ARANESP 25mcg / ml injection solution into the bottle medication leaflet

Aranesp 10 micrograms solution for injection in pre-filled syringe.

Aranesp 15 micrograms solution for injection in pre-filled syringe.

Aranesp 20 micrograms solution for injection in pre-filled syringe.

Aranesp 30 micrograms solution for injection in pre-filled syringe.

Aranesp 40 micrograms solution for injection in pre-filled syringe.

Aranesp 50 micrograms solution for injection in pre-filled syringe.

Aranesp 60 micrograms solution for injection in pre-filled syringe.

Aranesp 80 micrograms solution for injection in pre-filled syringe.

Aranesp 100 micrograms solution for injection in pre-filled syringe.

Aranesp 130 micrograms solution for injection in pre-filled syringe.

Aranesp 150 micrograms solution for injection in pre-filled syringe.

Aranesp 300 micrograms solution for injection in pre-filled syringe.

Aranesp 500 micrograms solution for injection in pre-filled syringe.

Aranesp 10 micrograms solution for injection in pre-filled pen.

Aranesp 15 micrograms solution for injection in pre-filled pen.

Aranesp 20 micrograms solution for injection in pre-filled pen.

Aranesp 30 micrograms solution for injection in pre-filled pen.

Aranesp 40 micrograms solution for injection in pre-filled pen.

Aranesp 50 micrograms solution for injection in pre-filled pen.

Aranesp 60 micrograms solution for injection in pre-filled pen.

Aranesp 80 micrograms solution for injection in pre-filled pen.

Aranesp 100 micrograms solution for injection in pre-filled pen.

Aranesp 130 micrograms solution for injection in pre-filled pen.

Aranesp 150 micrograms solution for injection in pre-filled pen.

Aranesp 300 micrograms solution for injection in pre-filled pen.

Aranesp 500 micrograms solution for injection in pre-filled pen.

Aranesp 25 micrograms solution for injection in vial.

Aranesp 40 micrograms solution for injection in vial.

Aranesp 60 micrograms solution for injection in vial.

Aranesp 100 micrograms solution for injection in vial.

Aranesp 200 micrograms solution for injection in vial.

Aranesp 300 micrograms solution for injection in vial.

Aranesp 10 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 10 micrograms of darbepoetin alfa in 0.4 mL (25 mcg/mL).

Aranesp 15 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 15 micrograms of darbepoetin alfa in 0.375 mL (40 mcg/mL).

Aranesp 20 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 20 micrograms of darbepoetin alfa in 0.5 mL (40 mcg/mL).

Aranesp 30 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 30 micrograms of darbepoetin alfa in 0.3 mL (100 mcg/mL).

Aranesp 40 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 40 micrograms of darbepoetin alfa in 0.4 mL (100 mcg/mL).

Aranesp 50 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 50 micrograms of darbepoetin alfa in 0.5 mL (100 mcg/mL).

Aranesp 60 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 60 micrograms of darbepoetin alfa in 0.3 mL (200 mcg/mL).

Aranesp 80 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 80 micrograms of darbepoetin alfa in 0.4 mL (200 mcg/mL).

Aranesp 100 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 100 micrograms of darbepoetin alfa in 0.5 mL (200 mcg/mL).

Aranesp 130 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 130 micrograms of darbepoetin alfa in 0.65 mL (200 mcg/mL).

Aranesp 150 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 150 micrograms of darbepoetin alfa in 0.3 mL (500 mcg/mL).

Aranesp 300 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 300 micrograms of darbepoetin alfa in 0.6 mL (500 mcg/mL).

Aranesp 500 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe contains 500 micrograms of darbepoetin alfa in 1 mL (500 mcg/mL).

Aranesp 10 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 10 micrograms of darbepoetin alfa in 0.4 mL (25 mcg/mL).

Aranesp 15 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 15 micrograms of darbepoetin alfa in 0.375 mL (40 mcg/mL).

Aranesp 20 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 20 micrograms of darbepoetin alfa in 0.5 mL (40 mcg/mL).

Aranesp 30 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 30 micrograms of darbepoetin alfa in 0.3 mL (100 mcg/mL).

Aranesp 40 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 40 micrograms of darbepoetin alfa in 0.4 mL (100 mcg/mL).

Aranesp 50 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 50 micrograms of darbepoetin alfa in 0.5 mL (100 mcg/mL).

Aranesp 60 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 60 micrograms of darbepoetin alfa in 0.3 mL (200 mcg/mL).

Aranesp 80 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 80 micrograms of darbepoetin alfa in 0.4 mL (200 mcg/mL).

Aranesp 100 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 100 micrograms of darbepoetin alfa in 0.5 mL (200 mcg/mL).

Aranesp 130 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 130 micrograms of darbepoetin alfa in 0.65 mL (200 mcg/mL).

Aranesp 150 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 150 micrograms of darbepoetin alfa in 0.3 mL (500 mcg/mL).

Aranesp 300 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 300 micrograms of darbepoetin alfa in 0.6 mL (500 mcg/mL).

Aranesp 500 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 500 micrograms of darbepoetin alfa in 1 mL (500 mcg/mL).

Aranesp 25 micrograms solution for injection in vial

Each vial contains 25 micrograms of darbepoetin alfa in 1 mL (25 mcg/mL).

Aranesp 40 micrograms solution for injection in vial

Each vial contains 40 micrograms of darbepoetin alfa in 1 mL (40 mcg/mL).

Aranesp 60 micrograms solution for injection in vial

Each vial contains 60 micrograms of darbepoetin alfa in 1 mL (60 mcg/mL).

Aranesp 100 micrograms solution for injection in vial

Each vial contains 100 micrograms of darbepoetin alfa in 1 mL (100 mcg/mL).

Aranesp 200 micrograms solution for injection in vial

Each vial contains 200 micrograms of darbepoetin alfa in 1 mL (200 mcg/mL).

Aranesp 300 micrograms solution for injection in vial

Each vial contains 300 micrograms of darbepoetin alfa in 1 mL (300 mcg/mL).

Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1).

For the full list of excipients, see section 6.1.

Solution for injection (injection) in pre-filled syringe.

Solution for injection (injection) in pre-filled pen (SureClick).

Solution for injection (injection) in vial.

Clear, colourless solution.

Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults andpaediatric patients (see section 4.2).

Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receivingchemotherapy.

Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.

Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; aphysician’s evaluation of the individual patient’s clinical course and condition is necessary. Aranespshould be administered either subcutaneously or intravenously in order to increase haemoglobin to notgreater than 12 g/dL (7.5 mmol/L). Subcutaneous use is preferable in patients who are not receivinghaemodialysis to avoid the puncture of peripheral veins.

Patients should be monitored closely to ensure that the lowest approved effective dose of Aranesp isused to provide adequate control of the symptoms of anaemia whilst maintaining a haemoglobinconcentration 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 haemoglobin response to

Aranesp, alternative explanations for the poor response should be considered (see sections 4.4and 5.1).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above andbelow the desired haemoglobin level may be observed. Haemoglobin variability should be addressedthrough dose management, with consideration for the haemoglobin target range of10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). A sustained haemoglobin level of greater than12 g/dL (7.5 mmol/L) should be avoided; guidance for appropriate dose adjustment for whenhaemoglobin values exceeding 12 g/dL (7.5 mmol/L) are observed are described below. A rise inhaemoglobin of greater than 2 g/dL (1.25 mmol/L) over a four week period should be avoided. If itoccurs, appropriate dose adjustment should be made as provided.

Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance isgiven separately for adult and paediatric patients.

Adult patients with chronic renal failure

Correction phase:

The initial dose by subcutaneous or intravenous administration is 0.45 mcg/kg body weight, as a singleinjection once weekly. Alternatively, in patients not on dialysis, the following initial doses can also beadministered subcutaneously as a single injection: 0.75 mcg/kg once every two weeks or 1.5 mcg/kgonce monthly. If the increase in haemoglobin is inadequate (less than 1 g/dL (0.6 mmol/L) in fourweeks) increase the dose by approximately 25%. Dose increases must not be made more frequentlythan once every four weeks.

If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/L) in four weeks reduce the dose byapproximately 25%. If the haemoglobin exceeds 12 g/dL (7.5 mmol/L), a dose reduction should beconsidered. If the haemoglobin continues to increase, the dose should be reduced byapproximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should betemporarily withheld until the haemoglobin begins to decrease, at which point therapy should bereinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter thehaemoglobin can be measured at longer intervals.

Maintenance phase:

In dialysis patients, Aranesp may continue to be administered as a single injection once weekly oronce every two weeks. Dialysis patients converting from once weekly to once every other week dosingwith 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 weeklyor once every two weeks or once monthly. For patients treated with Aranesp once every two weeks,after the target haemoglobin has been achieved, Aranesp may then be administered subcutaneouslyonce monthly using an initial dose equal to twice the previous once every two week dose.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended thatthe dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/L) in four weeks reduce the dose byapproximately 25%, depending on the rate of increase. If the haemoglobin exceeds12 g/dL (7.5 mmol/L), a dose reduction should be considered. If the haemoglobin continues toincrease, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobincontinues to increase, the dose should be temporarily withheld until the haemoglobin begins todecrease, at which point therapy should be reinitiated at approximately 25% lower than the previousdose.

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks.

Dose changes in the maintenance phase of treatment should not be made more frequently than everytwo weeks.

When changing the route of administration the same dose must be used and the haemoglobinmonitored every one or two weeks so that the appropriate dose adjustments can be made to keep thehaemoglobin at the desired level.

Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three timesweekly may be converted to once weekly or once every other week Aranesp. The initial weekly doseof Aranesp (mcg/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 (mcg/every other week) can be determined bydividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Becauseof individual variability, titration to optimal therapeutic doses is expected for individual patients.

When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or twoweeks and the same route of administration should be used.

Paediatric population with chronic renal failure

Treatment of paediatric patients younger than 1 year of age has not been studied in randomised clinicaltrials (see section 5.1).

Correction phase:

For patients ≥ 1 year of age, the initial dose by subcutaneous or intravenous administration is0.45 mcg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis,an initial dose of 0.75 mcg/kg may be administered subcutaneously as a single injection once everytwo weeks. If the increase in haemoglobin 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 onceevery four weeks.

If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/L) in four weeks reduce the dose byapproximately 25%, depending on the rate of increase. If the haemoglobin exceeds12 g/dL (7.5 mmol/L), a dose reduction should be considered. If the haemoglobin continues toincrease, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobincontinues to increase, the dose should be temporarily withheld until the haemoglobin begins todecrease, at which point therapy should be reinitiated at approximately 25% lower than the previousdose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter thehaemoglobin can be measured at longer intervals.

Correction of anaemia in paediatric patients with once monthly Aranesp dosing frequency has notbeen studied.

Maintenance phase:

For paediatric patients ≥ 1 year of age, in the maintenance phase, Aranesp may continue to beadministered as a single injection once weekly or once every two weeks. Patients < 6 years of age mayneed higher doses for maintenance of haemoglobin than patients above that age. Dialysis patientsconverting from once weekly to once every other week dosing with Aranesp should initially receive adose equivalent to twice the previous once weekly dose.

In patients ≥ 11 years of age not on dialysis, once the target haemoglobin has been achieved with onceevery two week dosing, Aranesp may be administered subcutaneously once monthly using an initialdose equal to twice the previous once every two week dose.

Clinical data in paediatric patients has demonstrated that patients receiving r-HuEPO two or threetimes weekly may be converted to once weekly Aranesp, and those receiving r-HuEPO once weeklymay be converted to once every other week Aranesp. The initial weekly paediatric dose of Aranesp(mcg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240. Theinitial every other week dose of Aranesp (mcg/every other week) can be determined by dividing thetotal cumulative dose of r-HuEPO administered over a two-week period by 240. Because of individualvariability, titration to optimal therapeutic doses is expected for individual patients. When substituting

Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the sameroute of administration should be used.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended thatthe dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/L) in four weeks reduce the dose byapproximately 25%, depending on the rate of increase. If the haemoglobin exceeds12 g/dL (7.5 mmol/L), a dose reduction should be considered. If the haemoglobin continues toincrease, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobincontinues to increase, the dose should be temporarily withheld until the haemoglobin begins todecrease, at which point therapy should be reinitiated at approximately 25% lower than the previousdose.

Patients starting dialysis during treatment with Aranesp should be closely monitored for adequatecontrol of their haemoglobin.

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks.

Dose changes in the maintenance phase of treatment should not be made more frequently than everytwo weeks.

When changing the route of administration the same dose must be used and the haemoglobinmonitored every one or two weeks so that the appropriate dose adjustments can be made to keep thehaemoglobin at the desired level.

Treatment of symptomatic chemotherapy-induced anaemia in cancer patients

Aranesp should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobinconcentration ≤ 10 g/dL (6.2 mmol/L)) in order to increase haemoglobin to not greater than12 g/dL (7.5 mmol/L). Anaemia symptoms and sequelae may vary with age, gender, and overallburden of disease; a physician’s evaluation of the individual patient’s clinical course and condition isnecessary.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above andbelow the desired haemoglobin level may be observed. Haemoglobin variability should be addressedthrough dose management, with consideration for the haemoglobin target range of10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). A sustained haemoglobin level of greater than12 g/dL (7.5 mmol/L) should be avoided; guidance for appropriate dose adjustments for whenhaemoglobin values exceeding 12 g/dL (7.5 mmol/L) are observed are described below.

The recommended initial dose is 500 mcg (6.75 mcg/kg) given once every three weeks, or onceweekly dosing can be given at 2.25 mcg/kg body weight. If the clinical response of the patient(fatigue, haemoglobin 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 reducedby 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintainhaemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between500 mcg, 300 mcg, and 150 mcg should be considered.

Patients should be monitored closely, if the haemoglobin exceeds 12 g/dL (7.5 mmol/L), the doseshould be reduced by approximately 25 to 50%. Treatment with Aranesp should be temporarilydiscontinued if haemoglobin levels exceed 13 g/dL (8.1 mmol/L). Therapy should be reinitiated atapproximately 25% lower than the previous dose after haemoglobin levels fall to12 g/dL (7.5 mmol/L) or below.

If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/L) in 4 weeks, the dose should be reducedby 25 to 50%.

Aranesp may be administered subcutaneously by the patient or a carer after being trained by a doctor,nurse or pharmacist.

Aranesp 10, 15, 20, 30, 40, 50, 60, 80, 100, 130, 150, 300, 500 micrograms solution for injection inpre-filled syringe

Aranesp is administered either subcutaneously or intravenously as described in the posology.

Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a pre-filled syringe.

Aranesp 10, 15, 20, 30, 40, 50, 60, 80, 100, 130, 150, 300, 500 micrograms solution for injection inpre-filled pen

Aranesp in a pre-filled pen is only for subcutaneous administration.

Rotate the injection sites to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a pre-filled pen.

Aranesp 25, 40, 60, 100, 200, 300 micrograms solution for injection in vial

Aranesp is administered either subcutaneously or intravenously as described in the posology.

Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a vial.

The instructions for use, handling and disposal are given in section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Poorly controlled hypertension.

In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of theadministered 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. Ifblood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may bereduced by decreasing or withholding the dose of Aranesp (see section 4.2). Cases of severehypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have beenobserved in CRF patients treated with Aranesp.

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to andduring treatment and supplementary iron therapy may be necessary.

Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies ofiron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.

Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, severealuminium toxicity, underlying haematologic diseases, or bone marrow fibrosis may also compromisethe erythropoietic response. A reticulocyte count should be considered as part of the evaluation. Iftypical causes of non-response are excluded, and the patient has reticulocytopenia, an examination ofthe bone marrow should be considered. If the bone marrow is consistent with PRCA, testing foranti-erythropoietin antibodies should be performed.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in associationwith 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 monitoredclosely for skin reactions. If signs and symptoms suggestive of these reactions appear, Aranesp shouldbe withdrawn immediately and an alternative treatment considered. If the patient has developed asevere cutaneous skin reaction such as SJS or TEN due to the use of Aranesp, treatment with Aranespmust not be restarted in this patient at any time.

Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported inassociation with ESAs, including Aranesp. This has been predominantly reported in patients with CRFtreated subcutaneously. These antibodies have been shown to cross-react with all erythropoieticproteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin shouldnot be switched to Aranesp (see section 4.8).

A paradoxical decrease in haemoglobin and development of severe anaemia associated with lowreticulocyte counts should prompt to discontinue treatment with epoetin and performanti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated withinterferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in themanagement of anaemia associated with hepatitis C.

Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are availablefrom patients with impaired liver function. Since the liver is thought to be the principal route ofelimination of darbepoetin alfa and r-HuEPO, Aranesp should be used with caution in patients withliver disease.

Aranesp should also be used with caution in those patients with sickle cell anaemia.

Misuse of Aranesp by healthy persons may lead to an excessive increase in packed cell volume. Thismay 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 oflatex), which may cause allergic reactions.

Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported inpatients receiving Aranesp.

The reported risk of thrombotic vascular events (TVEs) should be carefully weighed against thebenefits to be derived from treatment with darbepoetin alfa particularly in patients with pre-existingrisk 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 haemoglobin concentration should not exceed theupper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, anincreased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascularaccess thrombosis was observed when ESAs were administered to target a haemoglobin of greaterthan 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, seriouscardiovascular 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).

Controlled clinical trials have not shown significant benefits attributable to the administration ofepoetins when haemoglobin concentration is increased beyond the level necessary to controlsymptoms of anaemia and to avoid blood transfusion.

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

Serum potassium levels should be monitored regularly during Aranesp therapy. Potassium elevationhas been reported in a few patients receiving Aranesp, though causality has not been established. If anelevated or rising potassium level is observed then consideration should be given to ceasing Aranespadministration until the level has been corrected.

Cancer patients

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietinreceptors 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 progressionin patients with anaemia associated with cancer.

In controlled clinical studies, use of Aranesp and other ESAs have shown:

- shortened time to tumour progression in patients with advanced head and neck cancer receivingradiation therapy when administered to target a haemoglobin of greater than14 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 inpatients with metastatic breast cancer receiving chemotherapy when administered to target ahaemoglobin 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) inpatients 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 aprimary analysis and a 15% increased risk that cannot be statistically ruled out in patients withmetastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobinconcentration 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 survivalin patients with advanced stage non-small cell lung cancer receiving chemotherapy whenadministered to a target haemoglobin 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 treatmentfor the management of anaemia in patients with cancer. The decision to administer recombinanterythropoietins should be based on a benefit-risk assessment with the participation of the individualpatient, which should take into account the specific clinical context. Factors that should be consideredin 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 (seesection 5.1).

In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds12 g/dL (7.5 mmol/L), the dosage adaptation described in section 4.2 should be closely respected, inorder to minimise the potential risk of thromboembolic events. Platelet counts and haemoglobin levelshould also be monitored at regular intervals.

The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with othersubstances. However, there is potential for an interaction with substances that are highly bound to redblood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of thesetreatments, blood levels of these substances should be monitored and the dosage adjusted as thehaemoglobin rises.

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/foetaldevelopment, parturition or postnatal development. No alteration of fertility was detected.

Caution should be exercised when prescribing Aranesp to pregnant women.

It is unknown whether Aranesp is excreted in human milk. A risk to the suckling child cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom Aranesp therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

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

Identified adverse reactions associated with Aranesp are hypertension, stroke, thromboembolic events,convulsions, allergic reactions, rash/erythema and pure red cell aplasia (PRCA); see section 4.4.

Injection site pain was reported as attributable to treatment in studies where Aranesp was administeredvia subcutaneous injection. The injection site discomfort was generally mild and transient in natureand occurred predominantly after the first injection.

Incidence of adverse reactions are listed below by system organ class and frequency. Frequencies aredefined as: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare(≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the availabledata).

Data are presented separately for CRF and cancer patients reflecting the different adverse reactionprofile in these populations.

Chronic renal failure patients

Data presented from controlled studies included 1,357 patients, 766 who received Aranesp and591 patients who received r-HuEPO. In the Aranesp group, 83% were receiving dialysis and 17%were not receiving dialysis. Stroke was identified as an adverse reaction in an additional clinical study(TREAT, see section 5.1).

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

MedDRA system organ class Subject incidence Adverse reaction

Blood and lymphatic system Not known2 Pure red cell aplasiadisorders

Immune system disorders Very common Hypersensitivitya

Nervous system disorders Common Strokeb

Uncommon1 Convulsions

Cardiac disorders Very common Hypertension

Vascular disorders Uncommon Thromboembolic eventsc

Uncommon1 Dialysis vascular accessthrombosisd

Skin and subcutaneous tissue Common Rash/erythemaedisorders Not known2 SJS/TEN, erythema multiforme,blistering, skin exfoliation

General disorders and administration Common Injection site painsite conditions Uncommon1 Injection site bruising

Injection site haemorrhage

Source: Includes 5 randomised, double-blind, active-controlled studies (970200, 970235, 980117, 980202, and980211) except for the adverse reaction of stroke which was identified as an adverse reaction in the TREATstudy (study 20010184).1 Adverse reactions identified in the post-marketing environment. Per the Guideline on Summary of Product

Characteristics (Revision 2, September 2009), frequency of adverse reactions identified in the post-marketingsetting was determined using the “Rule of three”.2 Frequency cannot be estimated from the available data.a Hypersensitivity events includes all events under the hypersensitivity SMQ.b Stroke events includes PT haemorrhagic stroke, ischaemic stroke, cerebrovascular accident, and stroke inevolution.c Thromboembolic events adverse reaction includes PT embolism arterial, thrombophlebitis, thrombosis, venousthrombosis limb.d Dialysis vascular access thrombosis includes all adverse reactions under the dialysis vascular access thrombosis

AMQe Rash/erythema adverse reaction includes PT rash, rash pruritic, rash macular, rash generalised, erythema.

Cancer patients

Adverse reactions were determined based on pooled data from eight randomised, double-blind,placebo-controlled studies of Aranesp with a total of 4,630 patients (Aranesp 2,888, placebo 1,742).

Patients with solid tumours (e.g., lung, breast, colon, ovarian cancers) and lymphoid malignancies(e.g., lymphoma, multiple myeloma) were enrolled in the clinical studies.

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

MedDRA system organ class Subject incidence Adverse reaction

Immune system disorders Very common Hypersensitivitya

Nervous system disorders Uncommon1 Convulsions

Cardiac disorders Common Hypertension

Vascular disorders Common Thromboembolic eventsb,including pulmonary embolism

MedDRA system organ class Subject incidence Adverse reaction

Skin and subcutaneous tissue Common Rash/erythemacdisorders Not known2 SJS/TEN, erythema multiforme,blistering, skin exfoliation

General disorders and administration Common Oedemadsite conditions Common Injection site paine

Uncommon1 Injection site bruising

Injection site haemorrhage1 ADRs identified in the post marketing environment. Per the Guideline on Summary of Product Characteristics(Revision 2, September 2009), frequency of ADRs identified in the post marketing setting was determined usingthe “Rule of three”.2 Frequency cannot be estimated from the available data.

Source: includes 8 randomised, double-blind, placebo-controlled studies (980291-schedule 1 and 2, 980297,990114, 20000161, 20010145, 20030232, and 20070782)a Hypersensitivity events includes all events under the hypersensitivity SMQ.b Thromboembolic events adverse reactions includes PT embolism, thrombosis, deep vein thrombosis, jugularvein thrombosis, venous thrombosis, arterial thrombosis, pelvic venous thrombosis, peripheral embolism,pulmonary embolism, as well as thrombosis in device from SOC product issues.c Rash adverse reactions includes PT rash, rash pruritic, rash generalised, rash papular, erythema, exfoliativerash, rash maculo-papular, rash vesicular as well as rash pustular from SOC Infections and Infestations.d Oedema: includes PT Oedema Peripheral, Oedema, Generalised Oedema, Oedema due to Cardiac Disease,

Face oedemae Injection site pain adverse reaction includes PT injection site pain, administration site pain, catheter site pain,infusion site pain and vessel puncture site pain.

Chronic renal failure patients

Stroke was reported as common in CRF patients in TREAT (see section 5.1).

In isolated cases, neutralising anti-erythropoietin antibody mediated pure red cell aplasia (PRCA)associated with Aranesp therapy have been reported predominantly in patients with CRF treatedsubcutaneously. In case PRCA is diagnosed, therapy with Aranesp must be discontinued and patientsshould not be switched to another recombinant erythropoietic protein (see section 4.4).

The frequency of all hypersensitivity reactions was estimated from clinical trial data as very commonin CRF patients. Hypersensitivity reactions were also very common in the placebo groups. There havebeen reports, from post-marketing experience, of serious hypersensitivity reactions includinganaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticaria associated withdarbepoetin alfa.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported (seesection 4.4).

Convulsions have been reported in patients receiving darbepoetin alfa (see section 4.4). The frequencyis estimated from clinical trial data as uncommon in CRF patients.

In CRF patients on haemodialysis, events of vascular access thrombosis (such as vascular accesscomplication, arteriovenous fistula thrombosis, graft thrombosis, shunt thrombosis, arteriovenous fistulasite complication, etc.) have been reported in post-marketing data. The frequency is estimated fromclinical trial data as uncommon.

Cancer patients

Hypertension has been observed in cancer patients in post-marketing experience (see section 4.4). Thefrequency is estimated from clinical trial data as common in cancer patients and was also common inthe placebo groups.

Hypersensitivity reactions have been observed in cancer patients in post-marketing experience. Thefrequency of all hypersensitivity reactions was estimated from clinical trial data as very common incancer patients. Hypersensitivity reactions were also very common in the placebo groups. There havebeen reports of serious hypersensitivity reactions including anaphylactic reaction, angioedema, allergicbronchospasm, skin rash and urticaria associated with darbepoetin alfa.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported (seesection 4.4).

Convulsions have been reported in patients receiving darbepoetin alfa in post-marketing experience(see section 4.4). The frequency is estimated from clinical trial data as uncommon in cancer patients.

Convulsions were common in the placebo groups.

Paediatric chronic renal failure population

In all paediatric CRF studies, there were no additional adverse reactions identified for paediatricpatients compared to those previously reported for adult patients (see section 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The maximum amount of Aranesp that can be safely administered in single or multiple doses has notbeen determined. Therapy with Aranesp can result in polycythaemia if the haemoglobin is notcarefully monitored and the dose appropriately adjusted. Cases of severe hypertension have beenobserved following overdose with Aranesp (see section 4.4).

In the event of polycythaemia, Aranesp should be temporarily withheld (see section 4.2). If clinicallyindicated, phlebotomy may be performed.

Pharmacotherapeutic group: Anti-anaemic preparations, other anti-anaemic preparations, ATC Code:

B03XA02.

Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator oferythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitorcells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by thekidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin isimpaired in patients with chronic renal failure and the primary cause of their anaemia is due toerythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia ismultifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroidprogenitor cells to endogenous erythropoietin both contribute significantly towards their anaemia.

Darbepoetin alfa stimulates erythropoiesis by the same mechanism as the endogenous hormone.

Darbepoetin alfa has five N-linked carbohydrate chains whereas the endogenous hormone andrecombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues aremolecularly indistinct from those on the endogenous hormone. Due to its increased carbohydratecontent darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greaterin vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity forthe erythropoietin receptor.

Chronic renal failure patients

Patients with CRF experienced greater risks for death and serious cardiovascular events whenadministered ESAs to target higher versus lower haemoglobin levels (13.5 g/dL (8.4 mmol/L) versus11.3 g/dL (7.1 mmol/L); 14 g/dL (8.7 mmol/L) versus 10 g/dL (6.2 mmol/L) in two clinical studies.

In a randomised, double-blind correction study (n = 358) comparing once every two week and oncemonthly dosing schedules in patients with CRF not on dialysis, darbepoetin alfa once monthly dosingwas non-inferior to once every two week dosing for correcting anaemia. The median (quartile 1,quartile 3) time to achieve haemoglobin correction (≥ 10.0 g/dL and ≥ 1.0 g/dL increase frombaseline) was 5 weeks for both once every two week (3, 7 weeks) and once monthly dosing (3,9 weeks). During the evaluation period (weeks 29-33), the mean (95% CI) weekly equivalent dose was0.20 (0.17, 0.24) mcg/kg in the once every two week arm and 0.27 (0.23, 0.32) mcg/kg in the oncemonthly arm.

In a randomised, double-blind, placebo-controlled study (TREAT) of 4,038 CRF patients not ondialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dL, patients received either treatment withdarbepoetin alfa to target haemoglobin levels of 13 g/dL or placebo (with darbepoetin alfa rescue athaemoglobin less than 9 g/dL). The study did not meet either primary objective of demonstrating areduction in risk for all-cause mortality or cardiovascular morbidity (darbepoetin alfa vs placebo;

HR 1.05, 95% CI (0.94, 1.17)), or all-cause mortality or end stage renal disease (ESRD) (darbepoetinalfa vs placebo; HR 1.06, 95% CI (0.95, 1.19)). Analysis of the individual components of thecomposite endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), congestive heartfailure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), stroke 1.92 (1.38, 2.68),hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).

Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renalfailure patients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towardsincreased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associatedwith higher cumulative ESA doses independent of the diabetes or dialysis status was observed (seesections 4.2 and 4.4).

In a randomised clinical study 114 paediatric patients aged 2 to 18 with chronic kidney diseasereceiving or not receiving dialysis who were anaemic (haemoglobin < 10.0 g/dL) and not being treatedwith an ESA were administered darbepoetin alfa weekly (n = 58) or once every two weeks (n = 56) forthe correction of anaemia. Haemoglobin concentrations were corrected to ≥ 10 g/dL in > 98%(p < 0.001) of paediatric patients administered darbepoetin alfa once weekly and 84% (p = 0.293) onceevery two weeks. At the time haemoglobin ≥ 10.0 g/dL was first achieved, the mean (SD) weight-adjusted dose was 0.48 (0.24) mcg/kg (range: 0.0 to 1.7 mcg/kg) weekly for the once weekly groupand 0.76 (0.21) mcg/kg (range: 0.3 to 1.5 mcg/kg) biweekly for the once every two week group.

In a clinical study in 124 paediatric patients with chronic kidney disease receiving or not receivingdialysis aged 1 to 18, patients that were stable on epoetin alfa were randomised to receive eitherdarbepoetin alfa administered once weekly (subcutaneously or intravenously) using a dose conversionratio of 238:1 or to continue with epoetin alfa therapy at the current dose, schedule, and route ofadministration. The primary efficacy endpoint [change in haemoglobin between baseline and theevaluation period (week 21-28)] was comparable between the two groups. The mean haemoglobin forr-HuEPO and darbepoetin alfa at baseline was 11.1 (SD 0.7) g/dL and 11.3 (SD 0.6) g/dL,respectively. The mean haemoglobin at week 28 for r-HuEPO and darbepoetin alfa was 11.1 (SD1.4) g/dL and 11.1 (SD 1.1) g/dL, respectively.

In an European observational registry study which enrolled 319 paediatric patients with chronickidney disease (13 (4.1%) patients < 1 year of age, 83 (26.0%) patients 1-< 6 years of age, 90 (28.2%)patients 6-< 12 years of age, and 133 (41.7%) patients ≥ 12 years of age) receiving darbepoetin alfa,mean haemoglobin concentrations ranging between 11.3 and 11.5 g/dL and mean weight-adjusteddarbepoetin alfa doses remained relatively constant (between 2.31 mcg/kg month and 2.67 mcg/kgmonth) over the study period for the entire study population.

In these studies, no meaningful differences were identified between the safety profile for paediatricpatients and that previously reported for adult patients (see section 4.8).

Cancer patients receiving chemotherapy

EPO-ANE-3010, a randomised, open-label, multicentre study was conducted in 2,098 anaemic womenwith metastatic breast cancer, who received first line or second line chemotherapy. This was a noninferiority study designed to rule out a 15% risk increase in tumour progression or death of epoetinalfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, themedian progression free survival (PFS) per investigator assessment of disease progression was7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met.

Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus

SOC arm (2.8% versus 1.4%). At the final analysis, 1,653 deaths were reported. Median overallsurvival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOCalone group (HR 1.07, 95% CI: 0.97, 1.18). The median time to progression (TTP) based oninvestigator-determined progressive disease (PD) was 7.5 months in the epoetin alfa plus SOC groupand 7.5 months in the SOC group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRC-determined PD was 8.0 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group(HR 1.033, 95% CI: 0.924, 1.156).

In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancerpatients receiving platinum containing chemotherapy there was a significant reduction in transfusionrequirements (p < 0.001).

Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administeredas a single injection either once every three weeks, once every two weeks, or weekly without anyincrease in total dose requirements.

The safety and effectiveness of once every three weeks dosing of Aranesp therapy in reducing therequirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in arandomised, double-blind, multinational study. This study was conducted in 705 anaemic patients withnon-myeloid malignancies receiving multi-cycle chemotherapy. Patients were randomised to receive

Aranesp at 500 mcg once every three weeks or 2.25 mcg/kg once weekly. In both groups, the dose wasreduced by 40% of the previous dose (e.g., for first dose reduction, to 300 mcg in the once every threeweeks group and 1.35 mcg/kg in the once weekly group) if haemoglobin increased by more than1 g/dL in a 14-day period. In the once every three weeks group, 72% of patients required dosereductions. In the once weekly group, 75% of patients required dose reductions. This study supports500 mcg once every three weeks being comparable to once weekly administration with respect to theincidence of subjects receiving at least one red blood cell transfusion from week 5 to the end oftreatment phase.

In a prospective, randomised double-blind, placebo-controlled study conducted in 344 anaemicpatients with lymphoproliferative malignancies receiving chemotherapy there was a significantreduction in transfusion requirements and an improvement in haemoglobin response (p < 0.001).

Improvement in fatigue, as measured by the Functional Assessment of Cancer Therapy-fatigue(FACT-fatigue) scale, was also observed.

Erythropoietin is a growth factor that primarily stimulates red blood cell production. Erythropoietinreceptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a totalof 2,833 patients, of which four were double-blind placebo-controlled studies and one was anopen-label study. Two of the studies recruited patients who were being treated with chemotherapy.

The target haemoglobin concentration in two studies was > 13 g/dL; in the remaining three studies itwas 12-14 g/dL. In the open-label study there was no difference in overall survival between patientstreated with recombinant human erythropoietin and controls. In the four placebo-controlled studies thehazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studieshave shown a consistent unexplained statistically significant excess mortality in patients who haveanaemia associated with various common cancers who received recombinant human erythropoietincompared to controls. Overall survival outcome in the trials could not be satisfactorily explained bydifferences in the incidence of thrombosis and related complications between those given recombinanthuman erythropoietin and those in the control group.

In a randomised, double-blind, placebo-controlled phase 3 study 2,549 adult patients with anaemiareceiving chemotherapy for the treatment of advanced stage non-small cell lung cancer (NSCLC),were randomised 2:1 to darbepoetin alfa or placebo and treated to a maximum Hb of 12 g/dL. Theresults showed non-inferiority for the primary endpoint of overall survival with a median survival fordarbepoetin alfa versus placebo of 9.5 and 9.3 months, respectively (stratified HR 0.92; 95% CI: 0.83-1.01). The secondary endpoint of progression free survival was 4.8 and 4.3 months, respectively(stratified HR 0.95; 95% CI: 0.87-1.04), ruling out the pre-defined 15% risk increase.

A systematic review has also been performed involving more than 9,000 cancer patients participatingin 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of1.08 in favour of controls (95% CI: 0.99, 1.18; 42 trials and 8,167 patients).

An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and6,769 patients) was observed in patients treated with recombinant human erythropoietin. There istherefore consistent evidence to suggest that there may be significant harm to patients with cancer whoare treated with recombinant human erythropoietin. The extent to which these outcomes might applyto the administration of recombinant human erythropoietin to patients with cancer, treated withchemotherapy to achieve haemoglobin concentrations less than 13 g/dL, is unclear because fewpatients with these characteristics were included in the data reviewed.

A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-,radio-, chemoradio-, or no therapy) participating in 53 controlled clinical trials involving severalepoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 infavour of controls (95% CI: 1.00, 1.12; 53 trials and 13,933 patients) and for the cancer patientsreceiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk ofthromboembolic events in cancer patients receiving recombinant human erythropoietin (seesection 4.4).

Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains abovethe minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose ofr-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biologicalresponse.

Chronic renal failure patients

The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patientsfollowing intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is21 hours (SD 7.5) when administered intravenously. Clearance of darbepoetin alfa is 1.9 mL/hr/kg(SD 0.56) and the volume of distribution (Vss) is approximately equal to plasma volume (50 mL/kg).

Bioavailability is 37% with subcutaneous administration. Following monthly administration ofdarbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 mcg/kg, the terminal half-life was73 hours (SD 24). The longer terminal half-life of darbepoetin alfa administered subcutaneouslycompared to intravenously is due to subcutaneous absorption kinetics. In clinical studies, minimalaccumulation was observed with either route of administration. In preclinical studies it has beenshown that renal clearance is minimal (up to 2% of total clearance), and does not affect the serumhalf-life.

Data from 809 patients receiving Aranesp in European clinical studies were analysed to assess thedose required to maintain haemoglobin; no difference was observed between the average weekly doseadministered via the intravenous or subcutaneous routes of injection.

The pharmacokinetics of darbepoetin alfa in paediatric patients (2 to 16 years) with CRF who wereeither receiving or not receiving dialysis was assessed for sampling periods up to 2 weeks (336 hours)after one or two subcutaneous or intravenous doses. Where the same sampling duration was used,observed pharmacokinetic data and population pharmacokinetic modelling demonstrated that thepharmacokinetics of darbepoetin alfa was similar for paediatric and adult patients with CRF.

In a phase 1 pharmacokinetic study, following intravenous administration, an approximate 25%difference between paediatric and adult patients in the area under the curve from time 0 to infinity(AUC[0-∞]) was observed; however, this difference was less than the 2-fold range in AUC(0-∞)observed for the paediatric patients. AUC(0-∞) was similar between adult and paediatric patients with

CRF following subcutaneous administration. Half-life was also similar between adult and paediatricpatients with CRF following both intravenous and subcutaneous administration.

Cancer patients receiving chemotherapy

Following subcutaneous administration of 2.25 mcg/kg to adult cancer patients a mean peakconcentration of 10.6 ng/mL (SD 5.9) of darbepoetin alfa was reached at a mean time of 91 hours(SD 19.7). These parameters were consistent with dose linear pharmacokinetics over a wide doserange (0.5 to 8 mcg/kg weekly and 3 to 9 mcg/kg every two weeks). Pharmacokinetic parameters didnot change on multiple dosing over 12 weeks (dosing every week or every two weeks). There was anexpected moderate (< 2 fold) increase in serum concentration as steady state was approached, but nounexpected accumulation upon repeated administration. A pharmacokinetic study in patients withchemotherapy-induced anaemia treated with 6.75 mcg/kg darbepoetin alfa administered SC every3 weeks in combination with chemotherapy was conducted which allowed for full characterisation ofthe terminal half-life. In this study, mean (SD) terminal half-life was 74 (SD 27) hours.

In all studies in rats and dogs darbepoetin alfa produced marked increases in haemoglobin,haematocrits, red blood cell counts and reticulocytes, which correspond to the expectedpharmacological effects. Adverse events at very high doses were all considered to be related to anexaggerated pharmacological effect (decreased tissue perfusion due to increased blood viscosity).

These included myelofibrosis and splenic hypertrophy as well as broadening of the ECG-QRScomplex in dogs but no dysrhythmia and no effect on the QT interval were observed.

Darbepoetin alfa did not reveal any genotoxic potential nor did it have any effect on the proliferationof non-haematological cells in vitro or in vivo. In the chronic toxicity studies no tumourigenic orunexpected mitogenic responses were observed in any tissue type. The carcinogenic potential ofdarbepoetin alfa has not been evaluated in long-term animal studies.

In studies performed in rats and rabbits no clinically relevant evidence of harmful effects with respectto pregnancy, embryonal/ foetal development, parturition or postnatal development was observed.

Placental transfer was minimal. No alteration of fertility was detected.

Sodium phosphate monobasic

Sodium phosphate dibasic

Sodium chloride

Polysorbate 80

Water for injections

In the absence of incompatibility studies, this medicinal product must not be mixed or administered asan infusion with other medicinal products.

3 years.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the container in the outer carton in order to protect from light.

For the purpose of ambulatory use, Aranesp may be removed from storage once for a maximum singleperiod of seven days at room temperature (up to 25ºC). Once removed from the refrigerator and hasreached room temperature (up to 25ºC) it must either be used within 7 days or disposed of.

Aranesp 10 micrograms solution for injection in pre-filled syringe0.4 mL solution for injection (25 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 15 micrograms solution for injection in pre-filled syringe0.375 mL solution for injection (40 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 20 micrograms solution for injection in pre-filled syringe0.5 mL solution for injection (40 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 30 micrograms solution for injection in pre-filled syringe0.3 mL solution for injection (100 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 40 micrograms solution for injection in pre-filled syringe0.4 mL solution for injection (100 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 50 micrograms solution for injection in pre-filled syringe0.5 mL solution for injection (100 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 60 micrograms solution for injection in pre-filled syringe0.3 mL solution for injection (200 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 80 micrograms solution for injection in pre-filled syringe0.4 mL solution for injection (200 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 100 micrograms solution for injection in pre-filled syringe0.5 mL solution for injection (200 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 130 micrograms solution for injection in pre-filled syringe0.65 mL solution for injection (200 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 150 micrograms solution for injection in pre-filled syringe0.3 mL solution for injection (500 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 300 micrograms solution for injection in pre-filled syringe0.6 mL solution for injection (500 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

Aranesp 500 micrograms solution for injection in pre-filled syringe1 mL solution for injection (500 mcg/mL darbepoetin alfa) in a type 1 glass pre-filled syringe withstainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.

The syringes may be presented in either blistered (1- and 4-pack), with or without an automatic needleguard or non-blistered packaging (1-pack only).

The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex). Seesection 4.4.

Aranesp 10 micrograms solution for injection in pre-filled pen0.4 mL solution for injection (25 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 15 micrograms solution for injection in pre-filled pen0.375 mL solution for injection (40 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 20 micrograms solution for injection in pre-filled pen0.5 mL solution for injection (40 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 30 micrograms solution for injection in pre-filled pen0.3 mL solution for injection (100 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 40 micrograms solution for injection in pre-filled pen0.4 mL solution for injection (100 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 50 micrograms solution for injection in pre-filled pen0.5 mL solution for injection (100 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 60 micrograms solution for injection in pre-filled pen0.3 mL solution for injection (200 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 80 micrograms solution for injection in pre-filled pen0.4 mL solution for injection (200 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 100 micrograms solution for injection in pre-filled pen0.5 mL solution for injection (200 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 130 micrograms solution for injection in pre-filled pen0.65 mL solution for injection (200 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 150 micrograms solution for injection in pre-filled pen0.3 mL solution for injection (500 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 300 micrograms solution for injection in pre-filled pen0.6 mL solution for injection (500 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glasssyringe and stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

Aranesp 500 micrograms solution for injection in pre-filled pen1 mL solution for injection (500 mcg/mL darbepoetin alfa) in a pre-filled pen with type 1 glass syringeand stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled pens.

The needle cap of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4.

Aranesp 25 micrograms solution for injection in vial1 mL solution for injection (25 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Aranesp 40 micrograms solution for injection in vial1 mL solution for injection (40 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Aranesp 60 micrograms solution for injection in vial1 mL solution for injection (60 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Aranesp 100 micrograms solution for injection in vial1 mL solution for injection (100 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Aranesp 200 micrograms solution for injection in vial1 mL solution for injection (200 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Aranesp 300 micrograms solution for injection in vial1 mL solution for injection (300 mcg/mL darbepoetin alfa) in a type 1 glass vial with fluoropolymerlaminated elastomeric stopper and an aluminium seal with flip-off dust cover. Pack size of 1 or 4 vials.

Not all pack sizes may be marketed.

The carton contains a package leaflet with the full instructions for use and handling.

The Aranesp (SureClick) pre-filled pen delivers the complete dose of each presentation.

Aranesp is a sterile but unpreserved product. Do not administer more than one dose. Any medicinalproduct remaining should be disposed of.

Before administration the Aranesp solution should be inspected for visible particles. Only solutionswhich are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow thecontainer to reach room temperature before injecting.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

Aranesp 10 micrograms solution for injection pre-filled syringe

EU/1/01/185/001 1 Pack Blister

EU/1/01/185/002 4 Pack Blister

EU/1/01/185/033 1 Pack Unblistered

EU/1/01/185/074 1 blister pack with needle guard

EU/1/01/185/075 4 blister pack with needle guard

Aranesp 15 micrograms solution for injection pre-filled syringe

EU/1/01/185/003 1 Pack Blister

EU/1/01/185/004 4 Pack Blister

EU/1/01/185/034 1 Pack Unblistered

EU/1/01/185/076 1 blister pack with needle guard

EU/1/01/185/077 4 blister pack with needle guard

Aranesp 20 micrograms solution for injection pre-filled syringe

EU/1/01/185/005 1 Pack Blister

EU/1/01/185/006 4 Pack Blister

EU/1/01/185/035 1 Pack Unblistered

EU/1/01/185/078 1 blister pack with needle guard

EU/1/01/185/079 4 blister pack with needle guard

Aranesp 30 micrograms solution for injection pre-filled syringe

EU/1/01/185/007 1 Pack Blister

EU/1/01/185/008 4 Pack Blister

EU/1/01/185/036 1 Pack Unblistered

EU/1/01/185/080 1 blister pack with needle guard

EU/1/01/185/081 4 blister pack with needle guard

Aranesp 40 micrograms solution for injection pre-filled syringe

EU/1/01/185/009 1 Pack Blister

EU/1/01/185/010 4 Pack Blister

EU/1/01/185/037 1 Pack Unblistered

EU/1/01/185/082 1 blister pack with needle guard

EU/1/01/185/083 4 blister pack with needle guard

Aranesp 50 micrograms solution for injection pre-filled syringe

EU/1/01/185/011 1 Pack Blister

EU/1/01/185/012 4 Pack Blister

EU/1/01/185/038 1 Pack Unblistered

EU/1/01/185/084 1 blister pack with needle guard

EU/1/01/185/085 4 blister pack with needle guard

Aranesp 60 micrograms solution for injection pre-filled syringe

EU/1/01/185/013 1 Pack Blister

EU/1/01/185/014 4 Pack Blister

EU/1/01/185/039 1 Pack Unblistered

EU/1/01/185/086 1 blister pack with needle guard

EU/1/01/185/087 4 blister pack with needle guard

Aranesp 80 micrograms solution for injection pre-filled syringe

EU/1/01/185/015 1 Pack Blister

EU/1/01/185/016 4 Pack Blister

EU/1/01/185/040 1 Pack Unblistered

EU/1/01/185/088 1 blister pack with needle guard

EU/1/01/185/089 4 blister pack with needle guard

Aranesp 100 micrograms solution for injection pre-filled syringe

EU/1/01/185/017 1 Pack Blister

EU/1/01/185/018 4 Pack Blister

EU/1/01/185/041 1 Pack Unblistered

EU/1/01/185/090 1 blister pack with needle guard

EU/1/01/185/091 4 blister pack with needle guard

Aranesp 130 micrograms solution for injection pre-filled syringe

EU/1/01/185/069 1 Pack Blister

EU/1/01/185/070 4 Pack Blister

EU/1/01/185/071 1 Pack Unblistered

EU/1/01/185/092 1 blister pack with needle guard

EU/1/01/185/093 4 blister pack with needle guard

Aranesp 150 micrograms solution for injection pre-filled syringe

EU/1/01/185/019 1 Pack Blister

EU/1/01/185/020 4 Pack Blister

EU/1/01/185/042 1 Pack Unblistered

EU/1/01/185/094 1 blister pack with needle guard

EU/1/01/185/095 4 blister pack with needle guard

Aranesp 300 micrograms solution for injection pre-filled syringe

EU/1/01/185/021 1 Pack Blister

EU/1/01/185/022 4 Pack Blister

EU/1/01/185/043 1 Pack Unblistered

EU/1/01/185/096 1 blister pack with needle guard

EU/1/01/185/097 4 blister pack with needle guard

Aranesp 500 micrograms solution for injection pre-filled syringe

EU/1/01/185/031 1 Pack Blister

EU/1/01/185/032 4 Pack Blister

EU/1/01/185/044 1 Pack Unblistered

EU/1/01/185/098 1 blister pack with needle guard

EU/1/01/185/099 4 blister pack with needle guard

Aranesp 10 micrograms solution for injection pre-filled pen

EU/1/01/185/045 - 1 pack

EU/1/01/185/057 - 4 pack

Aranesp 15 micrograms solution for injection pre-filled pen

EU/1/01/185/046 - 1 pack

EU/1/01/185/058 - 4 pack

Aranesp 20 micrograms solution for injection pre-filled pen

EU/1/01/185/047 - 1 pack

EU/1/01/185/059 - 4 pack

Aranesp 30 micrograms solution for injection pre-filled pen

EU/1/01/185/048 - 1 pack

EU/1/01/185/060 - 4 pack

Aranesp 40 micrograms solution for injection pre-filled pen

EU/1/01/185/049 - 1 pack

EU/1/01/185/061 - 4 pack

Aranesp 50 micrograms solution for injection pre-filled pen

EU/1/01/185/050 - 1 pack

EU/1/01/185/062 - 4 pack

Aranesp 60 micrograms solution for injection pre-filled pen

EU/1/01/185/051 - 1 pack

EU/1/01/185/063 - 4 pack

Aranesp 80 micrograms solution for injection pre-filled pen

EU/1/01/185/052 - 1 pack

EU/1/01/185/064 - 4 pack

Aranesp 100 micrograms solution for injection pre-filled pen

EU/1/01/185/053 - 1 pack

EU/1/01/185/065 - 4 pack

Aranesp 130 micrograms solution for injection pre-filled pen

EU/1/01/185/072 - 1 pack

EU/1/01/185/073 - 4 pack

Aranesp 150 micrograms solution for injection pre-filled pen

EU/1/01/185/054 - 1 pack

EU/1/01/185/066 - 4 pack

Aranesp 300 micrograms solution for injection pre-filled pen

EU/1/01/185/055 - 1 pack

EU/1/01/185/067 - 4 pack

Aranesp 500 micrograms solution for injection pre-filled pen

EU/1/01/185/056 - 1 pack

EU/1/01/185/068 - 4 pack

Aranesp 25 micrograms solution for injection vial

EU/1/01/185/100 1 Pack

EU/1/01/185/101 4 Pack

Aranesp 40 micrograms solution for injection vial

EU/1/01/185/102 1 Pack

EU/1/01/185/103 4 Pack

Aranesp 60 micrograms solution for injection vial

EU/1/01/185/104 1 Pack

EU/1/01/185/105 4 Pack

Aranesp 100 micrograms solution for injection vial

EU/1/01/185/106 1 Pack

EU/1/01/185/107 4 Pack

Aranesp 200 micrograms solution for injection vial

EU/1/01/185/108 1 Pack

EU/1/01/185/109 4 Pack

Aranesp 300 micrograms solution for injection vial

EU/1/01/185/110 1 Pack

EU/1/01/185/111 4 Pack

Date of first authorisation: 8 June 2001

Date of latest renewal: 19 May 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu