Nespo

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1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 10 micrograms of darbepoetin alfa in 0.4 ml (25 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 10 µg Nespo solution for injection in 0.4 ml 
(25 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/001 1 Pack Blister 
EU/1/01/184/002 4 Pack Blister 
EU/1/01/184/033 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 15 micrograms of darbepoetin alfa in 0.375 ml (40 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 15 µg Nespo solution for injection in 
0.375 ml (40 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/003 1 Pack Blister 
EU/1/01/184/004 4 Pack Blister 
EU/1/01/184/034 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 20 micrograms of darbepoetin alfa in 0.5 ml (40 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 20 µg Nespo solution for injection in 0.5 ml 
(40 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/005 1 Pack Blister 
EU/1/01/184/006 4 Pack Blister 
EU/1/01/184/035 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 30 micrograms of darbepoetin alfa in 0.3 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 30 µg Nespo solution for injection in 0.3 ml 
(100 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/007 1 Pack Blister 
EU/1/01/184/008 4 Pack Blister 
EU/1/01/184/036 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 40 micrograms of darbepoetin alfa in 0.4 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 40 µg Nespo solution for injection in 0.4 ml 
(100 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/009 1 Pack Blister 
EU/1/01/184/010 4 Pack Blister 
EU/1/01/184/037 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 50 micrograms of darbepoetin alfa in 0.5 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 50 µg Nespo solution for injection in 0.5 ml 
(100 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/011 1 Pack Blister 
EU/1/01/184/012 4 Pack Blister 
EU/1/01/184/038 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 60 micrograms of darbepoetin alfa in 0.3 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 60 µg Nespo solution for injection in 0.3 ml 
(200 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/013 1 Pack Blister 
EU/1/01/184/- 014 4 Pack Blister 
EU/1/01/184/039 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 80 micrograms of darbepoetin alfa in 0.4 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 80 µg Nespo solution for injection in 0.4 ml 
(200 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/015 1 Pack Blister 
EU/1/01/184/016 4 Pack Blister 
EU/1/01/184/040 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 100 micrograms of darbepoetin alfa in 0.5 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 100 µg Nespo solution for injection in 0.5 ml 
(200 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/015 1 Pack Blister 
EU/1/01/184/016 4 Pack Blister 
EU/1/01/184/040 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 130 micrograms of darbepoetin alfa in 0.65 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 130 µg Nespo solution for injection in 
0.65 ml (200 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/069 1 Pack Blister 
EU/1/01/184/070 4 Pack Blister 
EU/1/01/184/071 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 150 micrograms of darbepoetin alfa in 0.3 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 150 µg Nespo solution for injection in 0.3 ml 
(500 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/019 1 Pack Blister 
EU/1/01/184/020 4 Pack Blister 
EU/1/01/184/042 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 300 micrograms of darbepoetin alfa in 0.6 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 300 µg Nespo solution for injection in 0.6 ml 
(500 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/021 1 Pack Blister 
EU/1/01/184/022 4 Pack Blister 
EU/1/01/184/043 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 micrograms solution for injection in a pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 500 micrograms of darbepoetin alfa in 1 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled syringe. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo is supplied ready for use in a pre-filled syringe.  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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa  retains a very narrow specificity 
for the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients.  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3 Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a syringe has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled syringe(s) of a 500 µg Nespo solution for injection in 1 ml 
(500 µg/ml). 
 
The syringes may be presented in either blistered (1- & 4-pack) or non-blistered packaging (1-pack 
only).  
 
The syringes are made from type 1 glass with stainless steel 27 gauge needles.  The needle cover of 
the pre-filled syringe contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per syringe. Any 
medicinal product remaining in the pre-filled syringe should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled syringe to reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/031 1 Pack Blister 
EU/1/01/184/032 4 Pack Blister 
EU/1/01/184/044 1 Pack Unblistered 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a vial. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a vial. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 0.45 
µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, an 
initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 
μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 
In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 



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Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 
4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 



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Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 73 
hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a vial has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four clear glass vial(s) with rubber stopper(s) of 15 µg Nespo solution for 
injection 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. 
 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per vial.  Any 
medicinal product remaining in the vial should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the vial to 
reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/023 1 Pack  
EU/1/01/184/024 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 25 micrograms solution for injection in a vial. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 25 micrograms of darbepoetin alfa in 1 ml (25 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a vial. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 0.45 
µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, an 
initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 
μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 
In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 



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Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 
4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 



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Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 73 
hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a vial has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four clear glass vial(s) with rubber stopper(s) of 25 µg Nespo solution for 
injection in 1 ml (25 µg/ml). 
 
The vials are made from type 1 glass with fluoropolymer coated rubber stoppers. 
 
Not all pack sizes may be marketed. 
 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per vial.  Any 
medicinal product remaining in the vial should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the vial to 
reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/025 1 Pack  
EU/1/01/184/026 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a vial. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 40 micrograms of darbepoetin alfa in 1 ml (40 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a vial. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 0.45 
µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, an 
initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 
μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 
In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 



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Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 
4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 



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Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 73 
hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a vial has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four clear glass vial(s) with rubber stopper(s) of 40 µg Nespo solution for 
injection in 1 ml (40 µg/ml). 
 
The vials are made from type 1 glass with fluoropolymer coated rubber stoppers. 
 
Not all pack sizes may be marketed. 
 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per vial.  Any 
medicinal product remaining in the vial should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the vial to 
reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/027 1 Pack 
EU/1/01/184/028 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a vial. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 60 micrograms of darbepoetin alfa in 1 ml (60 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a vial. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 0.45 
µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, an 
initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 
μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 
In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 



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Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 
4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 



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Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 73 
hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 3 
weeks in combination with chemotherapy was conducted which allowed for full characterisation of the 
terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a vial has been removed from the 
refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four clear glass vial(s) with rubber stopper(s) of 60 µg Nespo solution for 
injection in 1 ml (60 µg/ml). 
 
The vials are made from type 1 glass with fluoropolymer coated rubber stoppers. 
 
Not all pack sizes may be marketed. 
 



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6.6 Special precautions for disposal 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per vial.  Any 
medicinal product remaining in the vial should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the vial to 
reach 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/029 1 Pack 
EU/1/01/184/030 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 10 micrograms of darbepoetin alfa in 0.4 ml (25 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 10 µg Nespo solution for injection in 0.4 ml 
(25 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/045 1 pack 
EU/1/01/184/057 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 15 micrograms of darbepoetin alfa in 0.375 ml (40 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 15 µg Nespo solution for injection in 0.375 ml 
(40 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/046 1 pack 
EU/1/01/184/058 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 20 micrograms of darbepoetin alfa in 0.5 ml (40 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 20 µg Nespo solution for injection in 0.5 ml 
(40 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/047 1 pack 
EU/1/01/184/059 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 30 micrograms of darbepoetin alfa in 0.3 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 30 µg Nespo solution for injection in 0.3 ml 
(100 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/048 1 pack 
EU/1/01/184/060 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 40 micrograms of darbepoetin alfa in 0.4 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 40 µg Nespo solution for injection in 0.4 ml 
(100 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
  
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/049 1 pack 
EU/1/01/184/061 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 50 micrograms of darbepoetin alfa in 0.5 ml (100 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 50 µg Nespo solution for injection in 0.5 ml 
(100 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/050 1 pack 
EU/1/01/184/062 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 60 micrograms of darbepoetin alfa in 0.3 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 60 µg Nespo solution for injection in 0.3 ml 
(200 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/051 1 pack 
EU/1/01/184/063 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 80 micrograms of darbepoetin alfa in 0.4 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 80 µg Nespo solution for injection in 0.4 ml 
(200 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/052 1 pack 
EU/1/01/184/064 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 100 micrograms of darbepoetin alfa in 0.5 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 100 µg Nespo solution for injection in 0.5 ml 
(200 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/053 1 pack 
EU/1/01/184/065 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 130 micrograms of darbepoetin alfa in 0.65 ml (200 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 130 µg Nespo solution for injection in 0.65 ml 
(200 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/072 1 pack 
EU/1/01/184/073 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 150 micrograms of darbepoetin alfa in 0.3 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 150 µg Nespo solution for injection in 0.3 ml 
(500 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/054 1 pack 
EU/1/01/184/066 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 300 micrograms of darbepoetin alfa in 0.6 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 300 µg Nespo solution for injection in 0.6 ml 
(500 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/055 1 pack 
EU/1/01/184/067 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 micrograms solution for injection in a pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 500 micrograms of darbepoetin alfa in 1 ml (500 µg/ml). 
 
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). 
 
For excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) in a pre-filled pen. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and 
paediatric patients. 
 
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving 
chemotherapy. 
 
4.2 Posology and method of administration 
 
Nespo treatment should be initiated by physicians experienced in the above mentioned indications. 
 
Nespo (SureClick) is supplied ready for use in a pre-filled pen.  The pre-filled pen is only for 
subcutaneous administration. 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; a 
physician’s evaluation of the individual patient’s clinical course and condition is necessary.  Nespo 
should be administered either subcutaneously or intravenously in order to increase haemoglobin to not 
greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving 
haemodialysis to avoid the puncture of peripheral veins.   
 
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.    A rise in haemoglobin of 
greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate 
dose adjustment should be made as provided.  
 
Treatment with Nespo is divided into two stages – correction and maintenance phase. Guidance is 
given separately for adult and paediatric patients.  Treatment of paediatric patients younger than 1 year 
of age has not been studied: 
 



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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 single 
injection once weekly.  Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be 
administered subcutaneously as a single injection once every two weeks.  If the increase in 
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 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 by 
approximately 25%. If the haemoglobin exceeds 12 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 continues to increase, the dose should be temporarily 
withheld until the haemoglobin begins to decrease, at which 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 the 
haemoglobin can be measured at longer intervals.  
 
Maintenance Phase 
 
In the maintenance phase, Nespo may continue to be administered as a single injection once weekly or 
once every two weeks. Dialysis patients converting from once weekly to once every other week dosing 
with Nespo should initially receive a dose equivalent to twice the previous once weekly dose.  In 
patients not on dialysis, once the target haemoglobin has been achieved with once every two week 
dosing, Nespo may be administered subcutaneously once monthly using an initial dose equal to twice 
the previous once every two week dose.   
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 
increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin at the desired level.  
 
Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times 
weekly may be converted to once weekly or once every other week 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 the 
total cumulative dose of r-HuEPO administered over a two-week period by 200.  Because of 



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individual variability, titration to optimal therapeutic doses is expected for individual patients. When 
substituting Nespo for r-HuEPO the haemoglobin should be monitored every one or two weeks and 
the 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 
0.45 µg/kg body weight, as a single injection once weekly.  Alternatively, in patients not on dialysis, 
an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two 
weeks.  If the increase in 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 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 by 
approximately 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, 
the dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues 
to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at 
which 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 the 
haemoglobin can be measured at longer intervals.  
 
No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years 
of age. 
 
Maintenance Phase 
 
For paediatric patients ≥ 11 years of age, in the maintenance phase, Nespo may continue to be 
administered as a single injection once weekly or once every two weeks. Dialysis patients converting 
from once weekly to once every other week dosing with Nespo should initially receive a dose 
equivalent to twice the previous once weekly dose.  In patients not on dialysis, once the target 
haemoglobin has been achieved with once every two week dosing, Nespo may be administered 
subcutaneously once monthly using an initial dose equal to twice the previous once every two week 
dose.   
 
For pediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that 
patients receiving r-HuEPO two or three times weekly may be converted to once weekly Nespo, and 
those receiving r-HuEPO once weekly may be converted to once every other week Nespo.  The initial 
weekly or once every other week pediatric dose of Nespo (µg/week) can be determined by dividing 
the total weekly dose of r-HuEPO (IU/week) by 240.  Because of individual variability, titration to 
optimal therapeutic doses is expected for individual patients. When substituting Nespo for r-HuEPO 
the haemoglobin should be monitored every one or two weeks and the same route of administration 
should be used. 
 
Dosing should be titrated as necessary to maintain the haemoglobin target.  
 
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that 
the 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 by 
approximately 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, the 
dose should be reduced by approximately 25%.  If after a dose reduction, haemoglobin continues to 



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increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which 
point 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 to 
provide 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 every 
two weeks. 
 
When changing the route of administration the same dose must be used and the haemoglobin 
monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the 
haemoglobin 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. haemoglobin 
concentration ≤ 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 of 
disease; 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 and 
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed 
through 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 haemoglobin 
values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.  
 
The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly 
dosing can be given at 2.25 μg/kg body weight.   If the clinical response of the patient (fatigue, 
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 reduced 
by 25 to 50% in order to ensure that the lowest approved dose of Nespo is used to maintain 
haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 
500 μg, 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 dose 
should be reduced by approximately 25 to 50%.  Treatment with Nespo should be temporarily 
discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at 
approximately 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 reduced 
by 25 to 50%. 
 
4.3 Contraindications 
 
Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients. 
 
Poorly controlled hypertension.  
 



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4.4 Special warnings and precautions for use 
 
General  
 
Blood pressure should be monitored in all patients, particularly during initiation of Nespo therapy. If 
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be 
reduced 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 and 
during treatment and supplementary iron therapy may be necessary. 
 
Non-response to therapy with Nespo should prompt a search for causative factors. Deficiencies of 
iron, folic acid or vitamin B12 reduce the effectiveness of erythropoiesis stimulating agents and should 
therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 
haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis 
may also compromise the erythropoietic response. A reticulocyte count should be considered as part of 
the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, 
an examination of the bone marrow should be considered.  If the bone marrow is consistent with 
PRCA, testing for anti-erythropoietin antibodies should be performed. 
 
Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in 
association with recombinant erythropoietic proteins, including darbepoetin alfa. This has been 
predominantly reported in patients with CRF treated subcutaneously.  These antibodies have been 
shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have 
neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa (see section 4.8). 
 
Active liver disease was an exclusion criteria in all studies of Nespo, therefore no data are available 
from patients with impaired liver function. Since the liver is thought to be the principal route of 
elimination 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. This 
may be associated with life-threatening complications of the cardiovascular system. 
 
The needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions. 
 
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the 
upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an 
increased risk of death, serious cardiovascular events, and vascular access thrombosis was observed 
when erythropoiesis-stimulating agents (ESAs) were administered to target a haemoglobin of greater 
than 12 g/dl (7.5 mmol/l).   
 
Controlled clinical trials have not shown significant benefits attributable to the administration of 
epoetins when haemoglobin concentration is increased beyond the level necessary to control 
symptoms of anaemia and to avoid blood transfusion.  
 
Nespo should be used with caution in patients with epilepsy.  Convulsions have been reported in 
patients receiving Nespo. 
 
Chronic renal failure patients 
 
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l 
or whose transferrin saturation is below 20%.  
 



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In patients with chronic renal failure and clinical evidence of ischaemic heart disease or congestive 
heart failure, the target haemoglobin should be determined individually.  In these patients an upper 
limit of 12 g/dl (7.5 mmol/l) should be aimed for, unless severe symptoms (e.g. angina) dictate 
otherwise. 
 
Serum potassium levels should be monitored regularly during Nespo therapy. Potassium elevation has 
been reported in a few patients receiving Nespo, though causality has not been established. If an 
elevated or rising potassium level is observed then consideration should be given to ceasing Nespo 
administration until the level has been corrected. 
 
Cancer patients 
 
Effect on tumour growth 
 
Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin 
receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, 
there is a concern that epoetins could stimulate the growth of tumours.  In several controlled studies, 
epoetins have not been shown to improve overall survival or decrease the risk of tumour progression 
in patients with anaemia associated with cancer.  
 
In controlled clinical studies, use of Nespo and other erythropoiesis-stimulating agents (ESAs) have 
shown: 
 
• shortened time to tumour progression in patients with advanced head and neck cancer receiving 

radiation therapy when administered to target a haemoglobin of greater than 14 g/dl 
(8.7 mmol/l), ESAs are not indicated for use in this patient population. 

 
• shortened overall survival and increased deaths attributed to disease progression at 4 months in 

patients with metastatic breast cancer receiving chemotherapy when administered to target a 
haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l)  

 
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in 

patients with active malignant disease receiving neither chemotherapy nor radiation 
therapy.ESAs are not indicated for use in this patient population. 

 
In view of the above, in some clinical situations blood transfusion should be the preferred treatment 
for the management of anaemia in patients with cancer.  The decision to administer recombinant 
erythropoietins should be based on a benefit-risk assessment with the participation of the individual 
patient, which should take into account the specific clinical context.  Factors that should be considered 
in this assessment should include the type of tumour and its stage; the degree of anaemia; life-
expectancy; the environment in which the patient is being treated; and patient preference (see section 
5.1). 
 
In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 
12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in 
order to minimise the potential risk of thromboembolic events.  Platelet counts and haemoglobin level 
should also be monitored at regular intervals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, blood 
levels of these drugs should be monitored and the dosage adjusted as the haemoglobin rises. 
 



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4.6 Pregnancy and lactation 
 
For Nespo no clinical data on exposed pregnancies are available. 
 
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, 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 women 
who are breast-feeding. When Nespo therapy is absolutely indicated women must stop breast-feeding.  
 
4.7 Effects on ability to drive and use machines 
 
There have been no observed effects with Nespo on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
General 
 
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 591 
patients who received r-HuEPO. In the Nespo group, 83% were receiving dialysis and 17% were not 
receiving dialysis. 
 
Injection site pain was reported as attributable to treatment in studies where Nespo was administered 
via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site 
discomfort was generally mild and transient in nature and occurred predominantly after the first 
injection.  
 
Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Cardiac Disorders Very Common (≥ 1/10) Hypertension 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

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

Thromboembolic Events 

General Disorders and 
Administration Site Conditions 

Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
Cancer patients 
 
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).  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.  
 



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Incidence of undesirable effects considered related to treatment with Nespo from controlled clinical 
studies are: 
 
MedDRA system organ class Subject Incidence Adverse Drug Reaction 
Skin and Subcutaneous Tissue 
Disorders 

Common (≥ 1/100 to 
< 1/10) 

Rash/Erythema 

Vascular disorders Common (≥ 1/100 to 
< 1/10) 

Thromboembolic events, 
including pulmonary embolism 

General Disorders and 
Administration Site Conditions 

Very Common (≥ 1/10)  Oedema 

 Common (≥ 1/100 to 
< 1/10) 

Injection site pain 

 
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 pure 

red cell aplasia (PRCA) associated with Nespo therapy have been reported predominantly in 
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Nespo must 
be discontinued and patients should not be switched to another recombinant erythropoietic 
protein (see section 4.4). 

 
• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. 
 
• Convulsions. 
 
4.9 Overdose 
 
The therapeutic margin of Nespo is very wide.  Even at very high serum levels, no symptoms of 
overdose have been observed.  
 
In the event of polycythaemia, Nespo should be temporarily withheld (see section 4.2). If clinically 
indicated, phlebotomy may be performed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-anaemic ATC Code: B03XA02. 
 
Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of 
erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor 
cells in the bone marrow. The production of erythropoietin primarily occurs in and is regulated by the 
kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is 
impaired in patients with chronic renal failure and the primary cause of their anaemia is due to 
erythropoietin deficiency. In patients with cancer receiving chemotherapy the etiology of anaemia is 
multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid 
progenitor 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 and 
recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are 
molecularly indistinct from those on the endogenous hormone. Due to its increased carbohydrate 
content darbepoetin alfa has a longer terminal half-life than r-HuEPO and consequently a greater 



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in vivo activity. Despite these molecular changes, darbepoetin alfa retains a very narrow specificity for 
the erythropoietin receptor. 
 
Cancer patients receiving chemotherapy 
 
In a prospective, randomised double-blind, placebo-controlled study conducted in 314 lung cancer 
patients receiving platinum containing chemotherapy there was a significant reduction in transfusion 
requirements (p < 0.001).  
 
Clinical studies have demonstrated that darbepoetin alfa had similar effectiveness when administered 
as a single injection either once every three weeks, once every two weeks, or weekly without any 
increase in total dose requirements.  
 
The safety and effectiveness of once every three weeks dosing of Nespo therapy in reducing the 
requirement for red blood cell transfusions in patients undergoing chemotherapy was assessed in a 
randomised, double-blind, multinational study. This study was conducted in 705 anaemic patients with 
non-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 was 
reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 μg  in the once every three 
weeks group and 1.35 μg /kg in the once weekly group) if haemoglobin increased by more than 1 g/dl 
in a 14-day period. In the once every three weeks group, 72% of patients required dose reductions. In 
the once weekly group, 75% of patients required dose reductions. This study supports 500 μg once 
every three weeks being comparable to once weekly administration with respect to the incidence of 
subjects 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 anaemic 
patients with lymphoproliferative malignancies receiving chemotherapy there was a significant 
reduction 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. Erythropoietin 
receptors 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 total 
of 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.  The 
target haemoglobin concentration in two studies was > 13 g/dl; in the remaining three studies it was 
12-14 g/dl.  In the open-label study there was no difference in overall survival between patients treated 
with recombinant human erythropoietin and controls.  In the four placebo-controlled studies the hazard 
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls.  These studies have 
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia 
associated with various common cancers who received recombinant human erythropoietin compared 
to controls.  Overall survival outcome in the trials could not be satisfactorily explained by differences 
in the incidence of thrombosis and related complications between those given recombinant human 
erythropoietin and those in the control group. 
 
A systematic review has also been performed involving more than 9000 cancer patients participating 
in 57 clinical trials.  Meta-analysis of overall survival data produced a hazard ratio point estimate of 
1.08 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 and 
6769 patients) was observed in patients treated with recombinant human erythropoietin. There is 
therefore consistent evidence to suggest that there may be significant harm to patients with cancer who 
are treated with recombinant human erythropoietin.  The extent to which these outcomes might apply 
to the administration of recombinant human erythropoietin to patients with cancer, treated with 



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chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients 
with these characteristics were included in the data reviewed.  
 
5.2 Pharmacokinetic properties 
 
Due to its increased carbohydrate content the level of darbepoetin alfa in the circulation remains above 
the minimum stimulatory concentration for erythropoiesis for longer than the equivalent molar dose of 
r-HuEPO, allowing darbepoetin alfa to be administered less frequently to achieve the same biological 
response. 
  
Chronic renal failure patients 
 
The pharmacokinetics of darbepoetin alfa has been studied clinically in chronic renal failure patients 
following intravenous and subcutaneous administration. The terminal half-life of darbepoetin alfa is 
21 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 of 
darbepoetin alfa, at subcutaneous doses ranging from 0.6 to 2.1 µg/kg, the terminal half-life was 
73 hours (SD 24).  The longer terminal half-life of darbepoetin alfa administered subcutaneously 
compared to intravenously is due to subcutaneous absorption kinetics.  In clinical studies, minimal 
accumulation was observed with either route of administration. In preclinical studies it has been shown 
that 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 dose 
required to maintain haemoglobin; no difference was observed between the average weekly dose 
administered via the intravenous or subcutaneous routes of injection.  
 
Assessment of the pharmacokinetics of darbepoetin alfa in paediatric patients (3 to 16 years) with CRF 
who were either receiving or not receiving dialysis determined pharmacokinetic profiles for sampling 
periods up to 1 week (168 hours) after a single subcutaneous or intravenous dose. Compared with 
pharmacokinetic data from adults with CRF where the same sampling duration was used, the 
comparison showed that the pharmacokinetics of darbepoetin alfa were similar for paediatric and adult 
patients with CRF.  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 
pediatricpatients .  AUC(0-∞) was similar between adult and paediatric patients with CRF following 
subcutaneous 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 peak 
concentration 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 dose 
range (0.5 to 8 µg/kg weekly and 3 to 9 µg/kg every two weeks). Pharmacokinetic parameters did not 
change on multiple dosing over 12 weeks (dosing every week or every two weeks).  There was an 
expected moderate (< 2 fold) increase in serum concentration as steady state was approached, but no 
unexpected accumulation upon repeated administration.  A pharmacokinetic study in patients with 
chemotherapy-induced anaemia treated with 6.75 µg/kg darbepoetin alfa administered SC every 
3 weeks in combination with chemotherapy was conducted which allowed for full characterisation of 
the terminal half-life.  In this study, mean (SD) terminal half-life was 74 (SD 27) hours. 
 
5.3  Preclinical safety data 
 
In all studies in rats and dogs Nespo produced marked increases in haemoglobin, haematocrits, red 
blood 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 pharmacological 



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effect (decreased tissue perfusion due to increased blood viscosity). These included myelofibrosis and 
splenic hypertrophy as well as broadening of the ECG-QRS complex in dogs but no dysrhythmia and 
no 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 unexpected 
mitogenic responses were observed in any tissue type. The carcinogenic potential of darbepoetin 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 respect 
to pregnancy, embryonal/ foetal development, parturition or postnatal development was observed. 
Placental transfer was minimal. No alteration of fertility was detected.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic 
Sodium phosphate dibasic 
Sodium chloride 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, Nespo should not be mixed or administered as an infusion 
with other medicinal products. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
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 single 
period of seven days at room temperature (up to 25°C).  Once a pre-filled pen has been removed from 
the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or 
disposed of. 
 
6.5 Nature and contents of container 
 
Package containing one or four pre-filled pens of a 500 µg Nespo solution for injection in 1 ml 
(500 µg/ml). 
 
The syringes inside the pen are made from type 1 glass with stainless steel 27 gauge needles.  The 
needle cover of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4. 
 
Not all packs may be marketed. 
 



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6.6 Special precautions for disposal 
 
The carton contains a package leaflet with the full instructions for use and handling. 
 
The Nespo (SureClick) pre-filled pen delivers the complete dose of each presentation. 
 
Nespo is a sterile but unpreserved product. Do not administer more than one dose per pen.  Each pen 
may only be used once. Any medicinal product remaining in the pre-filled pen should be disposed of. 
 
Before administration the Nespo solution should be inspected for visible particles.  Only solutions 
which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-
filled pen to reach room temperature before injecting.  
 
Rotate the injection sites to avoid discomfort at the site of injection. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/184/056  1 pack 
EU/1/01/184/068 4 pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authoristion: 8 June 2001 
 Date of last renewal: 19 May 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/ 
 
 
 



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ANNEX II 
 
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURING AUTHORISATION 
HOLDER RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 



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A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Amgen Manufacturing Limited 
PO Box 4060, Road 31 km 24.6 
Juncos, PR 00777-4060 
Puerto Rico 
 
Name and address of the manufacturer responsible for batch release 
 
Amgen Europe B.V. 
Amgen European Logistics Center (ELC) 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2) 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system 
 
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 presented in 
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and 
whilst the product is on the market. 
 
Risk Management Plan 
 
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in 
the Pharmacovigilance Plan, as agreed in version 1 (20 April 2007) of the Risk Management Plan 
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent 
updates of the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted  
- When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities  



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- Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 
reached  

- At the request of the EMEA  
 
PSURs 
 
Paediatric specific PSUR reporting submissions to regulatory authorities will be made every 6 months 
for the first 2 years following approval of the expanded paediatric indicationfor NESPO in the CKD 
setting. 
 
 



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 10 micrograms darbepoetin alfa (25 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/001 1 pack 
EU/1/01/184/002 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.4 ml 
 



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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 10 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 10 micrograms darbepoetin alfa (25 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 



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12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/033  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 10 µg Injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.375 ml pre-filled syringe contains 15 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/003 1 pack 
EU/1/01/184/004 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.375 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 15 µg  
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.375 
 
6. OTHER 
 
Dompé Biotec S.p.A. 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.375 ml pre-filled syringe contains 15 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 



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12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/034  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 15 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.375 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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377 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 20 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/005 1 pack 
EU/1/01/184/006 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.5 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 20 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 20 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 



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12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/035  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 20 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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382 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 micrograms 
solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains30 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/007 1 pack 
EU/1/01/184/008 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.3 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 30 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains 30 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/036  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 30 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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387 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 40 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/009 1 pack 
EU/1/01/184/010 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.4 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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389 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 40 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 40 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/037  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 40 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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392 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 50 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/011 1 pack 
EU/1/01/184/012 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.5 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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394 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 50 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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395 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 50 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/038  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 50 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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397 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains 60 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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398 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/013 1 pack 
EU/1/01/184/014 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.3 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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399 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 60 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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400 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains 60 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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401 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/039  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 60 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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402 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 80 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/015 1 pack 
EU/1/01/184/016 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.4 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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404 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 80 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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405 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled syringe contains 80 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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406 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/040  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 80 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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407 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 100 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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408 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/017 1 pack 
EU/1/01/184/018 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.5 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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409 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 100 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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410 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled syringe contains 100 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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411 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/041  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 100 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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412 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.65 ml pre-filled syringe contains 130 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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413 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/069 1 pack 
EU/1/01/184/070 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.65 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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414 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 130 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.65 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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415 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.65 ml pre-filled syringe contains 130 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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416 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/071  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 130 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.65 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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417 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains 150 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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418 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/019 1 pack 
EU/1/01/184/020 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.3 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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419 

BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 150 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled syringe contains 150 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/042  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 150 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.6 ml pre-filled syringe contains 300 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/021 1 pack 
EU/1/01/184/022 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
0.6 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 300 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.6 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.6 ml pre-filled syringe contains 300 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/043  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 300 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.6 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
BLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml pre-filled syringe contains 500 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
4 single use pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/031 1 pack 
EU/1/01/184/032 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
PRE-FILLED SYRINGE BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 µg injection 
Darbepoetin alfa 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. OTHER 
 
IV/SC 
1 ml 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 



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BLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 500 µg 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
UNBLISTERED PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 micrograms solution for injection in a pre-filled syringe 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml pre-filled syringe contains 500 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use pre-filled syringe 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/044  
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
UNBLISTERED PRE-FILLED SYRINGE LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 500 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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432 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a vial 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml vial 15 micrograms darbepoetin alfa. 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use vial 
4 single use vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/023 1 pack 
EU/1/01/184/024 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 15 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 



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434 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 25 micrograms solution for injection in a vial 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml vial 25 micrograms darbepoetin alfa. 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use vial 
4 single use vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/025 1 pack 
EU/1/01/184/026 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 25 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 



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436 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a vial 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml vial 40 micrograms darbepoetin alfa. 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use vial 
4 single use vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/027 1 pack 
EU/1/01/184/028 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 40 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 



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438 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a vial 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml vial 60 micrograms darbepoetin alfa. 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 single use vial 
4 single use vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/029 1 pack 
EU/1/01/184/030 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 60 µg injection 
Darbepoetin alfa 
IV/SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A. 



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440 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 10 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled pen contains 10 micrograms darbepoetin alfa (25 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen  
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/045 1 pack 
EU/1/01/184/057 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 10 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 15 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.375 ml pre-filled pen contains 15 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/046 1 pack 
EU/1/01/184/058 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 15 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.375 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 20 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled pen contains 20 micrograms darbepoetin alfa (40 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/047 1 pack 
EU/1/01/184/059 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 20 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 30 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled pen contains 30 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/048 1 pack 
EU/1/01/184/060 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 30 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 40 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled pen contains 40 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/049 1 pack 
EU/1/01/184/061 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 40 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 50 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled pen contains 50 micrograms darbepoetin alfa (100 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/050 1 pack 
EU/1/01/184/062 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 50 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 60 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled pen contains 60 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/051 1 pack 
EU/1/01/184/063 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 60 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 80 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.4 ml pre-filled pen contains 80 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/052 1 pack 
EU/1/01/184/064 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 80 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 100 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.5 ml pre-filled pen contains 100 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/053 1 pack 
EU/1/01/184/065 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 100 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 130 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.65 ml pre-filled pen contains 130 micrograms darbepoetin alfa (200 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/072 1 pack 
EU/1/01/184/073 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 130 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.65 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 150 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.3 ml pre-filled pen contains 150 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/054 1 pack 
EU/1/01/184/066 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 150 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.3 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 300 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.6 ml pre-filled pen contains 300 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/055 1 pack 
EU/1/01/184/067 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 300 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.6 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nespo 500 micrograms solution for injection in a pre-filled pen 
Darbepoetin alfa 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml pre-filled pen contains 500 micrograms darbepoetin alfa (500 micrograms/ml). 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, 
water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
SureClick x1 
1 single use pre-filled pen 
This box containing 1 pre-filled pen, is part of a 4-multipack 
SureClick x4 
4 single use pre-filled pens 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/184/056 1 pack 
EU/1/01/184/068 4 pack 
 
13. BATCH NUMBER 
 
Lot: 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
PRE-FILLED PEN LABEL  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nespo 500 µg injection 
Darbepoetin alfa 
SC 
 
2. METHOD OF ADMINISTRATION 
 
3. EXPIRY DATE 
 
EXP.: 
 
4. BATCH NUMBER 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
6. OTHER 
 
Dompé Biotec S.p.A.  



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B.  PACKAGE LEAFLET 
 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Nespo 10 micrograms solution for injection in a pre-filled syringe 
Nespo 15 micrograms solution for injection in a pre-filled syringe 
Nespo 20 micrograms solution for injection in a pre-filled syringe 
Nespo 30 micrograms solution for injection in a pre-filled syringe 
Nespo 40 micrograms solution for injection in a pre-filled syringe 
Nespo 50 micrograms solution for injection in a pre-filled syringe 
Nespo 60 micrograms solution for injection in a pre-filled syringe 
Nespo 80 micrograms solution for injection in a pre-filled syringe 

Nespo 100 micrograms solution for injection in a pre-filled syringe 
Nespo 130 micrograms solution for injection in a pre-filled syringe 
Nespo 150 micrograms solution for injection in a pre-filled syringe 
Nespo 300 micrograms solution for injection in a pre-filled syringe 
Nespo 500 micrograms solution for injection in a pre-filled syringe 

darbepoetin alfa 
 
Please read this leaflet carefully before you start using this medicine. 
 
Keep this leaflet. You may need to read it again. 
 
If you have any further questions, ask your doctor, nurse or pharmacist. 
 
This medicine has been prescribed for you.   Do not pass it on to others. It may harm them, even if 
their symptoms are the same as yours. 
 
If  any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor, nurse or pharmacist. 
 
In this leaflet 
 
1. What Nespo is and what is it used for 
2. Before you use Nespo 
3. How to use Nespo 
4. Possible side effects 
5. How to store Nespo 
6. Further information  
7. Instructions for injecting with the Nespo pre-filled syringe 
 
 
1. WHAT NESPO IS AND WHAT IS IT USED FOR 
 
Your doctor has given you Nespo (an anti-anaemic) to treat your anaemia. Anaemia is when your 
blood does not contain enough red blood cells and the symptoms may be fatigue, weakness and 
shortness of breath.  
 
Nespo works in exactly the same way as the natural hormone erythropoietin. Erythropoietin is 
produced in your kidneys and encourages your bone marrow to produce more red blood cells. The 
active substance of Nespo is darbepoetin alfa produced by gene-technology in Chinese Hamster Ovary 
Cells (CHO-K1).  
 
If you have chronic renal failure  
 
Nespo is used to treat symptomatic anaemia that is associated with chronic renal failure (kidney 
failure) in adults and children.  In kidney failure, the kidney does not produce enough of the natural 
hormone erythropoietin which can often cause anaemia.  



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Because it will take your body some time to make more red blood cells, it will be about four weeks 
before you notice any effect. Your normal dialysis routine will not affect the ability of Nespo to treat 
your anaemia. 
 
If you are receiving chemotherapy 
 
Nespo is used to treat symptomatic anaemia in adult cancer patients with non-bone marrow cancers 
(non-myeloid malignancies) who are receiving chemotherapy. 
 
One of the main side effects of chemotherapy is that it stops the bone marrow producing enough blood 
cells. At first, only white blood cells seem to be affected. This is because the red blood cells have a 
much longer life span in the circulating blood. Towards the end of your chemotherapy course, 
particularly if you have had a lot of chemotherapy, your red blood cell count may fall making you 
anaemic. 
 
 
2. BEFORE YOU USE NESPO 
 
DO NOT use Nespo: 
 
• if you have been diagnosed with high blood pressure which is not being controlled with other 

medicines prescribed by your doctor; or 
 
• if you are allergic to Nespo (darbepoetin alfa), r-HuEPO or to any of the other ingredients in 

Nespo. 
 
Take special care with Nespo  
 
Please tell your doctor if you are suffering or have suffered from: 
 
• high blood pressure which is being controlled with medicines prescribed by your doctor; 
 
• sickle cell anaemia; 
 
• epileptic fits (seizures);  
 
• convulsions (fits or seizures);  
 
• liver disease; 
 
• significant lack of response to drugs used to treat anaemia; or 
 
• an allergy to latex (the needle cover on the pre-filled syinge contains a derivative of latex). 
 
Special warnings 
 
• If you have symptoms which include unusual tiredness and a lack of energy this could mean 

you have pure red cell aplasia (PRCA), which has been reported in patients. PRCA means that 
the body has stopped or reduced the production of red blood cells which causes severe anaemia. 
If you experience these symptoms you should contact your doctor who will determine the best 
course of action to treat your anaemia.   

 
• Your doctor should try to keep your haemoglobin between 10 and 12 g/dl.   
 



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• If you have chronic renal failure there is an increased risk of serious problems with your heart or 
blood vessels (cardiovascular events) if your haemoglobin is kept too high. 

 
• If you are a cancer patient you should be aware that Nespo may act as a blood cell growth factor 

and in some circumstances may have a negative impact on your cancer.  Depending on your 
individual situation a blood transfusion may be preferable.  Please discuss this with your doctor. 

 
• Misuse by healthy people can cause life-threatening problems with the heart or blood vessels. 
 
Using other medicines 
 
Cyclosporin and tacrolimus may be affected by the number of red cells in your blood.  It is important 
to tell your doctor if you are taking either of these drugs. 
 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription.   
 
Using Nespo with food and drink 
 
Food and drink do not affect Nespo. 
 
Pregnancy and breast-feeding 
 
Nespo has not been tested in pregnant women.  It is important to tell your doctor if you: 
 
• are pregnant;  
 
• think you may be pregnant; or 
 
• plan to get pregnant.  
 
It is not known whether darbepoetin alfa is excreted in human milk. You must stop breast-feeding if 
you use Nespo. 
 
Driving and using machines 
 
Nespo should not affect your ability to drive or use machinery. 
 
 
3. HOW TO USE NESPO  
 
Following blood tests, your doctor has decided you need Nespo as your haemoglobin level is 10 g/dl 
or less. Your doctor will tell you how much and how often you must take Nespoin order to maintain a 
haemoglobin level between 10 and 12 g/dl.  This may vary depending on whether you are an adult or a 
child.   
 
Injecting Nespo yourself 
 
Your doctor may decide that it is best for you or a carer to inject Nespo.  Your doctor, nurse or 
pharmacist will show you how to inject yourself with the pre-filled syringe.  Do not try to inject 
yourself if you have not been trained.  Never inject Nespo into a vein yourself.   
 
If you have chronic renal failure 
 
Nespo is given as a single injection, either once a week, once every two weeks, or once every month 
either under your skin (subcutaneous) or into a vein (intravenous). 



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In order to correct your anaemia, your initial dose of Nespo per kilogram of your body weight will be 
either: 
• 0.75 micrograms once every two weeks, or 
• 0.45 micrograms once weekly  
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose once every four weeks as necessary. 
 
Once your anaemia is corrected, your doctor will continue to regularly check your blood and your 
dose may be adjusted further in order to maintain long-term control of your anaemia. Your doctor will 
inform you if your dose changes. 
 
Your blood pressure will also be checked regularly, particularly at the beginning of your treatment. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
Your doctor may decide to change the way that your injection is given (either under the skin or into a 
vein).  If this changes you will start on the same dose as you have been receiving and your doctor will 
take blood samples to make sure that your anaemia is still being managed correctly. 
 
If your doctor has decided to change your treatment from r-HuEPO (erythropoietin produced by gene-
technology) to Nespo, they will choose whether you should receive your Nespo injection once weekly 
or once every two weeks.  The route of injection is the same as with r-HuEPO but your doctor will tell 
you how much you should take, and when, and may adjust your dose if necessary. 
 
If you are receiving chemotherapy 
 
Nespo is given as a single injection, either once a week or once every three weeks, under your skin.  
 
In order to correct your anaemia, your initial dose will be 
• 500 micrograms once every three weeks (6.75 micrograms of Nespo per kilogram of your body 

weight), or 
• 2.25 micrograms (once weekly) of Nespo per kilogram of your body weight. 
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose as necessary.  Your treatment will continue until approximately four weeks after the 
end of your chemotherapy.  Your doctor will tell you exactly when to stop taking Nespo. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
If you use more Nespo than you should 
 
You should have no serious problems if you take more Nespo than you need. However, you should 
contact your doctor, nurse or pharmacist if this does happen.  If you feel unwell in any way you should 
contact your doctor, nurse or pharmacist immediately. 
 
If you forget to inject Nespo 
 
If you have forgotten a dose of Nespo, you should contact your doctor to discuss when you should 
inject the next dose. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Nespo may cause side effects, although not everybody gets them. 
 
The following side effects have been experienced by some patients taking Nespo: 
 



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Very Common (seen in more than 10 in 100 people) 
 
• High blood pressure (hypertension) 
• Fluid retention (oedema) 
 
Common (seen in more than 1 in 100 people) 
 
• Blood clots (thrombosis) 
• Pain around the area injected  
• Rash and/or redness of the skin 
 
Rare (seen in more than 1 in 10,000 people) 
 
Serious allergic reactions which may include: 
• Sudden life-threatening allergic reactions (anaphylaxis) 
• Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or 

breathing (angioedema) 
• Shortness of breath (dyspnoea) 
• Skin rash 
• Hives (urticaria) 
 
Very rare (seen in less than 1 in 10,000 people) 
 
• Pure red cell aplasia (PRCA) – (anaemia, unusual tiredness, lack of energy) 
 
Convulsions (fits and seizures) have been reported in patients treated with Nespo. 
 
If you have any of these symptoms or you notice any side effects that are not mentioned in this leaflet, 
please tell your doctor, nurse or pharmacist. 
 
 
5. HOW TO STORE NESPO 
 
Keep out of the reach and sight of children.  Keep in the original package in order to protect from 
light. 
 
Store in a refrigerator (2°C – 8°C).  Do not freeze.  Do not use Nespo if you think it has been frozen. 
 
When your syringe has been removed from the refrigerator and left at room temperature for 
approximately 30 minutes before injection it must either be used within 7 days or disposed of. 
 
Do not use Nespo after the expiry date which is stated on the carton and on the pre-filled pen label 
after EXP.  The expiry date refers to the last day of that month. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required.  These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION  
 
What Nespo contains 
 
Nespo comes in a pre-filled syringe that contains either 10, 15, 20, 30, 40, 50, 60, 80, 100, 130, 150, 
300 or 500 micrograms of the active substance darbepoetin alfa.  
 



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Nespo also contains sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, 
polysorbate 80 and water for injections. 
 
What Nespo looks like and contents of the pack 
 
Nespo is a clear, colourless or slightly pearly liquid.  If it is cloudy or there are particles in it, you must 
not use it. 
 
Nespo is available in packs of 1 or 4 pre-filled syringes (not all pack sizes may be marketed).  The 
syringes are provided either with (1-& 4-pack) or without (1-pack) a blister-wrapping. 
 
Marketing Authorisation Holder: 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
Manufacturer: 
Amgen Europe B.V. 
Minervum 7061  
NL-4817 ZK Breda 
The Netherlands 
 
Further information 
 
If you want more information about this medicine, please contact the local representative of the 
company that is authorised to market Nespo. 
 
This leaflet was last approved in . 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 
 
7. INSTRUCTIONS FOR INJECTING WITH THE NESPO PRE-FILLED SYRINGE  
 
This section contains information on how to give yourself an injection of Nespo.  It is important that 
you do not try to give yourself the injection unless you have received training from your doctor, nurse 
or pharmacist.  If you have questions about how to inject, please ask your doctor, nurse or pharmacist 
for assistance. 
 
How do you or the person injecting you, use the Nespo pre-filled syringe? 
 
Your doctor has prescribed an Nespo pre-filled syringe for injection into the tissue just under the skin.  
Your doctor, nurse, or pharmacist will tell you how much Nespo you need and how frequently it 
should be injected.  
 
Equipment: 
 
To give yourself an injection you will need: 
 
• a new Nespo pre-filled syringe; and 
 
• alcohol wipes or similar. 
 
What should I do before I give myself a subcutaneous injection of Nespo? 



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1. Remove the pre-filled syringe from the refrigerator. Leave the pre-filled syringe at room 

temperature for approximately 30 minutes.  This will make the injection more comfortable.  Do 
not warm Nespo in any other way (for example, do not warm it in a microwave or in hot water).  
Additionally, do not leave the syringe exposed to direct sunlight. 

 
2. Do not shake the pre-filled syringe. 
 
3. Do not remove the cover from the syringe until you are ready to inject. 
 
4. Check that it is the correct dose that your doctor has prescribed. 
 
5. Check the expiry date on the pre-filled syringe label (EXP:).  Do not use it if the date has passed 

the last day of the month shown. 
 
6. Check the appearance of Nespo.  It must be a clear, colourless or slightly pearly liquid.  If it is 

cloudy or there are particles in it, you must not use it. 
 
7. Wash your hands thoroughly. 
 
8. Find a comfortable, well-lit, clean surface and put all the equipment you need within reach.  
 
How do I prepare my Nespo injection? 
 
Before you inject Nespo you must do the following: 
 
1. To avoid bending the needle, gently pull the cover from the needle 

without twisting as shown in pictures 1 and 2.   
2. Do not touch the needle or push the plunger. 
3. You may notice a small air bubble in the pre-filled syringe. You do 

not have to remove the air bubble before injecting. Injecting the 
solution with the air bubble is harmless. 

4. You can now use the pre-filled syringe. 
 
Where should I give my injection? 

 
The best places to inject yourself arethe top of your thighs andthe abdomen. If 
someone else is injecting for you, they can also use the back of your arms. 
 
You may change the injection site if you notice the area is red or sore.  
 
How do I give my injection? 
 

1. Disinfect your skin by using an alcohol wipe and pinch (without squeezing) the skin between 
your thumb and forefinger. 

 
2. Put the needle fully into the skin as shown by your nurse or doctor. 
 
3. Pull slightly on the plunger to check that a blood vessel has not been punctured.  If you see 

blood in the syringe, pull the needle out and re-insert it in another place. 
 
4. Push the plunger with a slow constant pressure, always keeping your skin pinched, until the 

syringe is empty. 
 
5. Remove the needle and let go of your skin. 
 



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6. If you notice a spot of blood you may gently dab it away with a cotton ball or tissue.  Do not rub 
the injection site.  If needed, you may cover the injection site with a plaster. 

 
7. Only use each syringe for one injection.  Do not use any Nespo that is left in the syringe. 
 
Remember:  If you have any problems, please do not be afraid to ask your doctor or nurse for help 
and advice. 
 
Disposing of used syringes 
 
• Do not put the cover back on used needles, as you may accidentally prick yourself. 
• Keep used syringes out of the reach and sight of children. 
• The used pre-filled syringe should be disposed of in accordance with local requirements. Ask 

your pharmacist how to dispose of medicines no longer required. These measures will help to 
protect the environment.  



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Nespo 15 micrograms solution for injection in a vial 
Nespo 25 micrograms solution for injection in a vial 
Nespo 40 micrograms solution for injection in a vial 
Nespo 60 micrograms solution for injection in a vial 

darbepoetin alfa 
 
Please read this leaflet carefully before you start using this medicine. 
 
Keep this leaflet. You may need to read it again. 
 
If you have any further questions, ask your doctor, nurse or pharmacist. 
 
This medicine has been prescribed for you.   Do not pass it on to others. It may harm them, even if 
their symptoms are the same as yours. 
 
If  any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor, nurse or pharmacist. 
 
In this leaflet 
 
1. What Nespo is and what is it used for 
2. Before you use Nespo 
3. How to use Nespo 
4. Possible side effects 
5. How to store Nespo 
6. Further information  
 
 
1. WHAT NESPO IS AND WHAT IS IT USED FOR 
 
Your doctor has given you Nespo (an anti-anaemic) to treat your anaemia. Anaemia is when your 
blood does not contain enough red blood cells and the symptoms may be fatigue, weakness and 
shortness of breath.  
 
Nespo works in exactly the same way as the natural hormone erythropoietin. Erythropoietin is 
produced in your kidneys and encourages your bone marrow to produce more red blood cells. The 
active substance of Nespo is darbepoetin alfa produced by gene-technology in Chinese Hamster Ovary 
Cells (CHO-K1).  
 
If you have chronic renal failure  
 
Nespo is used to treat symptomatic anaemia that is associated with chronic renal failure (kidney 
failure) in adults and children.  In kidney failure, the kidney does not produce enough of the natural 
hormone erythropoietin which can often cause anaemia.  
 
Because it will take your body some time to make more red blood cells, it will be about four weeks 
before you notice any effect. Your normal dialysis routine will not affect the ability of Nespo to treat 
your anaemia. 
 
If you are receiving chemotherapy 
 
Nespo is used to treat symptomatic anaemia in adult cancer patients with non-bone marrow cancers 
(non-myeloid malignancies) who are receiving chemotherapy. 
 



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One of the main side effects of chemotherapy is that it stops the bone marrow producing enough blood 
cells. At first, only white blood cells seem to be affected. This is because the red blood cells have a 
much longer life span in the circulating blood. Towards the end of your chemotherapy course, 
particularly if you have had a lot of chemotherapy, your red blood cell count may fall making you 
anaemic. 
 
 
2. BEFORE YOU USE NESPO 
 
DO NOT use Nespo: 
 
• if you have been diagnosed with high blood pressure which is not being controlled with other 

medicines prescribed by your doctor; or 
 
• if you are allergic to Nespo (darbepoetin alfa), r-HuEPO or to any of the other ingredients in 

Nespo. 
 
Take special care with Nespo  
 
Please tell your doctor if you are suffering or have suffered from: 
 
• high blood pressure which is being controlled with medicines prescribed by your doctor; 
 
• sickle cell anaemia; 
 
• epileptic fits (seizures);  
 
• convulsions (fits or seizures);  
 
• liver disease; 
 
• significant lack of response to drugs used to treat anaemia; or 
 
Special warnings 
 
• If you have symptoms which include unusual tiredness and a lack of energy this could mean 

you have pure red cell aplasia (PRCA), which has been reported in patients. PRCA means that 
the body has stopped or reduced the production of red blood cells which causes severe anaemia. 
If you experience these symptoms you should contact your doctor who will determine the best 
course of action to treat your anaemia.   

 
• Your doctor should try to keep your haemoglobin between 10 and 12 g/dl.   
 
• If you have chronic renal failure there is an increased risk of serious problems with your heart or 

blood vessels (cardiovascular events) if your haemoglobin is kept too high. 
 
• If you are a cancer patient you should be aware that Nespo may act as a blood cell growth factor 

and in some circumstances may have a negative impact on your cancer.  Depending on your 
individual situation a blood transfusion may be preferable.  Please discuss this with your doctor. 

 
• Misuse by healthy people can cause life-threatening problems with the heart or blood vessels. 
 
Using other medicines 
 
Cyclosporin and tacrolimus may be affected by the number of red cells in your blood.  It is important 
to tell your doctor if you are taking either of these drugs. 



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Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription.   
 
Using Nespo with food and drink 
 
Food and drink do not affect Nespo. 
 
Pregnancy and breast-feeding 
 
Nespo has not been tested in pregnant women.  It is important to tell your doctor if you: 
 
• are pregnant;  
 
• think you may be pregnant; or 
 
• plan to get pregnant.  
 
It is not known whether darbepoetin alfa is excreted in human milk. You must stop breast-feeding if 
you use Nespo. 
 
Driving and using machines 
 
Nespo should not affect your ability to drive or use machinery. 
 
 
3. HOW TO USE NESPO  
 
Following blood tests, your doctor has decided you need Nespo as your haemoglobin level is 10 g/dl 
or less. Your doctor will tell you how much and how often you must take Nespoin order to maintain a 
haemoglobin level between 10 and 12 g/dl.  This may vary depending on whether you are an adult or a 
child.   
 
If you have chronic renal failure 
 
Nespo is given as a single injection, either once a week, once every two weeks, or once every month 
either under your skin (subcutaneous) or into a vein (intravenous). 
 
In order to correct your anaemia, your initial dose of Nespo per kilogram of your body weight will be 
either: 
• 0.75 micrograms once every two weeks, or 
• 0.45 micrograms once weekly  
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose once every four weeks as necessary. 
 
Once your anaemia is corrected, your doctor will continue to regularly check your blood and your 
dose may be adjusted further in order to maintain long-term control of your anaemia. Your doctor will 
inform you if your dose changes. 
 
Your blood pressure will also be checked regularly, particularly at the beginning of your treatment. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
Your doctor may decide to change the way that your injection is given (either under the skin or into a 
vein).  If this changes you will start on the same dose as you have been receiving and your doctor will 
take blood samples to make sure that your anaemia is still being managed correctly. 



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If your doctor has decided to change your treatment from r-HuEPO (erythropoietin produced by gene-
technology) to Nespo, they will choose whether you should receive your Nespo injection once weekly 
or once every two weeks.  The route of injection is the same as with r-HuEPO but your doctor will tell 
you how much you should take, and when, and may adjust your dose if necessary. 
 
If you are receiving chemotherapy 
 
Nespo is given as a single injection, either once a week or once every three weeks, under your skin.  
 
In order to correct your anaemia, your initial dose will be 
• 500 micrograms once every three weeks (6.75 micrograms of Nespo per kilogram of your body 

weight), or 
• 2.25 micrograms (once weekly) of Nespo per kilogram of your body weight. 
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose as necessary.  Your treatment will continue until approximately four weeks after the 
end of your chemotherapy.  Your doctor will tell you exactly when to stop taking Nespo. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
If you use more Nespo than you should 
 
You should have no serious problems if you take more Nespo than you need. However, you should 
contact your doctor, nurse or pharmacist if this does happen.  If you feel unwell in any way you should 
contact your doctor, nurse or pharmacist immediately. 
 
If you forget to inject Nespo 
 
If you have forgotten a dose of Nespo, you should contact your doctor to discuss when you should 
inject the next dose. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Nespo may cause side effects, although not everybody gets them. 
 
The following side effects have been experienced by some patients taking Nespo: 
 
Very Common (seen in more than 10 in 100 people) 
 
• High blood pressure (hypertension) 
• Fluid retention (oedema) 
 
Common (seen in more than 1 in 100 people) 
 
• Blood clots (thrombosis) 
• Pain around the area injected  
• Rash and/or redness of the skin 
 
Rare (seen in more than 1 in 10,000 people) 
 
Serious allergic reactions which may include: 
• Sudden life-threatening allergic reactions (anaphylaxis) 
• Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or 

breathing (angioedema) 
• Shortness of breath (dyspnoea) 



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• Skin rash 
• Hives (urticaria) 
 
Very rare (seen in less than 1 in 10,000 people) 
 
• Pure red cell aplasia (PRCA) – (anaemia, unusual tiredness, lack of energy) 
 
Convulsions (fits and seizures) have been reported in patients treated with Nespo. 
 
If you have any of these symptoms or you notice any side effects that are not mentioned in this leaflet, 
please tell your doctor, nurse or pharmacist. 
 
 
5. HOW TO STORE NESPO 
 
Keep out of the reach and sight of children.  Keep in the original package in order to protect from 
light. 
 
Store in a refrigerator (2°C – 8°C).  Do not freeze.  Do not use Nespo if you think it has been frozen. 
 
When your vial has been removed from the refrigerator and left at room temperature for approximately 
30 minutes before injection it must either be used within 7 days or disposed of. 
 
Do not use Nespo after the expiry date which is stated on the carton and on the pre-filled pen label 
after EXP.  The expiry date refers to the last day of that month. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required.  These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION  
 
What Nespo contains 
 
Nespo comes in a vial that contains either 15, 25, 40 or 60 micrograms of the active substance 
darbepoetin alfa.  
 
Nespo also contains sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, 
polysorbate 80 and water for injections. 
 
What Nespo looks like and contents of the pack 
 
Nespo is a clear, colourless or slightly pearly liquid.  If it is cloudy or there are particles in it, you must 
not use it. 
 
Nespo is available in packs of 1 or 4 vials (not all pack sizes may be marketed). 
 
Marketing Authorisation Holder: 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
Manufacturer: 
Amgen Europe B.V. 
Minervum 7061  



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NL-4817 ZK Breda 
The Netherlands 
 
Further information 
 
If you want more information about this medicine, please contact the local representative of the 
company that is authorised to market Nespo. 
 
This leaflet was last approved in . 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Nespo 10 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 15 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 20 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 30 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 40 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 50 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 60 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 80 micrograms solution for injection in a pre-filled pen (SureClick) 

Nespo 100 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 130 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 150 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 300 micrograms solution for injection in a pre-filled pen (SureClick) 
Nespo 500 micrograms solution for injection in a pre-filled pen (SureClick) 

darbepoetin alfa 
 
Please read this leaflet carefully before you start using this medicine. 
 
Keep this leaflet. You may need to read it again. 
 
If you have any further questions, ask your doctor, nurse or pharmacist. 
 
This medicine has been prescribed for you.  Do not pass it on to others. It may harm them, even if their 
symptoms are the same as yours. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor, nurse or pharmacist. 
 
In this leaflet 
 
1. What Nespo is and what is it used for 
2. Before you use Nespo 
3. How to use Nespo 
4. Possible side effects 
5. How to store Nespo 
6. Further information 
7. Instructions for injecting with the Nespo pre-filled pen  
 
 
1. WHAT NESPO IS AND WHAT IS IT USED FOR 
 
Your doctor has given you Nespo (an anti-anaemic) to treat your anaemia. Anaemia is when your 
blood does not contain enough red blood cells and the symptoms may be fatigue, weakness and 
shortness of breath.  
 
Nespo works in exactly the same way as the natural hormone erythropoietin. Erythropoietin is 
produced in your kidneys and encourages your bone marrow to produce more red blood cells. The 
active substance of Nespo is darbepoetin alfa produced by gene-technology in Chinese Hamster Ovary 
Cells (CHO-K1).  
 
If you have chronic renal failure  
 
Nespo is used to treat symptomatic anaemia that is associated with chronic renal failure (kidney 
failure) in adults and children.  In kidney failure, the kidney does not produce enough of the natural 
hormone erythropoietin which can often cause anaemia.  



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Because it will take your body some time to make more red blood cells, it will be about four weeks 
before you notice any effect. Your normal dialysis routine will not affect the ability of Nespo to treat 
your anaemia. 
 
If you are receiving chemotherapy 
 
Nespo is used to treat symptomatic anaemia in adult cancer patients with non-bone marrow cancers 
(non-myeloid malignancies) who are receiving chemotherapy. 
 
One of the main side effects of chemotherapy is that it stops the bone marrow producing enough blood 
cells. At first, only white blood cells seem to be affected. This is because the red blood cells have a 
much longer life span in the circulating blood. Towards the end of your chemotherapy course, 
particularly if you have had a lot of chemotherapy, your red blood cell count may fall making you 
anaemic. 
 
 
2. BEFORE YOU USE NESPO 
 
DO NOT use Nespo: 
 
• if you have been diagnosed with high blood pressure which is not being controlled with other 

medicines prescribed by your doctor; or 
 
• if you are allergic to Nespo (darbepoetin alfa), r-HuEPO or to any of the other ingredients in 

Nespo. 
 
Take special care with Nespo  
 
Please tell your doctor if you are suffering or have suffered from: 
 
• high blood pressure which is being controlled with medicines prescribed by your doctor; 
 
• sickle cell anaemia; 
 
• epileptic fits (seizures);  
 
• convulsions (fits or seizures);  
 
• liver disease; 
 
• significant lack of response to drugs used to treat anaemia; or 
 
• an allergy to latex (the needle cover on the pre-filled pen contains a derivative of latex). 
 
Special warnings 
 
• If you have symptoms which include unusual tiredness and a lack of energy this could mean 

you have pure red cell aplasia (PRCA), which has been reported in patients. PRCA means that 
the body has stopped or reduced the production of red blood cells which causes severe anaemia. 
If you experience these symptoms you should contact your doctor who will determine the best 
course of action to treat your anaemia.   

 
• Your doctor should try to keep your haemoglobin between 10 and 12 g/dl.   
 



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• If you have chronic renal failure there is an increased risk of serious problems with your heart or 
blood vessels (cardiovascular events) if your haemoglobin is kept too high. 

 
• If you are a cancer patient you should be aware that Nespo may act as a blood cell growth factor 

and in some circumstances may have a negative impact on your cancer.  Depending on your 
individual situation a blood transfusion may be preferable.  Please discuss this with your doctor. 

 
• Misuse by healthy people can cause life-threatening problems with the heart or blood vessels. 
 
Using other medicines 
 
Cyclosporin and tacrolimus may be affected by the number of red cells in your blood.  It is important 
to tell your doctor if you are taking either of these drugs. 
 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription.   
 
Using Nespo with food and drink 
 
Food and drink do not affect Nespo. 
 
Pregnancy and breast-feeding 
 
Nespo has not been tested in pregnant women.  It is important to tell your doctor if you: 
 
• are pregnant;  
 
• think you may be pregnant; or 
 
• plan to get pregnant.  
 
It is not known whether darbepoetin alfa is excreted in human milk. You must stop breast-feeding if 
you use Nespo. 
 
Driving and using machines 
 
Nespo should not affect your ability to drive or use machinery. 
 
 
3. HOW TO USE THE NESPO PRE-FILLED PEN (SURECLICK) 
 
Following blood tests, your doctor has decided you need Nespo as your haemoglobin level is 10 g/dl 
or less. Your injection is to be given under the skin (subcutaneous), and so you may use the Nespo 
pre-filled pen. Your doctor will tell you how much and how often you must take Nespoin order to 
maintain a haemoglobin level between 10 and 12 g/dl.  This may vary depending on whether you are 
an adult or a child.  
 
Injecting Nespo yourself 
 
Your doctor has decided that the Nespo pre-filled pen is the best way for you, a nurse, or a carer to 
inject Nespo.  Your doctor, nurse or pharmacist will show you how to inject yourself with the pre-
filled pen.  Do not try to inject yourself if you have not been trained.  Never inject Nespo into a vein 
yourself.  The pre-filled pen is designed to inject the area under your skin only. 
 
For instructions on use of the pre-filled pen, please read the section at the end of this leaflet. 
 



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If you have chronic renal failure 
 
The Nespo pre-filled pen is given as a single injection, either once a week, once every two weeks, or 
once every month. 
 
In order to correct your anaemia, your initial dose of Nespo per kilogram of your body weight will be 
either: 
• 0.75 micrograms once every two weeks, or 
• 0.45 micrograms once weekly  
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose once every four weeks as necessary. 
 
Once your anaemia is corrected, your doctor will continue to regularly check your blood and your 
dose may be adjusted further in order to maintain long-term control of your anaemia. Your doctor will 
inform you if your dose changes. 
 
Your blood pressure will also be checked regularly, particularly at the beginning of your treatment. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
Your doctor may decide to change the way that your injection is given (either under the skin or into a 
vein).  If this changes you will start on the same dose as you have been receiving and your doctor will 
take blood samples to make sure that your anaemia is still being managed correctly. 
 
If your doctor has decided to change your treatment from r-HuEPO (erythropoietin produced by gene-
technology) to Nespo, they will choose whether you should receive your Nespo injection once weekly 
or once every two weeks.  The route of injection is the same as with r-HuEPO but your doctor will tell 
you how much you should take, and when, and may adjust your dose if necessary. 
 
If you are receiving chemotherapy 
 
Nespo is given as a single injection, either once a week or once every three weeks, under your skin.  
 
In order to correct your anaemia, your initial dose will be 
• 500 micrograms once every three weeks (6.75 micrograms of Nespo per kilogram of your body 

weight, or 
• 2.25 micrograms (once weekly) of Nespo per kilogram of your body weight. 
Your doctor will take regular blood samples to measure how your anaemia is responding and may 
adjust your dose as necessary.  Your treatment will continue until approximately four weeks after the 
end of your chemotherapy.  Your doctor will tell you exactly when to stop taking Nespo. 
 
In some cases, your doctor may recommend that you take iron supplements. 
 
If you use more Nespo than you should 
 
You should have no serious problems if you take more Nespo than you need. However, you should 
contact your doctor, nurse or pharmacist if this does happen.  If you feel unwell in any way you should 
contact your doctor, nurse or pharmacist immediately. 
 
If you forget to inject Nespo 
 
If you have forgotten a dose of Nespo, you should contact your doctor to discuss when you should 
inject the next dose. 
 
 



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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Nespo may cause side effects, although not everybody gets them. 
 
The following side effects have been experienced by some patients taking Nespo: 
 
Very Common (seen in more than 10 in 100 people) 
 
• High blood pressure (hypertension) 
• Fluid retention (oedema) 
 
Common (seen in more than 1 in 100 people) 
 
• Blood clots (thrombosis) 
• Pain around the area injected  
• Rash and/or redness of the skin 
 
Rare (seen in more than 1 in 10,000 people) 
 
Serious allergic reactions which may include: 
• Sudden life-threatening allergic reactions (anaphylaxis) 
• Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or 

breathing (angioedema) 
• Shortness of breath (dyspnoea) 
• Skin rash 
• Hives (urticaria) 
 
Very rare (seen in less than 1 in 10,000 people) 
 
• Pure red cell aplasia (PRCA) – (anaemia, unusual tiredness, lack of energy) 
 
Convulsions (fits and seizures) have been reported in patients treated with Nespo. 
 
If you have any of these symptoms or you notice any side effects that are not mentioned in this leaflet, 
please tell your doctor, nurse or pharmacist. 
 
 
5. HOW TO STORE NESPO 
 
Keep out of the reach and sight of children.  Keep the pre-filled pen in the original package in order to 
protect from light. 
 
Store in a refrigerator (2°C – 8°C).  Do not freeze.  Do not use Nespo if you think it has been frozen. 
 
When your pen has been removed from the refrigerator and left at room temperature for approximately 
30 minutes before injection it must either be used within 7 days or disposed of. 
 
Do not use Nespo after the expiry date which is stated on the carton and on the pre-filled pen label 
after EXP.  The expiry date refers to the last day of that month. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required.  These measures will help to protect the environment. 
 
 



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6. FURTHER INFORMATION  
 
What Nespo contains 
 
Nespo (SureClick) comes in a pre-filled pen that contains either 10, 15, 20, 30, 40, 50, 60, 80, 100, 
130, 150, 300 or 500 micrograms of the active substance darbepoetin alfa.  
 
Nespo also contains sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, 
polysorbate 80 and water for injections. 
 
What Nespo looks like and contents of the pack 
 
Nespo is a clear, colourless or slightly pearly liquid.  If it is cloudy or there are particles in it, you must 
not use it. 
 
Nespo (SureClick) is available in packs containing 1 or 4 pre-filled pens (not all pack sizes may be 
marketed).   
 
Marketing Authorisation Holder: 
Dompé Biotec S.p.A. 
Via San Martino 12  
I-20122 Milan 
Italy 
 
Manufacturer: 
Amgen Europe B.V. 
Minervum 7061  
NL-4817 ZK Breda 
The Netherlands 
 
Further information 
 
If you want more information about this medicine, please contact the local representative of the 
company that is authorised to market Nespo. 
 
This leaflet was last approved in . 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/ 
 
 
7. INSTRUCTIONS FOR INJECTING WITH THE NESPO PRE-FILLED PEN 

(SURECLICK) 
 
This section contains information on how to properly use the Nespo pre-filled pen.  It is important that 
you do not try to give yourself the injection unless you have received training from your doctor, nurse, 
or pharmacist.  If you have questions about how to inject, please ask your doctor, nurse, pharmacist for 
assistance. 
 
How do you, or the person injecting you, use Nespo pre-filled pen (SureClick)? 
 
Your doctor has prescribed the Nespo pre-filled pen for injection into the tissue just under the skin.  
Your doctor, nurse, or pharmacist will tell you how much Nespo you need and how frequently it 
should be injected. Only use each pre-filled pen for one injection. 



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Equipment: 
 
To give yourself an injection you will need: 
 
• a new Nespo pre-filled pen and  
 
• alcohol wipes or similar. 
 
Preparing for an Nespo injection? 
 
1. Remove the pen from the refrigerator. For a more comfortable injection, leave the pen at room 

temperature for approximately 30 minutes.  Do not warm Nespo in any other way (for example, 
do not warm it in a microwave or in hot water).  Additionally, do not leave the pre-filled pen 
exposed to direct sunlight. 

 
2. Do not shake the pre-filled pen. 
 
3.  Do not remove the grey needle cap from the pre-filled pen until you are ready to inject.  
 
4. Check that it is the correct dose that your doctor has prescribed. 
 
5. Check the expiry date on the pre-filled pen label (EXP:).  Do not use it if the date has passed the 

last day of the month shown 
 
6. Check the appearance of Nespo through the inspection window.  It must be a clear, colourless or 

slightly pearly liquid.  If it is cloudy or there are particles in it, you must not use it. 
 
7. Wash your hands thoroughly. 
 
8. Find a comfortable, well-lit, clean surface and put all the equipment you need within reach.  
  

 
 

 
 
 
 
 
 
7a. Choosing and preparing an injection site   
 
1. Choose an injection site 
 
The injection site must be firm for the device to work properly. 
 
The preferred injection site for using the Nespo pre-filled pen is the front of the thigh.  
 
Rotate injection site: 
You may rotate the site for each injection to avoid soreness at any one site.  
 
Do not inject into areas where the skin is tender, bruised, red, or hard.  Avoid areas with scars or 
stretch marks. 
 

Grey needle cap Red button 

Inspection window



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2a. Instructions for preferred injection site 
 

 

The front of the thigh is the 
preferred injection site. 

 

 
2b. Instructions for alternate injection sites  
 
When using alternate injection sites, it is particularly important to create enough surface tension on the 
site to be able to successfully complete the injection. 
 

  
Stretch technique 
 
Make sure that skin under and around the pre-filled pen is firm and 
tight to provide enough resistance to fully retract the safety guard 
and “unlock” the pen. 

 
 

You can use the abdomen, except for the 2 inch/5 cm area around the 
belly button (navel). For the abdomen, it is recommended to lie down on 
your back, and stretch the skin at the injection site to create a firm and 
tight surface. 

 

If someone else is giving you the injection, they can also use the outer 
area of the upper arms. For the upper arms, it is recommended to 
stretch the skin at the injection site to create a firm and tight surface.  

 
3. Prepare the site 
 
To prepare the area of skin where Nespo will be injected, wipe the injection site with an alcohol wipe.  
Do not touch this area again before giving the injection. 
 
7b. Injecting Nespo using the pre-filled pen 
 

Stretch 



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1. Pull off the grey needle cap.  
 
 

 
 

 
 
 
 
 
 
 
 
 
 
 

 
 
 
2. Do not touch the red button.  Press the pre-filled pen onto the skin to unlock the safety guard. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
∅ Do not press the red button until the safety guard is fully retracted. 
 

 Do keep enough downward pressure to fully retract the yellow safety guard and to keep the red 
button unlocked. 

 Do hold the pre-filled pen at a right angle (90º) to the injection site. 
 

Do pull the grey cap 
straight off 

∅ Do not twist the grey 
needle cap 

∅ Do not try to put the 
needle cap back onto 
the pre-filled pen 

Safety guard 

Pull off the grey needle cap 

Unlocked with safety 
guard fully retracted 

Locked with safety guard 
out

 



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3. Briefly press and release red button. 
 

 
 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4. Count slowly to 15 seconds for injection to end.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
∅ Do not move the pre-filled pen during the injection. 
 

 Do wait for the injection to finish before releasing pressure. 
 You may hear a second click as the red button pops back up. 

Medicine will be automatically 
injected 

Do maintain pressure on 
the skin during the 
injection 

Release button 

CLIC



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5. Check window to confirm delivery of full dose 

 
 
 
 

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

There may be a little bleeding at the injection site.  You can press a cotton ball or gauze over the 
injection site 
 
Do not rub the injection site.  If needed, you may cover the injection site with a plaster. 
 
Remember 
 
If you have any problems, please do not be afraid to ask your doctor or nurse for help and advice. 
 
Disposing of used pre-filled pens 
 
• The Nespo pre-filled pen should NEVER be reused. 
• NEVER put the grey needle cap back into the used pre-filled pen.  
• The used pre-filled pen should be disposed of in accordance with local requirements.  Ask your 

pharmacist how to dispose of medicines no longer required. These measures will help to protect 
the environment. 

 
 
Optional separate additional insert: 
 
FRONT- Nespo getting started guide: 
 

Nespo SureClick Pre-filled pen - Read package leaflet before use 
Preferred site is front of 
the thigh 

Alternate sites are 
the abdomen or outer 
area of upper arms 

Stretch the skin on 
alternate injection 
sites 
 

Turn over for 
injection steps 

  Stretch  

EN
G

LISH
 

  Injection site must 
be firm and tight 

 

 

Do check the inspection window 
to confirm it has turned yellow.   

! If the inspection window is not 
yellow, you must contact your 
doctor, nurse or pharmacist. 

Safety guard down after use. 



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BACK- Neso getting started guide: 
 

(1) Pull off grey 
needle cap 

(2) Do not touch 
red button.  Press 
the pen onto the 
skin to unlock 
safety guard. 

(3) Briefly press 
and release red 
button. 

(4) Count slowly 
to 15 for 
injection to end. 

(5) Check 
window 
 
 

∅ Do not twist 
the grey 
needle cap 

X Locked Click   Complete 
when yellow 

EN
G

LISH
 

  Unlocked Keep unlocked 
against skin 

  

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVESUBSTANCE AND MANUFACTURING AUTHORISATIONHOLDER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET