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General: Blood pressure should be adequately controlled prior to initiation of Epoetin alfa therapy. 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. Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during Epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal. 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. The safety and efficacy of Epoetin alfa therapy have not been established in patients with underlying haematological diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassemia, porphyria). 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 erythropoiesis-stimulating agents 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 these TVEs should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident). In all patients, haemoglobin levels should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the concentration 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, 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. Very rarely, development 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 erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file. Patients should only be switched from one ESA (such as EPODION) to another ESA under appropriate supervision of physician.
Pure Red Cell Aplasia: Antibody-mediated pure red cell aplasia (PRCA) has been rarely reported after months to years of subcutaneous Epoetin treatment mainly in chronic renal failure patients. Cases also have been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are not approved in the management of anemia 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, haemolysis should be investigated. If the reticulocyte count corrected for anemia (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 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 cross-reaction. Appropriate therapy, such as blood transfusions, may be given to patients when indicated.
Treatment of symptomatic anaemia in adult 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 greater than 12 g/dL may be associated with a higher risk of cardiovascular events, including death. Chronic renal failure patients treated with Epoetin alfa by the subcutaneous route should be monitored regularly for loss of efficacy, defined as absent or decreased response to Epoetin alfa treatment in patients who previously responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an increase in Epoetin alfa dosage. Some patients with more extended dosing intervals (greater than once weekly) of Epoetin alfa may not maintain adequate haemoglobin levels and may require an increase in Epoetin alfa dose. Haemoglobin levels should be monitored regularly. 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. 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. 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 optimal. 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. Rarely, exacerbation of porphyria has been observed in Epoetin alfa-treated patients with chronic renal failure. Epoetin alfa should be used with caution in patients with known porphyria.
Treatment of patients with chemotherapy-induced anaemia: Cancer patients being treated with Epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter. The target haemoglobin should be up to 12 g/dL [7.5 mmol/L] in men and women and it should not be exceeded. In cancer patients receiving chemotherapy, should the rate of increase in haemoglobin exceed 1 g/dL per two week or 2 g/dL per month or the haemoglobin concentration is approaching 12 g/dL or the haemoglobin concentration exceeds 12 g/dL, the dose adjustment detailed in Dosage & Administration-Cancer patients should be followed to minimize potential risk factors of thrombotic events. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving erythropoiesis-stimulating agents 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 these TVEs should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident). 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 order to ensure optimum response to Epoetin alfa, adequate iron stores should be assured, and folic acid and vitamin B12 deficiencies should be excluded prior to initiating therapy. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. Therefore, iron supplementation, eg, 200-300 mg/day orally is recommended for all cancer patients whose transferrin saturation is below 20%. In cancer patients receiving chemotherapy, the 2 to 3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be taken into account when assessing whether or not Epoetin alfa therapy is appropriate (in particular for patient at risk of being transfusion).
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.
Surgery patients in autologous predonation programmes: All special warnings and special precautions associated with autologous predonation programmes, especially routine volume replacement, should be respected in patients being supplemented with Epoetin alfa.
Adult perisurgery patients (without autologous blood donation): In patients scheduled for major elective orthopaedic surgery the cause of anaemia should be established and treated, if possible, before the start of Epoetin alfa treatment. In patients scheduled for major elective orthopaedic surgery, thrombotic events can be a risk and this possibility should be carefully weighed against the benefit if 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).
Effects on ability to drive and use machines: Due to increased risk of hypertension during the initial phase of Epoetin alfa treatment, patients with chronic renal failure should use caution when performing potentially hazardous activities, such as driving or operating machinery until the optimal maintenance dose of Epoetin alfa has been established.
Use in Children: The safety of the children is not established.
Use in the Elderly: Since the physiological ability in elderly patients is normally decreased and the risk of cardiovascular diseases is high, some parameters (such as blood pressure, haemoglobin, and dosing frequency) should be monitored carefully.
