Nespo - summary of medicine characteristics

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 ^g/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 PARTICULARS4.1 Therapeutic indications

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

Treatment of symptomatic anaemia in adult cancer 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:

Adult patients with chronic renal failure

Correction Phase

The initial dose by subcutaneous or intravenous administration is 0.45 ^g/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 ^g/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

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 (^g/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 (^g/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting 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 ^g/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 ^g/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 (^g/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 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 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 ^g (6.75 ^g/kg) given once every three weeks, or once weekly dosing can be given at 2.25 ^g/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 ^g, 300 ^g, and 150 ^g 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.

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.

nal 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 p.g/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.

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. Erythropo

receptors may be expressed on the surface of a variety of tumour cells. As with all gro there is a concern that epoetins could stimulate the growth of tumours. In several c epoetins have not been shown to improve overall survival or decrease the risk 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; lifeexpectancy; the environment in which the patient is being treated; and patient preference (see section 5.1).

ith solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds mol/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.

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.

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

4

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

5. PHARMACOLOGICAL PROPERTIES5.1 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 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 ^g once every three weeks or 2.25 ^g /kg once weekly. In both groups, the dose was reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 ^g in the once every three weeks group and 1.35 ^g /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 ^g 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 openlabel 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 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 ^g/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.

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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-œ]) was observed; however, this difference was less than the 2-fold range in AUC(0-œ) observed for the pediatricpatients. AUC(0-œ) 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 ^g/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 ^g/kg weekly and 3 to 9 ^g/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 ^g/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 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 nonhaematological 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 PARTICULARS6.1 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 st

  °C).

  
  

Store in a refrigerator (2°C Do not freeze.

Keep the container in the o

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 gg Nespo solution for injection in 0.4 ml (25 gg/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.

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 prefilled 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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authoristion: 8 June 2001

Date of last renewal: 19 May 2006