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 also be used with caution in the presence of epilepsy and chronic liver failure.
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 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 target 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) should be considered and treated prior to initiating therapy with epoetin alfa. 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: Iron supplementation, e.g. 200-300 mg/day orally (100-200 mg/day for paediatric patients) is recommended for chronic renal failure patients whose serum ferritin levels are below 100 ng/ml.
Oral iron substitution of 200-300 mg/day is recommended for all cancer patients whose transferrin saturation is below 20%.
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, 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 to another under appropriate supervision.
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. Alvoetin is not approved in the management of anaemia associated with hepatitis C.
In 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) should be investigated.
A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with Alvoetin 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 paediatric 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 target haemoglobin concentration as recommended in Dosage & Administration. In clinical trials, an increased risk of death and serious cardiovascular events was observed when ESAs were administered to target haemoglobin of greater than 12 g/dl (7.5 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.
Chronic renal failure patients treated with Alvoetin by the subcutaneous route should be monitored regularly for loss of efficacy, defined as absent or decreased response to Alvoetin treatment in patients who previously responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an increase in Alvoetin 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.
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 Alvoetin 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).
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 previously mentioned, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. 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 (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 taken into account when assessing if epoetin alfa therapy is appropriate (patient at risk of being transfused).
As an increased incidence of thrombotic vascular events (TVEs) has been observed in cancer patients receiving ESAs (see Adverse Reactions), this risk should be carefully weighed against the benefit to be derived from treatment with epoetin alfa particularly in cancer patients with an increased risk of thrombotic vascular events, such as obesity and patients with a prior history of TVEs (e.g. deep venous thrombosis or pulmonary embolism).
An investigational study (BEST study) in women with metastatic breast cancer was designed to determine whether epoetin alfa treatment that extended beyond the correction of anaemia could improve treatment outcomes. In that study the incidence of fatal thromboembolic events was higher in patients receiving epoetin alfa than in those receiving placebo.
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: 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. 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 baseline haemoglobin > 13 g/dl, 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.
Albumin: Alvoetin contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely low risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Zidovudine-treated HIV-infected patients: In contrast to CRF patients, epoetin alfa therapy has not been linked to exacerbation of hypertension, seizures, and thrombotic events in HIV-infected patients. However, the clinical data do not rule out an increased risk for serious cardiovascular events.
Precautions: The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur.
In clinical trials, while transient rashes were occasionally observed concurrently with epoetin alfa therapy, no serious allergy or anaphylactic reactions were reported.
The safety and efficacy of epoetin alfa therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g. sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).
In some female patients, menses have resumed following epoetin alfa therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.
In preclinical studies in dogs and rats, but not in monkeys, epoetin alfa therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors.
The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with epoetin alfa for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with epoetin alfa.
Hemoglobin in CRF patients should be measured twice a week; zidovudine-treated HIV-infected and cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.
Effects on ability to drive and use machines: Alvoetin has no or negligible influence on the ability to drive and use machines.
Nevertheless, patients on dialysis are advised not to engage in potentially hazardous activities, such as driving or operating heavy machinery, during the first 90 days of epoetin alfa therapy.