Aranesp

/ Amgen

Treatment of Symptomatic Anemia in Chronic Renal Failure Patients
Anemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.
ARANESP® should be administered either subcutaneously or intravenously in order to increase hemoglobin to not greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving hemodialysis to avoid the puncture of peripheral veins.
Patients should be monitored closely to ensure that the lowest approved effective dose of ARANESP® is used to provide adequate control of the symptoms of anemia whilst maintaining a hemoglobin concentration below or at 12 g/dl (7.5 mmol/l). Caution should be exercised with escalation of ARANESP® doses in patients with chronic renal failure. In patients with a poor hemoglobin response to ARANESP®, alternative explanations for the poor response should be considered.
Due to intra-patient variability, occasional individual hemoglobin values for a patient above and below the desired hemoglobin level may be observed. Hemoglobin variability should be addressed through dose management, with consideration for the hemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained hemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when hemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.
A rise in hemoglobin of greater than 2 g/dl (1.25 mmol/l) over a four week period, should be avoided. If it occurs, appropriate dose adjustment should be made as provided.
Treatment with ARANESP® is divided into two stages – correction and maintenance phase:
Adult patients with chronic renal failure:
Correction phase: The initial ARANESP® dosage by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis the following initial doses can also be administered subcutaneously as a single injection: 0.75 μg/kg once every two weeks or 1.5 μg/kg once monthly. If the increase in hemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately
25%. Dose increases must not be made more frequently than once every four weeks.
If the rise in hemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the ARANESP® dose by approximately 25%. If the hemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the hemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, hemoglobin continues to increase, the dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
The hemoglobin should be measured every one or two weeks until it is stable. Thereafter the hemoglobin can be measured at longer intervals.
Maintenance phase: In dialysis patients, ARANESP® may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with ARANESP® should initially receive a dose equivalent to twice the previous once weekly dose.
In patients not on dialysis, ARANESP® may continue to be administered as a single injection once weekly or once every two weeks or once monthly. For patients treated with ARANESP® once every two weeks, after the target hemoglobin has been achieved, ARANESP® may then be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.
Dosing should be titrated as necessary to maintain the hemoglobin target.
If a dose adjustment is required to maintain hemoglobin at the desired level, it is recommended that the dose of ARANESP® is adjusted by approximately 25%.
If the rise in hemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the hemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the hemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, hemoglobin continues to increase, the dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
After any dose or schedule adjustment the hemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.
When changing the route of administration the same dose must be used and the hemoglobin monitored every one or two weeks so that the appropriate ARANESP® dose adjustments can be made to keep the hemoglobin at the desired level.
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times weekly may be converted to once weekly or once every other week ARANESP® The initial weekly dose of ARANESP® (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 200. The initial every other week dose of ARANESP® (μg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting ARANESP® for r-HuEPO the hemoglobin should be monitored every one or two weeks and the same route of administration should be used.
Pediatric population with chronic renal failure (≥ 1 year of age):
Treatment of pediatric patients younger than 1 year of age has not been studied in randomized clinical trials.
Correction phase: For patients ≥ 1 year of age, the initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in hemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.
If the rise in hemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the hemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the hemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, hemoglobin continues to increase, the dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
The hemoglobin should be measured every one or two weeks until it is stable. Thereafter the hemoglobin can be measured at longer intervals.
Correction of anemia in pediatric patients with once monthly ARANESP® dosing frequency has not been studied.
Maintenance phase: For pediatric patients ≥ 1 year of age, in the maintenance phase, ARANESP® may continue to be administered as a single injection once weekly or once every two weeks. Patients < 6 years of age may need higher doses for maintenance of hemoglobin than patients above that age. Dialysis patients converting from once weekly to once every other week dosing with ARANESP® should initially receive a dose equivalent to twice the previous once weekly dose.
Clinical data in pediatric patients has demonstrated that patients receiving r-HuEPO two or three times weekly may be converted to once weekly ARANESP®, and those receiving r-HuEPO once weekly may be converted to once every other week ARANESP®. The initial weekly pediatric dose of ARANESP® (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240. The initial every other week dose of ARANESP® (μg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two week period by 240. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting ARANESP® for r-HuEPO the hemoglobin should be monitored every one or two weeks and the same route of administration should be used.
Dosing should be titrated as necessary to maintain the hemoglobin target.
If a dose adjustment is required to maintain hemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.
If the rise in hemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the hemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the hemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, hemoglobin continues to increase, the dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
Patients starting dialysis during treatment with ARANESP® should be closely monitored for adequate control of their hemoglobin.
After any dose or schedule adjustment the hemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.
When changing the route of administration the same dose must be used and the hemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the hemoglobin at the desired level.
Treatment of Symptomatic Chemotherapy-Induced Anemia in Cancer Patients
ARANESP® should be administered by the subcutaneous route to patients with anemia (e.g hemoglobin concentration ≤ 10 g/dl (6.2 mmol/l) in order to increase hemoglobin to not greater than 12 g/dl (7.5 mmol/l). Anemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.
Due to intra-patient variability, occasional individual hemoglobin values for a patient above and below the desired hemoglobin level may be observed. Hemoglobin variability should be addressed through dose management, with consideration for the hemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained hemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustments for when hemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinical response of the patient (fatigue, hemoglobin response) is inadequate after nine weeks, further therapy may not be effective.
ARANESP® therapy should be discontinued approximately four weeks after the end of chemotherapy.
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approved dose of ARANESP® is used to maintain hemoglobin at a level that controls the symptoms of anemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered.
Patients should be monitored closely, if the hemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50%. Treatment with ARANESP® should be temporarily discontinued if hemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at approximately 25% lower than the previous dose after hemoglobin levels fall to 12 g/dl (7.5 mmol/l) or below.
If the rise in hemoglobin is greater than 2 g/dl (1.25 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

For the treatment of symptomatic anemia associated with chronic
renal failure (CRF) in adults and pediatric patients ≥ 1 year of age.
Aranesp 150, 300 and 500 are indicated for the treatment of anemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

Hypersensitivity to the active substance or any of the excipients; poorly controlled hypertension.

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. 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 aluminium 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 the 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 neutralising 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 neutralising antibodies to erythropoietin should not be switched to ARANESP®.
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, i.e. 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 at the attached doctor’s leaflet. 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.
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).
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.
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.

Identified adverse reactions associated with ARANESP® are hypertension, stroke, thromboembolic events, convulsions, allergic reactions, rash/erythema and pure red cell aplasia (PRCA).
Injection site pain was reported as attributable to treatment in studies where ARANESP® was administered via subcutaneous injection. The injection site discomfort was generally mild and transient in nature and occurred predominantly after the first injection.
See prescribing information for full details.

The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other substances. However, there is potential for an interaction with drugs that are highly bound to red blood cells (e.g. cyclosporin, tacrolimus). If ARANESP® is given concomitantly with any of these drugs, blood levels of these drugs should be monitored and the dosage adjusted as the hemoglobin rises.

Pregnancy: There are no adequate and well-controlled studies with ARANESP® in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. No alteration of fertility was detected.
Caution should be exercised when prescribing ARANESP® to pregnant women.
Lactation: It is unknown whether ARANESP® is excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ARANESP® therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

The maximum amount of ARANESP® that can be safely administered in single or multiple doses has not been determined. Therapy with ARANESP® can result in polycythemia if the hemoglobin is not carefully monitored and the dose appropriately adjusted. Cases of severe hypertension have been observed following overdose with ARANESP®.
In the event of polycythemia, ARANESP® should be temporarily withheld. If
clinically indicated, phlebotomy may be performed.

Incompatibilities: In the absence of incompatibility studies, ARANESP® must not be mixed or administered as an infusion with other medicinal products.
Shelf Life: 36 months.
Storage: Store in a refrigerator at 2°C to 8°C. Do not freeze. Keep the container in the outer carton, in order to protect from light.