Eprex

/ J-C Health Care Ltd

Method of administration
Before use, leave the syringe to stand until it reaches room temperature. This usually takes between 15 and 30 minutes.
Intravenous injection: Administer over at least one to five minutes, depending on the total dose. In haemodialysed patients, a bolus injection may be given during the dialysis session through a suitable venous port in the dialysis line. Alternatively, the injection can be given at the end of the dialysis session via the fistula needle tubing, followed by 10 ml of isotonic saline to rinse the tubing and ensure satisfactory injection of the product into the circulation.
A slower injection is preferable in patients who react to the treatment with “flu-like” symptoms
subcutaneous injection: A maximum volume of 1 ml at one injection site should generally not be exceeded. In case of larger volumes, more than one site should be chosen for the injection.
The injections are given in the limbs or the anterior abdominal wall.
Posology
All other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase the dose. In order to ensure optimum response to epoetin alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary.
Treatment of symptomatic anaemia in adult chronic renal failure:
The recommended desired haemoglobin concentration range is between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Haemoglobin levels should be increased to no more than 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 should be avoided. If it occurs, appropriate dose adjustment should be made as provided.
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L).
A sustained haemoglobin level of greater than 12 g/dL (7.5 mmol/L) should be avoided. If the haemoglobin is rising by more than 2 g/dL (1.25 mmol/L) per month, or if the sustained haemoglobin exceeds 12 g/dL (7.5 mmol/L) reduce the dose by 25%. If the haemoglobin exceeds 13 g/dL (8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinstitute therapy at a dose 25% below the previous dose. Patients should be monitored closely to ensure that the lowest approved effective dose is used to provide adequate control of anaemia and of the symptoms of anaemia whilst maintaining a haemoglobin concentration below or at 12 g/dL (7.5 mmol/L).
Adult haemodialysis patients
The treatment is divided into two stages:
Correction phase
50 IU/kg, 3 times per week.
If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired
haemoglobin concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L) is achieved (this should be done in steps of at least four weeks).
Maintenance phase:
The recommended total weekly dose is between 75 IU/kg and 300 IU/kg.
Paediatric haemodialysis patients:
Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.
In paediatric patients the recommended target haemoglobin range is between 9.5 and 11 g/dl (5.9-6.8 mmol/l). Haemoglobin levels should be increased to no more than 11 g/dL (6.8
mmol/l).
Correction phase
The starting dose is 50 IU/kg intravenously, 3 times per week.
If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired haemoglobin concentration range of between 9.5 g/dl to 11 g/dl (5.9 to 6.8 mmol/l) is achieved (this should be done in steps of at least four weeks).
Maintenance phase:
Appropriate adjustment of the dose should be made in order to maintain the haemoglobin levels within the desired range between 9.5 g/dl and 11 g/dl (5.9 to 6.8 mmol/l).
Adult patients with renal insufficiency not yet undergoing dialysis:
The treatment is divided into two stages:
Correction phase
Starting dose of 50 IU/kg, 3 times per week, followed if necessary by a dosage increase with 25 IU/kg increments (3 times per week) until the desired goal is achieved (this should be done in steps of at least four weeks).
Maintenance phase
During the maintenance phase, this medical product can be administered either 3 times per week, and in the case of subcutaneous administration, once weekly or once every 2 weeks.
Appropriate adjustment of dose and dose intervals should be made in order to maintain haemoglobin values at the desired level: Hb between 10 and 12 g/dL (6.2 7.5 mmol/L). Extending dose intervals may require an increase in dose.
The maximum dosage should not exceed 150 IU/kg 3 times per week, 240 IU/kg (up to a maximum of 20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU) once every 2 weeks.
Adult peritoneal dialysis patients
Correction phase
Starting dose of 50 IU/kg, 2 times per week.
Maintenance phase
The recommended maintenance dose is between 25 IU/kg and 50 IU/kg, 2 times per week in 2 equal injections.
Appropriate adjustment of the dose should be made in order to maintain haemoglobin values at the desired level between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L).
Treatment of patients with chemotherapy-induced anaemia
Appropriate adjustment of the dose should be made in order to maintain haemoglobin concentrations within the desired concentration range between 10 g/dl and 12 g/dl (6.2 and 7.5 mmol/l).
The initial dose is 150 IU/kg given subcutaneously 3 times per week.
Alternatively, this medical product can be administered at an initial dose of 40,000IU once weekly.
If the haemoglobin has increased by at least 1 g/dL (0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/mL above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg 3 times per week or 40,000IU once weekly.
If the haemoglobin increase is < 1 g/dL (< 0.62 mmol/L) and the reticulocyte count has increased <40,000 cells/mL above baseline, increase the dose to 300 IU/kg 3 times per week or 60,000 IU once weekly.
If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week or 60,000 IU once weekly, the haemoglobin has increased ≥ 1 g/dL (≥ 0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/mL, the dose should remain at 300 IU/kg 3 times per week or 60,000 IU once weekly.
However, if the haemoglobin has increased < 1 g/dL (< 0.62 mmol/L) and the reticulocyte count has increased < 40,000 cells/mL above baseline, response is unlikely and treatment should be discontinued.
See prescribing information for full details.

Treatment of severe anemia associated with chronic renal failure, anemia
in Zidovudine-treated HIV-infected patients, anemia in cancer patients on chemotherapy.
To increase the yield of autologous blood from patients in a predonation programme initiated to avoid the use of homologous blood.
Treatment is indicated in patients with moderate anemia (packed cell volume (PCV) approximately 33 to 39%, no iron deficiency) if blood conserving procedures are not available or insufficient either:
* When the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males)
* When the period necessary to obtain the required volume of autologous blood is too short.
Perisurgery:
Reduction of allogeneic blood transfusion in surgery patients:
Treatment of anemic patients (hemoglobin 9-11 g/dl) scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.
Treatment is indicated for patients at high risk for periopertive transfusions with significant, anticipated blood loss.
Treatment is not indicated for anemic patients who are willing to donate autologous blood.
The safety of the perioperative use of this medical product has been studied only in patients who are receiving anticoagulant prophylaxis.
Treatment is indicated before surgeries known be associated with excessive blood loss (at least 2 units).

* Hypersensitivity to the active substance or to any of the excipients
* Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive this medical product or any other erythropoietin.
* Uncontrolled hypertension
* All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with this medical product.
* The use of this medical product in patients scheduled for major elective orthopaedic surgery and not participating in an autologous blood predonation programme is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
* Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.

General: In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase anti-hypertensive treatment. If blood pressure cannot be controlled, epoetin alfa treatment should be discontinued. Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases. Epoetin alfa should also be used with caution in the presence of chronic liver failure. The safety of Epoetin alfa has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with Epoetin alfa. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs. These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported. The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with pre-existing risk factors. 9 Chronic renal failure and cancer patients on epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter. In all patients, haemoglobin concentration should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin concentration above the range for the indication of use. There may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with epoetin alfa. This regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count is regularly monitored during the first 8 weeks of therapy. All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies, aluminium intoxication, infection or inflammation and bone marrow fibrosis of any origin) should be considered and treated prior to initiating therapy with epoetin alfa and when deciding to increase the dose. 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 alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary:
Iron supplementation is recommended for chronic renal failure patients whose serum ferritin levels are below 100 ng/ml. Iron supplementation is recommended for cancer patients whose transferrin saturation is below 20%. For patients in an autologous predonation programme, iron supplementation should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting Epoetin alfa therapy, and throughout the course of Epoetin alfa therapy. For patients scheduled for major elective orthopaedic surgery, iron supplementation should be administered throughout the course of Epoetin alfa therapy. If possible, iron supplementation should be initiated prior to starting Epoetin alfa therapy to achieve adequate iron stores. All of these additive factors of anaemia should also be carefully considered when deciding to increase the dose of epoetin alfa in cancer patients. Very rarely, the initial presentation of or exacerbation of porphyria has been observed in epoetin alfa-treated patients. Epoetin alfa should be used with caution in patients with porphyria. In order to improve the traceability of the ESA all measures necessary and possible to ensure it should be taken (e.g. exact information on the product used should be documented in an appropriate way). Furthermore, patients should only be switched from one ESA to another under appropriate supervision. The safety and efficacy of Epoetinum alfa therapy have not been established in patients with underlying haematologic diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassemia).
Pure Red Cell Aplasia: Antibody-mediated pure red cell aplasia (PRCA) has been reported after months to years of subcutaneous epoetin treatment mainly in chronic renal failure patients. Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. EPREX is not approved in the management of anaemia associated with hepatitis C. In chronic renal failure patients developing sudden lack of efficacy defined by a decrease in haemoglobin (1 to 2 g/dl per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g. iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss and haemolysis and bone marrow fibrosis of any origin) should be investigated. A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with EPREX and perform anti-erythropoietin antibody testing. A bone marrow examination should also be considered for diagnosis of PRCA. No other ESA therapy should be commenced because of the risk of cross-reaction.
Treatment of symptomatic anaemia in adult and chronic renal failure patients: In chronic renal failure patients the rate of increase in haemoglobin should be approximately 1 g/dl (0.62 mmol/l) per month and should not exceed 2 g/dl (1.25 mmol/l) per month to minimise risks of an increase in hypertension. In patients with chronic renal failure maintenance haemoglobin concentration should not exceed the upper limit of the haemoglobin concentration range as recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when ESAs were administered to target a haemoglobin of greater than 11g/dl . 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. Chronic renal failure patients treated with EPREX by the subcutaneous route should be monitored regularly for loss of efficacy, defined as absent or decreased response to EPREX treatment in patients who previously responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an increase in EPREX dosage. Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.). Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients. Hyperkalaemia has been observed in isolated cases though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to appropriate treatment of the hyperkalaemia, consideration should be given to ceasing epoetin alfa administration until the serum potassium level has been corrected. An increase in heparin dose during haemodialysis is frequently required during the course of therapy with epoetin alfa as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum. Based on information available to date, correction of anaemia with epoetin alfa in adult patients with renal insufficiency not yet undergoing dialysis does not accelerate the rate of progression of renal insufficiency. Patients with chronic renal failure and insufficient hemogloblin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. 11 In some female chronic renal failure patients, menses have resumed following Epoetinum alfa therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
Treatment of patients with chemotherapy induced anaemia: Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours. In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer. In controlled clinical studies, use of EPREX and other ESAs have shown: Decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14 g/dl (8.7 mmol/l), Shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l), Another ESA (darbepoietin alfa) increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population. In view of the above, the decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference. In cancer patients receiving chemotherapy, the 2-3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be taken into account when assessing if epoetin alfa therapy is appropriate (patient at risk of being transfused).
Surgery patients in autologous predonation programmes: All special warnings and special precautions associated with autologous predonation programmes, especially routine volume replacement, should be respected. Patients scheduled for major elective orthopaedic surgery Good blood management practices should always be used in the perisurgical setting. Thrombotic events can be a risk in this population and this possibility should be carefully weighed against the benefit to be derived from the treatment in this patient group.
Patients scheduled for major elective orthopaedic surgery: should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline haemoglobin of > 13 g/dl (8.1 mmol/l), the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline haemoglobin > 13 g/dl (8.1 mmol/l). This medicinal product contains less than 1 mmol sodium (23 mg) per dose i.e essentially “sodium free”.
HIV-Infected Patients If HIV-infected patients fail to respond or maintain a response to Epoetinum alfa, other etiologies including iron deficiency anaemia should be considered and evaluate.
For full details see prescribing information.

Common: Headache, Hypertension, Venous and arterial thromboses, Cough, Rash, Arthralgia, Bone pain, Myalgia, Pain in extremity, Chills, Influenza like illness, Injection site reaction, Oedema peripheral.
Very common: Diarrhoea, Nausea, Vomiting, Pyrexia.
See prescribing information for full details.

No evidence exists that indicates that treatment with epoetin alfa alters the metabolism of other drugs. Drugs that decrease erythropoiesis may decrease the response to Epoetin alfa. However, since cyclosporin is bound by RBCs there is potential for a drug interaction. If epoetin alfa is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the haematocrit rises. No evidence exists that indicates an interaction between epoetin alfa and G-CSF or GM-CSF with regard to haematological differentiation or proliferation of tumour biopsy specimens in vitro. The effect of Epoetinum alfa may be potentiated by the simultaneous therapeutic administration of a haematinic agent, such as ferrous sulphate, when a deficiency state exists. In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL Epoetinum alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Consequently, epoetin alfa should be used in pregnancy only if
the potential benefit outweighs the potential risk to the foetus. The use of epoetin alfa is not
recommended in pregnant surgical patients participating in an autologous blood predonation.
Lactation: It is not known whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should be used with caution in nursing women. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin alfa should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin alfa therapy to the woman.
The use of epoetin alfa is not recommended in lactating surgical patients participating in an autologous blood predonation programme.

The therapeutic margin of epoetin alfa is very wide. Overdosage of epoetin alfa may produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high haemoglobin levels occur. Additional supportive care should be provided as necessary.

Storage: Store in a refrigerator (2°C-8°C). This temperature range should be closely maintained until administration to the patient. Store in the original package in order to protect from light. Do not freeze or shake.
For the purpose of ambulatory use, the patient may remove EPREX from the refrigerator and store it not above 25°C for one single period of up to 7 days.