting on these and a further 7 cases, the manufacturers considered the reaction to be extremely rare and that the contribution of concurrent medication could not be discounted. In two groups of dialysis patients treated with recombinant human erythropoietin, 15 of 134 and 2 of 103 experienced visual hallucinations.Increasing age appeared to be a risk factor. Hallucination, associated with hypertension, has occurred during epoetin therapy in a patient with a history of bone marrow transplantation.
Effects on the skin.
Skin rashes may occur during treatment with recombinant human erythropoietin.
Pseudoporphyria cutanea tarda, a photosensitivity disorder, has been reported in 2 children undergoing peritoneal dialysis and receiving erythropoietin. However, it was pointed out that this disorder has occurred in adults undergoing dialysis and the children were also receiving other potential photosensitisers.
Effects on the spleen.
Aggravation of splenomegaly was reported in 2 patients with myeloproliferative disorders after use of recombinant human erythropoietin. Splenic infarction has been reported in a patient with aplastic anaemia given erythropoietin, and peliosis of the spleen was discovered at autopsy in a patient with end-stage renal failure who had been receiving erythropoietin.
Effects of subcutaneous injection.
Localised pain can occur on subcutaneous injection of human recombinant erythropoietin. In comparisons of preparations it has been suggested that different excipients may affect this. It has generally been reported that epoetin alfa preparations containing citrate buffer are more painful than those with phosphate buffer, and that epoetin beta preparations are less painful than epoetin alfa preparations.
Treatment of adverse effects.
Venesection and erythropheresis have been used to treat raised haematocrit and haemoglobin concentrations caused by recombinant human erythropoietin overdose. Venesection also successfully reduced the blood pressure in 4 patients with life-threatening hypertension associated with recombinant human erythropoietin . None of the patients had a raised haematocrit and the hypertension had been unresponsive to antihypertensive therapy.
Precautions
Recombinant human erythropoietin should be used with caution in patients with hypertension, a history of seizures, thrombocytosis, chronic hepatic impairment, ischaemic vascular disease, or in patients with malignant tumours. Hypertension should be well controlled before treatment is started and blood pressure monitored during treatment.
Response to recombinant human erythropoietin may be diminished by iron deficiency, infection or inflammatory disorders, haemolysis, or aluminium intoxication. Anaemia due to folic acid and vitamin B12 deficiencies should also be excluded, since these may also reduce the response. Patients developing sudden lack of efficacy should be investigated. If pure red cell aplasia is diagnosed treatment should be stopped and testing for epoetin antibodies considered; patients should not be transferred to another epoetin.
Patients undergoing dialysis may require increased doses of heparin in view of the increase in packed cell volume.
Platelet counts, haemoglobin concentrations, and serum-potassium concentrations should be monitored regularly.
Dosage must be carefully controlled to avoid too fast an increase in haematocrit and haemoglobin and recommended haematocrit and haemoglobin values should not be exceeded because of the increased risks of hypertension and thrombotic events.
For reference to the uncertainty of the effect of epoetins on tumour progression and progression-free survival when used in patients with cancer, see under Anaemias in Uses and Administration.
Abuse.
The potential dangers from abuse of recombinant human erythropoietin by athletes have been reviewed.Normally, optimal athletic conditioning leads to little change in red cell volume but a significant increase in plasma volume and total blood volume. In contrast, the artificial increase in the red cell mass induced by epoetin is usually accompanied by a decrease in plasma volume and no change in total blood volume. Lack of medical supervision and fluid loss during endurance events increase the risk of serious adverse consequences of these changes in blood viscosity produced by such misuse of epoetin. In one case,cerebral sinus thrombosis in a cyclist was attributed to the combined use of epoetin, human growth hormone, and high doses of vitamins A and E.
Haematocrit.
A study involving 1233 patients undergoing haemodialysis and suffering from heart failure or ischaemic heart disease found that erythropoietin in doses sufficient to increase haematocrit to 42% (within the normal range) was associated with lack of benefit and a trend towards increased mortality when compared with doses sufficient to maintain a lower haematocrit of around 30%. However, these results are difficult to interpret, since within each group, increased haematocrit was associated with lower mortality, despite the between-group differences. The possibility that intravenous iron supplementation might have contributed to these adverse results was considered, but commentators suggested that until further data was available aiming for a haematocrit of 33 to 36%, and using intravenous iron supplementation where necessary, was still appropriate.
Resistance.
Many factors may contribute to a poor response to recombinant human erythropoietin (see Precautions). A study in patients with anaemia of end-stage renal disease found that inadequate dialysis was associated with a reduced response to erythropoietin treatment. The dialysis time and mode of dialysis may also influence response to erythropoietin therapy.Antibodies to recombinant human erythropoietin have also been reported. Delayed clinical response to recombinant human erythropoietin in a patient could have been due to an inherited subclinical pyruvate kinase deficiency.
Pharmacokinetics
Epoetin alfa and epoetin beta exhibit some differences in their pharmacokinetics, possibly due to differences in glycosylation and in the formulation of the commercial preparations.
Epoetin alfa is slowly and incompletely absorbed after subcutaneous injection, and a relative bioavailability of about 10 to 20% has been reported. Peak concentrations after epoetin alfa intravenously are attained within 15 minutes, and within 5 to 24 hours after subcutaneous injection.
The elimination half-life of epoetin alfa after intravenous doses has been reported to be 4 to 13 hours in patients with chronic renal failure; the half-life is generally less in patients with normal renal function. An estimated elimination half-life of about 24 hours has been reported for epoetin alfa given subcutaneously.
Epoetin beta is similarly slowly and incompletely absorbed after subcutaneous injection, and its absolute bioavailability has been reported to be 23 to 42%. Peak serum concentrations are attained within 12 to 28 hours of subcutaneous doses. An elimination half-life of 4 to 12 hours has been reported after intravenous doses and a terminal half-life of 13 to 28 hours after subcutaneous doses.
Uses and Administration
Erythropoietin is a glycosylated protein hormone and a haematopoietic growth factor. It is secreted primarily by the kidneys, although a small amount is produced in extrarenal sites such as the liver. Erythropoietin regulates erythropoiesis by stimulating the differentiation and proliferation of erythroid precursors, the release of reticulocytes into the circulation, and the synthesis of cellular haemoglobin. The release of erythropoietin is promoted by hypoxia or anaemia, and up to 1000 times the normal serum-erythropoietin concentration may be reached under these conditions; this response may be impaired in some disease states such as chronic renal failure. The haematological response to erythropoietin is reduced if there is an inadequate supply of iron. For an outline of blood cell formation in general and average cell counts in adults see Haematopoiesis.
Epoetin alfa and epoetin beta are recombinant human erythropoietins available for clinical use that have the same pharmacological actions as endogenous erythropoietin. They are used in the management of anaemia associated with chronic renal failure in dialysis and predialysis patients; they may reduce or obviate the need for blood transfusions in these patients. Epoetin delta is under investigation for anaemia in chronic renal failure. Epoetin alfa and epoetin beta are also used in the management of chemotherapy-induced anaemia in patients with non-myeloid malignant disease. Epoetin alfa is used in zidovudine-related anaemia in HIV-positive patients. Epoetin beta is used in the management of anaemia of prematurity. Recombinant human erythropoietin is also being evaluated in the management of other types of normocytic-normochromic anaemias, including that associated with inflammatory disorders such as rheumatoid arthritis. In all patients, iron status should be monitored and supplementation provided if necessary.
Epoetin alfa and epoetin beta may also be used in patients with moderate anaemia (but no iron deficiency) before elective surgery to increase the yield of blood collected for autologous blood transfusion. Epoetin alfa may also be used in such patients to reduce the need for allogeneic blood transfusion.
In the management of anaemia of chronic renal failure epoetin alfa or epoetin beta may be given subcutaneously or intravenously, depending on the formulation. The intravenous route is recommended for patients on haemodialysis. The aim of treatment is to increase the haemoglobin concentration to 10 to 12 g per 100 mL or to increase the haematocrit to 30 to 36%. The rate of rise in haemoglobin should be gradual to minimise adverse effects such as hypertension; a rate not exceeding 2 g per 100 mL per month is suggested.
Epoetin alfa may be given by intravenous injection over at least 1 minute; slow intravenous injection over 5 minutes may be used in patients who experience flu-like symptoms as adverse effects. Epoetin alfa may also be given subcutaneously, but preparations that contain polysorbate 80 should only be given intravenously in this group of patients (see Effects on the Blood).
In predialysis and haemodialysis patients, a recommended initial dose of epoetin alfa is 50 international units/kg three times weekly; a higher initial dose of 50 to 100 units/kg three times weekly has been suggested in the USA.
Doses may be increased at 4-week intervals in increments of 25 units/kg three times weekly until the target is reached.
In patients on peritoneal dialysis an initial dose of 50 units/kg given intravenously twice weekly may be used.
Once the target is reached doses may need to be adjusted, and even decreased, for maintenance therapy.
The usual total weekly maintenance dose of epoetin alfa in predialysis patients is 50 to 100 units/kg given in three divided doses, and in haemodialysis patients it is about 75 to 300 units/kg given in three divided doses. In predialysis patients a total weekly dose of 600 units/kg should not be exceeded. In patients on peritoneal dialysis, the usual total weekly maintenance dose is 50 to 100 units/kg given intravenously in two divided doses.
In children, epoetin alfa may be given intravenously to those on haemodialysis.
The initial dose is 50 units/kg three times weekly. The dose may be increased at 4-week intervals in increments of 25 units/kg three times weekly until a target haemoglobin concentration of 9.5 to 11 g per 100 mL is reached.
The usual total weekly maintenance dose given in three divided doses is:
225 to 450 units/kg for those weighing less than 10 kg
180 to 450 units/kg for those weighing 10 to 30 kg
90 to 300 units/kg for those weighing over 30 kg.
Epoetin beta is used similarly in the management of anaemia of chronic renal failure in dialysis and predialysis patients. It may be given subcutaneously or by intravenous injection over 2 minutes. The following dosages may be used in adults and children:
For subcutaneous injection the initial dose is 60 units/kg weekly for 4 weeks; the total weekly dose may be divided to be given in daily doses or three times a week.
For intravenous injection the initial dose is 40 units/kg three times weekly for 4 weeks; the dose may then be increased to 80 units/kg three times weekly.
Thereafter the dose of epoetin beta may be increased at 4-week intervals, for both subcutaneous and intravenous injection, in increments of 60 units/kg weekly in divided doses, until the target haemoglobin concentration or haematocrit is reached. A total weekly dose of 720 units/kg of epoetin beta should not be exceeded.
For maintenance, the dose is halved initially and then adjusted every 1 to 2 weeks according to response. The weekly subcutaneous maintenance dose may be divided into 1, 3, or 7 doses; in patients stabilised on a once-weekly dose, it may be possible to adjust to a single dose every 2 weeks.
In patients with non-myeloid malignant disease receiving chemotherapy, epoetin alfa or epoetin beta may be given by subcutaneous injection in an initial dose of 150 units/kg three times weekly. The dose may be increased after 4 or 8 weeks, if necessary, to 300 units/kg three times weekly. If the response is still inadequate after 4 weeks at this higher dose, treatment should be stopped. As alternative regimens, the total weekly dose of epoetin beta may be given as a single dose or divided into 3 to 7 doses. Epoetin alfa may also be given in once-weekly doses of 450 units/kg or 40 000 units; the dose may be increased to 60 000 units after 4 weeks if necessary. The rise in haemoglobin should be gradual; a rate not exceeding 2 g per 100 mL per month, and a target haemoglobin concentration of not more than 12 g per 100 mL, are suggested. After the end of chemotherapy, epoetin alfa or epoetin beta may be continued for up to one month.
In HIV-positive patients on zidovudine therapy, epoetin alfa may be beneficial if the endogenous serum-erythropoietin concentration is 500 milliunits/mL or less. Epoetin alfa is given by subcutaneous or intravenous injection in an initial dose of 100 units/kg three times weekly for 8 weeks. The dose may then be increased every 4 to 8 weeks by 50 to 100 units/kg three times weekly according to response. However, patients are unlikely to benefit from doses above 300 units/kg three times weekly if this dose has failed to elicit a satisfactory response.
In the management of anaemia of prematurity epoetin beta is given subcutaneously in a dose of 250 units/kg three times weekly. Treatment should be started as early as possible and continued for 6 weeks.
To increase the yield of autologous blood, epoetin alfa or epoetin beta may be used with iron supplementation. The dose depends on the volume of blood required for collection and on factors such as the patient's whole blood volume and haematocrit. Suggested regimens are:
epoetin alfa 600 units/kg given intravenously twice weekly starting 3 weeks before surgery
up to 800 units/kg of epoetin beta intravenously, or up to 600 units/kg subcutaneously, twice weekly for 4 weeks before surgery
To reduce the need for allogeneic blood transfusion epoetin alfa may be given in a dose of 600 units/kg subcutaneously once weekly starting 3 weeks before surgery, with a fourth dose given on the day of surgery; alternatively, when the time before surgery is short, 300 units/kg subcutaneously daily may be given for 10 days before surgery, on the day of surgery, and for 4 days after.
Administration in neonates.
Recombinant human erythropoietin may be given to neonates for anaemia of prematurity (see Anaemias). It is usually given by subcutaneous injection. Intravenous infusion in total parenteral nutrition solutions produced satisfactory results in a group of 20 neonates. Enteral dosage in one small study increased plasma-erythropoietin concentrations and peak reticulocyte counts, but in another larger study it had no effect.
Anaemias.
Epoetins are used in normocytic-normochromic anaemias associated with low endogenous erythropoietin concentrations.
Anaemia associated with chronic renal disease is primarily a result of inadequate production of erythropoietin in the kidney. Other factors that can contribute to the anaemia include iron deficiency, blood loss associated with dialysis, and severe hyperparathyroidism. The use of epoetins in the management of renal anaemia is well established, as consistently good results have been obtained not only for correction of anaemia but also for improvement in quality of life. Studies have also shown epoetins to be associated with improved oxygen utilisation, muscle strength and function, cognitive function, cardiac function, and sexual function. In predialysis patients, epoetins also correct anaemia, reduce the requirement for blood transfusions, and improve quality of life and exercise capacity, but there may be increased hypertension and it is not known whether the need for dialysis is delayed. Over 90% of patients with renal anaemia respond to treatment with epoetins. Many factors can contribute to a poor response (see Precautions) and the patient should always be investigated and the cause corrected where possible. Common causes of inadequate response are iron deficiency, inflammatory disorders, chronic blood loss, hyperparathyroidism, and aluminium toxicity.
Epoetins may be given intravenously or subcutaneously, depending on the formulation (see Uses and Administration). Epoetin given subcutaneously produces lower but more sustained plasma concentrations and total weekly maintenance doses are reduced. The intravenous route is usually reserved for haemodialysis patients who cannot tolerate subcutaneous dosage. The subcutaneous route is also preferred in patients not on haemodialysis, partly because of the need to avoid venepuncture of veins that are likely to be needed for future haemodialysis access. The dosage frequency may also be important in maximising the response to treatment. Giving epoetins 2 or 3 times a week allows a lower total weekly dose than once weekly, but daily dosage is no more effective than 3 times a week. However, dosing once weekly may be more convenient for maintenance therapy. A systematic review concluded that there was no evidence to support one frequency over another in terms of maintaining target haemoglobin. Darbepoetin alfa is given at longer dosage intervals than epoetins and there is no difference in weekly dosage requirements between subcutaneous and intravenous routes.
Intraperitoneal use of epoetins has also been proposed and investigated. Although some do not recommend intraperitoneal use because of poor bioavailability and an increased risk of peritonitis, others consider that it may be considered in peritoneal dialysis patients when other routes are not feasible. Intraperitoneal doses must be given into a dry abdomen or one with a minimal amount of dialysate, and dose requirements may be higher than those for intravenous or subcutaneous use.
Blood transfusions are often used to treat anaemia of prematurity, and epoetins have been investigated as a means of reducing transfusion requirements. A systematic review found that although epoetin reduced transfusion needs, the effect was only modest and there was considerable variation between studies. More selective reviews of very-low-birth-weight infants (less than 1500 g) also found modest reductions in transfusion requirements, whether epoetin was started within the first week of life or after one week, although transfusion requirements were unlikely to be eliminated completely. Response to the late use of epoetin was also found to be dose-dependent.
Factors contributing to cancer-related anaemia include chemotherapy, radiotherapy, and the malignancy itself. Epoetin therapy can reduce the need for blood transfusions in cancer patients and improve quality of life. Guidelines for the use of epoetins in chemotherapy-induced anaemia have been issued (see Anaemia). There has, however, been some concern raised about the effect of epoetin therapy on patient survival. A placebo-controlled study of epoetin alfa to maintain normal haemoglobin concentrations in patients receiving chemotherapy for metastatic breast cancer was terminated early when an increase in disease progression and thrombotic and vascular events was found in the epoetin group. In another placebo-controlled study of patients with head and neck cancer undergoing radiotherapy, epoetin beta was associated with correction of anaemia but poorer locoregional progression-free survival. In contrast, analysis of a study in patients with lymphoproliferative malignancies found no effect of epoetin beta on patient survival. Similarly, a meta-analysis of 9 studies found reduced rates of progression and death in patients treated with epoetin beta, but these studies were not designed to assess tumour progression or survival. Further prospective studies of the effects of epoetin on survival are underway.
Epoetins are sometimes used to treat anaemias from other causes. Potential applications include zidovudine-induced anaemia in AIDS patients (see Effects on the Blood under Zidovudine), postpartum anaemia, anaemia in critically ill patients, and anaemia of chronic diseases such as rheumatoid arthritis, inflammatory bowel disease, and chronic heart failure.
Cardiovascular diseases.
There is some interest in the non-haematopoietic effects of erythropoietin, including protection from apoptosis, antoxidant activity, and pro-angiogenic effects. A possible role in the management of ischaemic stroke and myocardial infarction is under investigation.
Surgery.
Concern over the safety of blood transfusions and the need to conserve blood supplies has led to interest in methods of reducing blood use in surgery. Recombinant human erythropoietin has been used to increase the number of units harvested for autologous transfusion and to reduce transfusion requirements. It has also been used as an alternative to blood transfusions in Jehovah's Witnesses.