Eprex Special Precautions

epoetin alfa




Full Prescribing Info
Special Precautions
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 initiate or increase anti-hypertensive treatment during Epoetin alfa therapy. 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 be used with caution in patients with 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 (see Adverse Reactions). 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.
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 concentrations above the range for the indication of use.
The safety and efficacy of Epoetin alfa therapy have not been established in patients with underlying haematologic diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassemia).
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 should be regularly monitored during the first 8 weeks of therapy.
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 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: For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for adults and 100-200mg/day orally for paediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferring saturation is below 20%.
For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) 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 (elemental iron 200 mg/day orally) 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.
Very rarely, the initial presentation or exacerbation of porphyria has been observed in Epoetin alfa-treated patients. Epoetin alfa should be used with caution in patients with porphyria.
Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be emphasised that patients should only be switched from one ESA (such as EPREX) to another ESA with the authorisation of the treating physician.
Pure Red Cell Aplasia: Antibody-mediated pure red cell aplasia (PRCA) has been very rarely reported after months to years of subcutaneous Epoetin treatment in chronic renal failure patients. Cases also have been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are 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, aluminum intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be investigated. If the reticulocyte count corrected for anaemia (i.e., the reticulocyte “index”) is low (<20,000/mm3 or <20,000/μL or <0.5%) platelet and white blood cell counts are normal, and if no other cause of loss of effect has been found, anti-erythropoietin antibodies should be determined and a bone marrow examination should be considered for diagnosis of PRCA.
If anti-erythropoietin, antibody-mediated PRCA is suspected, therapy with Epoetin alfa should be discontinued immediately. No other ESA therapy should be commenced because of the risk of cross-reaction. Appropriate therapy, such as blood transfusions, may be given to patients when indicated.
Geriatric Use: Among 1051 patients enrolled in the 5 clinical studies of Epoetin alfa for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received Epoetin alfa and 306 received placebo. Of the 745 patients who received Epoetin alfa, 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epoetin alfa in geriatric and younger patients within the 4 studies using the three times per week schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.
Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received Epoetin alfa and 125 received placebo. Of the 757 patients who received Epoetin alfa, 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the haemoglobin concentration range (See Dosage & Administration).
Insufficient numbers of patients age 65 or older were enrolled in clinical studies for the treatment of anaemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.
Renal Failure Patients: Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients: Chronic renal failure patients being treated with Epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.
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 (1.2 mmol/l) per month to minimise risks of an increase in hypertension. Dose should be reduced when haemoglobin approaches 12 g/dL.
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the haemoglobin concentration range as recommended under Dosage & Administration. Haemoglobin levels targeted to 13 g/dL or higher may be associated with a higher risk of cardiovascular events, including death.
Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not maintain adequate haemoglobin levels (see Pharmacology: Pharmacodynamics under Actions) and may require an increase in epoetin alfa dose. Haemoglobin levels should be monitored regularly.
Patients with chronic renal failure and insufficient haemogloblin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients.
Based on information available to date, the use of Epoetin alfa in predialysis (end stage renal insufficiency) patients does not accelerate the rate of progression of renal insufficiency.
Shunt thromboses have occurred in hemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g., stenoses, aneurisms, 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 the appropriate treatment of the hyperkalaemia, consideration should be given to ceasing Epoetin alfa administration until the serum potassium level has been corrected.
As a result of an increase in packed cell volume, haemodialysis patients receiving Epoetin alfa frequently require an increase in heparin dose during dialysis. If heparinisation is not optimal, occlusion of the dialysis system is possible.
In some female chronic renal failure patients, menses have resumed following Epoetin alfa therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
Cancer Patients: Cancer patients on Epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter.
ESAs 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 ESAs could stimulate the growth of tumours.
In controlled clinical studies, use of Epoetin alfa and other ESAs have shown: Decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to a haemoglobin target 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 a haemoglobin target 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 to consider in this assessment 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 (see Pharmacology: Pharmacodynamics under Actions).
In cancer patients receiving chemotherapy, the 2-3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be considered when assessing whether or not Epoetin alfa therapy is appropriate (in particular for patients at risk of transfusion).
Human Immunodeficiency Virus (HIV)-Infected Patients: If HIV-infected patients fail to respond or maintain a response to Epoetin alfa, other etiologies including iron deficiency anaemia should be considered and evaluated.
Adult Surgery Patients in an Autologous Pre Donation Programme: All special warnings and special precautions associated with autologous blood donation programmes, especially routine volume replacement, should be respected in patients being supplemented with Epoetin alfa.
Adult Perisurgery Patients (Without Autologous Blood Donation): Good blood management practices should always be used in the perisurgical setting.
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).
The use of Epoetin alfa is not recommended in perisurgery patients with a baseline haemoglobin of >13 g/dL (8.1 mmol/l).  
Use in MDS patients and Risk of Acute Myeloid Leukemia (AML) Progression: There is a theoretical concern that the use of epoetin alfa could enhance the rate of progression to AML in subjects with MDS because leukemic cells may express the erythropoietin receptor. Published reports of epoetin alfa monotherapy studies have been inconsistent in describing the observed rate of progression to AML and most did not include long-term follow up. In a study conducted by the Eastern Cooperative Oncology Group (ECOG 1996) where patients were initially exposed to epoetin alfa monotherapy for four months and then had long-term follow up (median follow-up time for survival of 32.8 months), there was no evidence of increased leukemic proliferation.
Effects on Ability to Drive and Use Machines: No studies on the effects of Epoetin alfa on the ability to drive and use machines have been performed.
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