Special Warning : אזהרת שימוש

4.4 Special Warnings and Precautions for Use

General
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.

Blood pressure should be monitored in all patients, particularly during initiation of ARANESP® therapy. If blood pressure is difficult to control by initiation of appropriate measures, the hemoglobin may be reduced by decreasing or withholding the dose of ARANESP® (see section 4.2). Cases of severe hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been observed in CRF patients treated with ARANESP®.

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.

Non-response to therapy with ARANESP® should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.
Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, hemolysis, severe aluminum toxicity, underlying hematologic diseases, or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. If the bone marrow is consistent with PRCA, testing for anti-erythropoietin antibodies should be performed.

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 If signs and symptoms suggestive of these reactions appear, ARANESP® should be withdrawn immediately and an alternative treatment considered.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 ARANESP®, treatment with ARANESP® must not be restarted in this patient at any time.

Pure red cell aplasia caused by neutralizing anti-erythropoietin antibodies has been reported in association with ESAs, including ARANESP®. This has been predominantly reported in patients with CRF treated subcutaneously. These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralizing antibodies to erythropoietin should not be switched to ARANESP® (see section 4.8).

A paradoxical decrease in hemoglobin 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.

Active liver disease was an exclusion criterion in all studies of ARANESP®, therefore no data are available from patients with impaired liver function. Since the liver is thought to be the principal route of elimination of darbepoetin alfa and r-HuEPO, ARANESP® should be used with caution in patients with liver disease.

ARANESP® should also be used with caution in those patients with sickle cell anemia.

Misuse of ARANESP® 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.
The needle cap of the pre-filled syringe or pre-filled pen contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

ARANESP® should be used with caution in patients with epilepsy. Convulsions have been reported in patients receiving ARANESP®.

The reported risk of thrombotic vascular events (TVEs) should be carefully weighed against the benefits to be derived from treatment with darbepoetin 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).

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

Chronic Renal Failure Patients

In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin concentration recommended in section 4.2. In clinical studies, an increased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascular access thrombosis was observed when ESAs were administered to target a hemoglobin of greater than 12 g/dL (7.5 mmol/L).

Caution should be exercised with escalation of ARANESP® 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 hemoglobin response to epoetins, alternative explanations for the poor response should be considered (see sections 4.2 and 5.1).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when hemoglobin concentration is increased beyond the level necessary to control symptoms of anemia and to avoid blood transfusion.

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 mcg/L or whose transferrin saturation is below 20%.

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

Cancer Patients

Effect on tumor growth
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumor cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumors. In several controlled studies, epoetins have 
not been shown to improve overall survival or decrease the risk of tumor progression in patients with anemia associated with cancer.

In controlled clinical studies, use of ARANESP® and other ESAs have shown: 
•   shortened time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin of greater than 14 g/dL (8.7 mmol/L), ESAs are not indicated for use in this patient population.

•   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 hemoglobin of 12-14 g/dL (7.5-8.7 mmol/L).

•   increased risk of death when administered to target a hemoglobin 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 hemoglobin concentration range of 10 to 12 g/dL (6.2 to 7.5 mmol/L).

•   non-inferiority of darbepoetin alfa to placebo for overall survival and progression free survival in patients with advanced stage non-small cell lung cancer receiving chemotherapy when administered to a target hemoglobin of 12 g/dL (7.5 mmol/L) (see section 5.1).

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 tumor 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).

In patients with solid tumors or lymphoproliferative malignancies, if the hemoglobin value exceeds 12 g/dL (7.5 mmol/L), the dosage adaptation described in section 4.2 should be closely respected, in order to minimize the potential risk of thromboembolic events. Platelet counts and hemoglobin level should also be monitored at regular intervals.

Effects on Driving

4.7 Effects on Ability to Drive and Use Machines

ARANESP® has no or negligible influence on the ability to drive and use machines.