NESPO 15mcg 15mcg / ml injection solution into the bottle medication leaflet

Nespo 15 micrograms solution for injection in a vial.

Each vial contains 15 micrograms of darbepoetin alfa in 1 ml (15 µg/ml).

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

For excipients, see section 6.1.

Solution for injection (injection) in a vial.

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

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

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

Nespo is supplied in vials. The instructions for use, handling and disposal are given in section 6.6.

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. Nesposhould 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.

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 of 10 g/dl(6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl(7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobinvalues exceeding 12 g/dl (7.5 mmol/l) are observed are described below. A rise in haemoglobin ofgreater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriatedose adjustment should be made as provided.

Treatment with Nespo is divided into two stages - correction and maintenance phase. Guidance isgiven separately for adult and paediatric patients. Treatment of paediatric patients younger than 1 yearof age has not been studied:

Adult patients with chronic renal failure

Correction Phase

The initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a singleinjection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may beadministered subcutaneously as a single injection once every two weeks. If the increase inhaemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose byapproximately 25%. Dose increases must not be made more frequently than 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 by approximately25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarilywithheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated atapproximately 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 the maintenance phase, Nespo 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 Nespo should initially receive a dose equivalent to twice the previous once weekly dose. Inpatients not on dialysis, once the target haemoglobin has been achieved with once every two weekdosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twicethe 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 exceeds 12 g/dl(7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, thedose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues toincrease, the dose should be temporarily withheld until the haemoglobin begins to decrease, at whichpoint therapy should be reinitiated at approximately 25% lower than the previous dose.

Patients should be monitored closely to ensure that the lowest approved dose of Nespo is used toprovide adequate control of the symptoms of anaemia.

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 Nespo. The initial weekly dose of

Nespo (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 Nespo (μg/every other week) can be determined by dividing thetotal cumulative dose of r-HuEPO administered over a two-week period by 200. Because ofindividual variability, titration to optimal therapeutic doses is expected for individual patients. Whensubstituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks andthe same route of administration should be used.

Paediatric patients with chronic renal failure

Correction Phase

For patients ≥11 years of age, the initial dose by subcutaneous or intravenous administration is 0.45µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, aninitial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every twoweeks. 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 to increase,the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continuesto increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, atwhich point therapy should be reinitiated 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.

No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 yearsof age.

Maintenance Phase

For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to beadministered as a single injection once weekly or once every two weeks. Dialysis patients convertingfrom once weekly to once every other week dosing with Nespo should initially receive a doseequivalent to twice the previous once weekly dose. In patients not on dialysis, once the targethaemoglobin has been achieved with once every two week dosing, Nespo may be administeredsubcutaneously once monthly using an initial dose equal to twice the previous once every two weekdose.

For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated thatpatients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, andthose receiving r-HuEPO once weekly may be converted to once every other week Nespo. The initialweekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividingthe total weekly dose of r-HuEPO (IU/week) by 240. Because of individual variability, titration tooptimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPOthe haemoglobin should be monitored every one or two weeks and the same route of administrationshould 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 exceeds 12 g/dl(7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, thedose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues toincrease, the dose should be temporarily withheld until the haemoglobin begins to decrease, at whichpoint therapy should be reinitiated at approximately 25% lower than the previous dose.

Patients should be monitored closely to ensure that the lowest approved dose of Nespo is used toprovide adequate control of the symptoms of anaemia.

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

Nespo 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 than 12 g/dl(7.5 mmol/l). Anaemia symptoms and sequelae may vary with age, gender, and overall burden ofdisease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

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 of 10 g/dl(6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl(7.5 mmol/l) should be avoided; guidance for appropriate dose adjustments for when haemoglobinvalues 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 weeklydosing can be given at 2.25 μg/kg body weight. If the clinical response of the patient (fatigue,haemoglobin response) is inadequate after nine weeks, further therapy may not be effective.

Nespo 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 Nespo is used to maintainhaemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500μg, 300 μg, and 150 μg 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 Nespo 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 to 12 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%.

Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients.

Poorly controlled hypertension.

Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. Ifblood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may bereduced by decreasing or withholding the dose of Nespo (see section 4.2).

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 Nespo should prompt a search for causative factors. Deficiencies ofiron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and shouldtherefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss,haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosismay also compromise the erythropoietic response. A reticulocyte count should be considered as part ofthe evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia,an examination of the bone marrow should be considered. If the bone marrow is consistent with

PRCA, testing for anti-erythropoietin antibodies should be performed.

Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported inassociation with recombinant erythropoietic proteins, including darbepoetin alfa. This has beenpredominantly reported in patients with CRF treated subcutaneously. These antibodies have beenshown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to haveneutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8).

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

Nespo should also be used with caution in those patients with sickle cell anaemia or epilepsy.

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

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 events, and vascular access thrombosis was observedwhen erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greaterthan 12 g/dl (7.5 mmol/l).

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.

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

Chronic renal failure patients

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

In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestiveheart failure, the target haemoglobin should be determined individually. In these patients an upperlimit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictateotherwise.

Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation hasbeen reported in a few patients receiving Nespo, though causality has not been established. If anelevated or rising potassium level is observed then consideration should be given to ceasing Nespoadministration 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 Nespo and other erythropoiesis-stimulating agents (ESAs) haveshown:

* shortened time to tumour progression in patients with advanced head and neck cancer receivingradiation therapy when administered to target a haemoglobin 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 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 radiationtherapy.ESAs are not indicated for use in this patient population.

In view of the above, in some clinical situations blood transfusion should be the preferred 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 (see section5.1).

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 Nespo 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 darbepoetin alfa is given concomitantly with any of these drugs, bloodlevels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises.

For Nespo no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetaldevelopment, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women.

As there is no clinical experience with lactating women Nespo should not be administered to womenwho are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.

There have been no observed effects with Nespo on the ability to drive and use machines.

There have been reports of serious allergic reactions including anaphylactic reaction, angioedema,dyspnoea, skin rash and urticaria associated with darbepoetin alfa.

Clinical Trial Experience

Chronic renal failure patients

Data presented from controlled studies included 1357 patients, 766 who received Nespo and 591patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were notreceiving dialysis.

Injection site pain was reported as attributable to treatment in studies where Nespo was administeredvia subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection sitediscomfort was generally mild and transient in nature and occurred predominantly after the firstinjection.

Incidence of undesirable effects considered related to treatment with Nespo from controlled clinicalstudies are:

MedDRA system organ class Subject Incidence Adverse Drug Reaction

Cardiac Disorders Very Common (≥ 1/10) Hypertension

Skin and Subcutaneous Tissue Common (≥ 1/100 to Rash/Erythema

Disorders < 1/10)

Vascular disorders Uncommon (≥ 1/1,000 to Thromboembolic Events< 1/100)

General Disorders and Common (≥ 1/100 to Injection site pain

Administration Site Conditions < 1/10)

Adverse reactions were determined based on pooled data from seven randomised, double-blind,placebo-controlled studies of Nespo with a total of 2112 patients (Nespo 1200, placebo 912). Patientswith 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 undesirable effects considered related to treatment with Nespo from controlled clinicalstudies are:

MedDRA system organ class Subject Incidence Adverse Drug Reaction

Skin and Subcutaneous Tissue Common (≥ 1/100 to Rash/Erythema

Disorders < 1/10)

Vascular disorders Common (≥ 1/100 to Thromboembolic events,< 1/10) including pulmonary embolism

General Disorders and Very Common (≥ 1/10) Oedema

Administration Site Conditions

Common (≥ 1/100 to Injection site pain< 1/10)

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Nespo:

* Pure Red Cell Aplasia. In isolated cases, neutralising anti-erythropoietin antibody mediated purered cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly inpatients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo mustbe discontinued and patients should not be switched to another recombinant erythropoieticprotein (see section 4.4).

* Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria.

* Convulsions.

The therapeutic margin of Nespo is very wide. Even at very high serum levels, no symptoms ofoverdose have been observed.

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

Pharmacotherapeutic group: Anti-anaemic 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.

Cancer patients receiving chemotherapy

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 Nespo 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 randomized to receive

Nespo at 500 μg once every three weeks or 2.25 μg /kg once weekly. In both groups, the dose wasreduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg in the once every threeweeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dlin a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. Inthe once weekly group, 75% of patients required dose reductions. This study supports 500 μg onceevery three weeks being comparable to once weekly administration with respect to the incidence ofsubjects receiving at least one red blood cell transfusion from week 5 to the end of treatment 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.

Erythropoetin 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 2833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. Thetarget haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was12-14 g/dl. In the open-label study there was no difference in overall survival between patients treatedwith recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazardratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies haveshown a consistent unexplained statistically significant excess mortality in patients who have anaemiaassociated with various common cancers who received recombinant human erythropoietin comparedto controls. Overall survival outcome in the trials could not be satisfactorily explained by differencesin the incidence of thrombosis and related complications between those given recombinant humanerythropoietin and those in the control group.

A systematic review has also been performed involving more than 9000 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 8167 patients).

An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06, 35 trials and6769 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 few patientswith these characteristics were included in the data reviewed.

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 (SD0.56) 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 µg/kg, the terminal half-life was 73hours (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 been shownthat renal clearance is minimal (up to 2% of total clearance), and does not affect the serum half-life.

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

Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRFwho were either receiving or not receiving dialysis determined pharmacokinetic profiles for samplingperiods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared withpharmacokinetic data from adults with CRF where the same sampling duration was used, thecomparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adultpatients with CRF. Following intravenous administration, an approximate 25% difference betweenpaediatric and adult patients in the area under the curve from time 0 to infinity (AUC[0-∞]) wasobserved; however, this difference was less than the 2-fold range in AUC(0-∞) observed for thepediatricpatients . AUC(0-∞) was similar between adult and paediatric patients with CRF followingsubcutaneous administration. Half-life was also similar between adult and paediatric patients with

CRF following both intravenous and subcutaneous administration.

Cancer patients receiving chemotherapy

Following subcutaneous administration of 2.25 µg/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 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did notchange 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 µg/kg darbepoetin alfa administered SC every 3weeks in combination with chemotherapy was conducted which allowed for full characterisation of theterminal half-life. In this study, mean (SD) terminal half-life was 74 (SD 27) hours.

In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, redblood cell counts and reticulocytes, which correspond to the expected pharmacological effects.

Adverse events at very high doses were all considered to be related to an exaggerated pharmacologicaleffect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis andsplenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia andno effect on the QT interval were observed.

Nespo did not reveal any genotoxic potential nor did it have any effect on the proliferation of non-haematological cells in vitro or in vivo. In the chronic toxicity studies no tumourigenic or unexpectedmitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin alfahas 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, Nespo should not be mixed or administered as an infusionwith other medicinal products.

2 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, Nespo may be removed from storage once for a maximum singleperiod of seven days at room temperature (up to 25°C). Once a vial has been removed from therefrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days ordisposed of.

Package containing one or four clear glass vial(s) with rubber stopper(s) of 15 µg Nespo solution forinjection in 1 ml (15 µg/ml).

The vials are made from type 1 glass with fluoropolymer coated rubber stoppers.

Not all pack sizes may be marketed.

Nespo is a sterile but unpreserved product. Do not administer more than one dose per vial. Anymedicinal product remaining in the vial should be disposed of.

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

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

Any unused product or waste material should be disposed of in accordance with local requirements.

Dompé Biotec S.p.A.

Via San Martino 12

I-20122 Milan

Italy

EU/1/01/184/023 1 Pack

EU/1/01/184/024 4 pack

Date of first authoristion: 8 June 2001

Date of last renewal: 19 May 2006

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

Agency (EMEA) http://www.emea.europa.eu/