Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Recormon should be used with caution in the presence of refractory anemia with excess blasts in transformation, epilepsy, thrombocytosis, and chronic liver failure. Folic acid and vitamin B12 deficiencies should be ruled out as they reduce the effectiveness of Recormon.

Caution should be exercised with escalation of Recormon 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 sections 4.2 and 5.1).

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary and conducted in accordance with therapeutic guidelines.

Severe aluminium overload due to treatment of renal failure may compromise the effectiveness of Recormon.

The indication for treatment with Recormon of nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible acceleration of progression of renal failure cannot be ruled out with certainty.

Pure red cell aplasia (PRCA)
PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy, including Recormon. These antibodies have been shown to cross-react with all erythropoietic proteins, 
and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to Recormon (see section 4.8).

PRCA in patients with Hepatitis C
A paradoxical decrease in haemoglobin and development of severe anemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing.
Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anemia associated with hepatitis C.

Blood pressure monitoring
An increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase can occur. These increases in blood pressure can be treated with medicinal products. If blood pressure rises cannot be controlled by drug therapy, a transient interruption of Recormon therapy is recommended. Particularly at beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyses.
Hypertensive crisis with encephalopathy-like symptoms may occur and require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning sign.

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 (see section 4.8). 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, Recormon 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 Recormon, treatment with ESA must not be restarted in this patient at any time.

Chronic renal failure
In chronic renal failure patients there may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with Recormon, especially after intravenous administration. This regresses during the course of continued therapy. It is recommended that the platelet count be monitored regularly during the first 8 weeks of therapy.

Haemoglobin concentration
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 11 g/dl.

No trial has identified a hemoglobin target level, epoetin dose, or dosing strategy that does not Increase these risks.

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 anemia and to avoid blood transfusion.

Effect on tumour growth
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 anemia associated with cancer.
In controlled clinical studies, use of Recormon and other erythropoiesis-stimulating agents (ESAs) have shown: -      shortened time to tumour progression 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 above, in some clinical situations blood transfusion should be the preferred treatment for the management of anemia in patients with cancer. The decision to administer recombinant erythropoietins 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 anemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see section 5.1)

There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, in particular in the initial treatment phase in cancer patients.

Platelet counts and haemoglobin level should also be monitored at regular intervals in cancer patients.

In patients in an autologous blood predonation programme there may be an increase in platelet count, mostly within the normal range. Therefore, it is recommended that the platelet count be determined at least once a week 9 in these patients. If there is an increase in platelets of more than 150 x 10 /l or if platelets rise above the normal range, treatment with Recormon should be discontinued.

In chronic renal failure patients an increase in heparin dose during haemodialysis is frequently required during the course of therapy with Recormon as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, should be considered in chronic renal failure patients at risk of shunt thrombosis.

Serum potassium and phosphate levels should be monitored regularly during therapy with Recormon. Potassium elevation has been reported in a few uraemic patients receiving Recormon, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing administration of Recormon until the level has been corrected.

For use of Recormon in an autologous predonation programme, the official guidelines on principles of blood donation must be considered, in particular:
-     Only patients with a PCV  33 % (haemoglobin  11 g/dl [6.83 mmol/l]) should donate; -     Special care should be taken with patients below 50 kg weight;
-     The single volume drawn should not exceed approx. 12 % of the patient's estimated blood volume.
Treatment should be reserved for patients in whom it is considered of particular importance to avoid homologous blood transfusion taking into consideration the risk/benefit assessment for homologous transfusions.

Misuse
Misuse by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life-threatening complications of the cardiovascular system.

Excipients
Recormon in pre-filled syringe contains up to 0.3 mg phenylalanine/syringe as an excipient. Therefore this should be taken into consideration in patients affected with severe forms of phenylketonuria.

This medicinal product contains less than 1 mmol sodium (23 mg) per syringe, i.e. essentially “sodium-free”.

Traceability of Recormon
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.

Effects on Driving

4.7   Effects on ability to drive and use machines
Recormon has no influence on the ability to drive and use machines.