Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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.

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 (see section 4.8).

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.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.8). 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 Page 10 of 25
 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 (see section 4.2): 
•   For chronic renal failure patients, iron supplementation (elemental iron 200 to 300 mg/day orally for adults and 100 to 200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below 100 ng/mL.

•   For cancer patients, iron supplementation (elemental iron 200 to 300 mg/day orally) is recommended if transferrin 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, 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.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment. More severe cases have been observed with long-acting epoetins.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, EPREX should be withdrawn immediately and an alternative treatment considered.

If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of EPREX treatment with EPREX must not be restarted in this patient at any time.

The needle cover on the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause severe allergic reactions in individuals sensitive to latex 
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 epoetin alfa treatment.
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Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. Epoetin alfa 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, 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 epoetin alfa 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 
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 (1.25 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 achieve a haemoglobin concentration level 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.

Caution should be exercised with escalation of EPREX doses in patients with chronic renal failure since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered (see section 4.2 and 5.1).

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 (see section 4.8).

Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not maintain adequate haemoglobin levels (see section 5.1) 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 Page 12 of 25
 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

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.

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.

The role of ESAs on tumour progression or reduced progression-free survival cannot be excluded. In controlled clinical studies, use of epoetin alfa and other ESAs have been associated with decreased locoregional tumour control or decreased overall survival:
•     decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to achieve a haemoglobin concentration level 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 achieve a haemoglobin concentration range of 12 to 14 g/dL (7.5 to 8.7 mmol/L),
•     increased risk of death when administered to achieve a haemoglobin concentration level 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,
•     an observed 9% increase in risk for PD or death in the epoetin alfa plus SOC group from a primary analysis and a 15% increased risk that cannot be statistically ruled out in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 10 to 12 g/dL (6.2 to 7.5 mmol/L).

In view of the above, 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 section 5.1).

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 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
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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, the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, epoetin alfa should not be used in patients with baseline haemoglobin > 13 g/dL.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free.”

Effects on Driving

4.7 Effects on ability to drive and use machines
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No studies on the effects on the ability to drive and use machines have been performed.