ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Aranesp 10 micrograms solution for injection in a pre-filled syringe.
2.
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).
Excipients:
Each pre-filled syringe contains 1.52 mg of sodium in 0.4 ml.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection) in a pre-filled syringe.
Clear, colourless solution.
4.
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.
Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.
Posology
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. Aranesp
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.
2
Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is
given separately for adult and paediatric patients.
Adult patients with chronic renal failure
Correction phase:
The initial dose by subcutaneous or intravenous administration is 0.45 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, Aranesp may continue to be administered as a single injection once weekly
or once every two weeks. Dialysis patients converting from once weekly to once every other week
dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose.
In patients not on dialysis, once the target haemoglobin has been achieved with once every two week
dosing, Aranesp 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 Aranesp 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 Aranesp. The initial weekly dose
3
of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by
200. The initial every other week dose of Aranesp (μg/every other week) can be determined by
dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because
of individual variability, titration to optimal therapeutic doses is expected for individual patients.
When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two
weeks and the same route of administration should be used.
Paediatric population with chronic renal failure
Treatment of paediatric patients younger than 1 year of age has not been studied.
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, Aranesp may continue to be
administered as a single injection once weekly or once every two weeks. Dialysis patients converting
from once weekly to once every other week dosing with Aranesp should initially receive a dose
equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target
haemoglobin has been achieved with once every two week dosing, Aranesp may be administered
subcutaneously once monthly using an initial dose equal to twice the previous once every two week
dose.
For paediatric 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 Aranesp, and
those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The
initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly
dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other
week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a
two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is
expected for individual patients. When substituting Aranesp for r-HuEPO the 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%.
4
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 Aranesp 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
Aranesp 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.
Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced
by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain
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 Aranesp 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%.
Method of administration
Aranesp is administered either subcutaneously or intravenously as described in the posology.
5
Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.
Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and
disposal are given in section 6.6.
Hypersensitivity to darbepoetin alfa, r-HuEPO or to any of the excipients.
Poorly controlled hypertension.
General
In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the
administered ESA should be clearly recorded (or stated) in the patient file.
Blood pressure should be monitored in all patients, particularly during initiation of Aranesp therapy. If
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be
reduced by decreasing or withholding the dose of Aranesp (see section 4.2). Cases of severe
hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been
observed in CRF patients treated with Aranesp.
In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and
during treatment and supplementary iron therapy may be necessary.
Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies of
iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.
Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 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 ESAs, including Aranesp. This has been predominantly reported in patients with CRF
treated subcutaneously. These antibodies have been shown to cross-react with all erythropoietic
proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should
not be switched to Aranesp (see section 4.8).
A paradoxical decrease in haemoglobin and development of severe anaemia associated with low
reticulocyte counts should prompt to discontinue treatment with epoetin and perform
anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with
interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the
management of anaemia associated with hepatitis C.
Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are available
from patients with impaired liver function. Since the liver is thought to be the principal route of
elimination of darbepoetin alfa Aranesp and r-HuEPO, Aranesp should be used with caution in
patients with liver disease.
Aranesp should also be used with caution in those patients with sickle cell anaemia.
Misuse of Aranesp by healthy persons may lead to an excessive increase in packed cell volume. This
may be associated with life-threatening complications of the cardiovascular system.
6
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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported in
patients receiving Aranesp.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-
free’.
Chronic renal failure patients
In patients with chronic renal failure, maintenance 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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l
or whose transferrin saturation is below 20%.
Serum potassium levels should be monitored regularly during Aranesp therapy. Potassium elevation
has been reported in a few patients receiving Aranesp, though causality has not been established. If an
elevated or rising potassium level is observed then consideration should be given to ceasing Aranesp
administration until the level has been corrected.
Cancer patients
Effect on 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 Aranesp and other 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.
7
•
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.
The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other
substances. However, there is potential for an interaction with substances that are highly bound to red
blood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of these
treatments, blood levels of these substances should be monitored and the dosage adjusted as the
haemoglobin rises.
For Aranesp 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 Aranesp should not be administered to women
who are breast-feeding. When Aranesp therapy is absolutely indicated women must stop
breast-feeding.
Aranesp has no or negligible influence on the ability to drive and use machines.
General
There have been reports of serious allergic reactions including anaphylactic reaction, angioedema,
allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.
Clinical trial experience
8
Chronic renal failure patients
Data presented from controlled studies included 1357 patients, 766 who received Aranesp and 591
patients who received r-HuEPO. In the Aranesp group, 83% were receiving dialysis and 17% were not
receiving dialysis.
Injection site pain was reported as attributable to treatment in studies where Aranesp 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 adverse reactions 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
Nervous system disorders
Common (≥ 1/100 to
< 1/10)
Stroke
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 Aranesp with a total of 2112 patients (Aranesp 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 adverse reactions 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 Aranesp:
•
Pure Red Cell Aplasia. In isolated cases, neutralising anti-erythropoietin antibody mediated pure
red cell aplasia (PRCA) associated with Aranesp therapy have been reported predominantly in
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Aranesp
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.
Frequency is not known (cannot be estimated from the available data).
9
•
Convulsions. Frequency is not known (cannot be estimated from the available data).
•
Hypertension. Frequency is not known (cannot be estimated from the available data).
The therapeutic margin of darbepoetin alfa is very wide. Even at very high serum levels, no symptoms
of overdose have been observed.
In the event of polycythaemia, Aranesp should be temporarily withheld (see section 4.2). If clinically
indicated, phlebotomy may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-anemic preparations, other Antianemic preparations. 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.
Chronic renal failure patients
Patients with CRF experienced greater risks for death and serious cardiovascular events when
administered ESAs to target higher versus lower haemoglobin levels (13.5 g/dl (8.4 mmol/l) versus
11.3 g/dl (7.1 mmol/l); 14 g/dl (8.7 mmol/l) versus 10 g/dl (6.2 mmol/l) in two clinical studies.
In a randomised, double-blind, placebo-controlled study (TREAT) of 4,038 CRF patients not on
dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dl, patients received either treatment with
darbepoetin alfa to target haemoglobin levels of 13 g/dl or placebo (with darbepoetin alfa rescue at
haemoglobin less than 9 g/dl). The study did not meet either primary objective of demonstrating a
reduction in risk for all-cause mortality or cardiovascular morbidity (darbepoetin alfa vs placebo;
HR
1.05, 95% CI (0.94, 1.17)), or all-cause mortality or end stage renal disease (ESRD) (darbepoetin alfa
vs placebo;
HR 1.06, 95% CI (0.95, 1.19)). Analysis of the individual components of the composite
endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), congestive heart failure (CHF)
0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), stroke 1.92 (1.38, 2.68), hospitalisation
for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).
10
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 Aranesp 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
Aranesp 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
chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients
with these characteristics were included in the data reviewed.
11
A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-,
radio-,chemoradio-, or no therapy) participating in 53 controlled clinical trials involving several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4).
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 (V
ss
) 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 Aranesp 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
12
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 darbepoetin alfa 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.
Darbepoetin alfa 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.
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, Aranesp 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 pre-filled syringe in the outer carton in order to protect from light.
For the purpose of ambulatory use, Aranesp may be removed from storage once for a maximum 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
0.4 ml solution for injection (25 µg/ml darbepoetin alfa) in a type 1 glass pre-filled syringe with
stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.
13
The syringes may be presented in either blistered (1- & 4-pack), with or without an automatic needle
guard or non-blistered packaging (1-pack only).
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex). See
section 4.4.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Aranesp 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 Aranesp 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
The Netherlands
8.
EU/1/01/185/001 1 Pack Blister
EU/1/01/185/002 4 Pack Blister
EU/1/01/185/033 1 Pack Unblistered
EU/1/01/185/074 1 blister pack with needle guard
EU/1/01/185/075 4 blister pack with needle guard
9.
Date of first authorisation: 8 June 2001
Date of last renewal: 19 May 2006
Detailed information on this product is available on the website of the European Medicines Agency
14
1.
Aranesp 15 micrograms solution for injection in a pre-filled syringe.
2.
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).
Excipients:
Each pre-filled syringe contains 1.42 mg of sodium in 0.375 ml.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection) in a pre-filled syringe.
Clear, colourless solution.
4.
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.
Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.
Posology
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. Aranesp
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.
15
Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is
given separately for adult and paediatric patients.
Adult patients with chronic renal failure
Correction phase:
The initial dose by subcutaneous or intravenous administration is 0.45 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, Aranesp may continue to be administered as a single injection once weekly
or once every two weeks. Dialysis patients converting from once weekly to once every other week
dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose.
In patients not on dialysis, once the target haemoglobin has been achieved with once every two week
dosing, Aranesp 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 Aranesp 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 Aranesp. The initial weekly dose
16
of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by
200. The initial every other week dose of Aranesp (μg/every other week) can be determined by
dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because
of individual variability, titration to optimal therapeutic doses is expected for individual patients.
When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two
weeks and the same route of administration should be used.
Paediatric population with chronic renal failure
Treatment of paediatric patients younger than 1 year of age has not been studied.
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, Aranesp may continue to be
administered as a single injection once weekly or once every two weeks. Dialysis patients converting
from once weekly to once every other week dosing with Aranesp should initially receive a dose
equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target
haemoglobin has been achieved with once every two week dosing, Aranesp may be administered
subcutaneously once monthly using an initial dose equal to twice the previous once every two week
dose.
For paediatric 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 Aranesp, and
those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The
initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly
dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other
week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a
two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is
expected for individual patients. When substituting Aranesp for r-HuEPO the 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%.
17
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 Aranesp 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
Aranesp 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.
Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced
by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain
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 Aranesp 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%.
Method of administration
Aranesp is administered either subcutaneously or intravenously as described in the posology.
18
Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.
Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and
disposal are given in section 6.6.
Hypersensitivity to darbepoetin alfa, r-HuEPO or to any of the excipients.
Poorly controlled hypertension.
General
In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the
administered ESA should be clearly recorded (or stated) in the patient file.
Blood pressure should be monitored in all patients, particularly during initiation of Aranesp therapy. If
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be
reduced by decreasing or withholding the dose of Aranesp (see section 4.2). Cases of severe
hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been
observed in CRF patients treated with Aranesp.
In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and
during treatment and supplementary iron therapy may be necessary.
Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies of
iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.
Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 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 ESAs, including Aranesp. This has been predominantly reported in patients with CRF
treated subcutaneously. These antibodies have been shown to cross-react with all erythropoietic
proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should
not be switched to Aranesp (see section 4.8).
A paradoxical decrease in haemoglobin and development of severe anaemia associated with low
reticulocyte counts should prompt to discontinue treatment with epoetin and perform
anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with
interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the
management of anaemia associated with hepatitis C.
Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are available
from patients with impaired liver function. Since the liver is thought to be the principal route of
elimination of darbepoetin alfa Aranesp and r-HuEPO, Aranesp should be used with caution in
patients with liver disease.
Aranesp should also be used with caution in those patients with sickle cell anaemia.
Misuse of Aranesp by healthy persons may lead to an excessive increase in packed cell volume. This
may be associated with life-threatening complications of the cardiovascular system.
19
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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported in
patients receiving Aranesp.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-
free’.
Chronic renal failure patients
In patients with chronic renal failure, maintenance 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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l
or whose transferrin saturation is below 20%.
Serum potassium levels should be monitored regularly during Aranesp therapy. Potassium elevation
has been reported in a few patients receiving Aranesp, though causality has not been established. If an
elevated or rising potassium level is observed then consideration should be given to ceasing Aranesp
administration until the level has been corrected.
Cancer patients
Effect on 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 Aranesp and other 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.
20
•
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.
The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other
substances. However, there is potential for an interaction with substances that are highly bound to red
blood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of these
treatments, blood levels of these substances should be monitored and the dosage adjusted as the
haemoglobin rises.
For Aranesp 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 Aranesp should not be administered to women
who are breast-feeding. When Aranesp therapy is absolutely indicated women must stop
breast-feeding.
Aranesp has no or negligible influence on the ability to drive and use machines.
General
There have been reports of serious allergic reactions including anaphylactic reaction, angioedema,
allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.
Clinical trial experience
21
Chronic renal failure patients
Data presented from controlled studies included 1357 patients, 766 who received Aranesp and 591
patients who received r-HuEPO. In the Aranesp group, 83% were receiving dialysis and 17% were not
receiving dialysis.
Injection site pain was reported as attributable to treatment in studies where Aranesp 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 adverse reactions 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
Nervous system disorders
Common (≥ 1/100 to
< 1/10)
Stroke
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 Aranesp with a total of 2112 patients (Aranesp 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 adverse reactions 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 Aranesp:
•
Pure Red Cell Aplasia. In isolated cases, neutralising anti-erythropoietin antibody mediated pure
red cell aplasia (PRCA) associated with Aranesp therapy have been reported predominantly in
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Aranesp
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.
Frequency is not known (cannot be estimated from the available data).
22
•
Convulsions. Frequency is not known (cannot be estimated from the available data).
•
Hypertension. Frequency is not known (cannot be estimated from the available data).
The therapeutic margin of darbepoetin alfa is very wide. Even at very high serum levels, no symptoms
of overdose have been observed.
In the event of polycythaemia, Aranesp should be temporarily withheld (see section 4.2). If clinically
indicated, phlebotomy may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-anemic preparations, other Antianemic preparations. 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.
Chronic renal failure patients
Patients with CRF experienced greater risks for death and serious cardiovascular events when
administered ESAs to target higher versus lower haemoglobin levels (13.5 g/dl (8.4 mmol/l) versus
11.3 g/dl (7.1 mmol/l); 14 g/dl (8.7 mmol/l) versus 10 g/dl (6.2 mmol/l) in two clinical studies.
In a randomised, double-blind, placebo-controlled study (TREAT) of 4,038 CRF patients not on
dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dl, patients received either treatment with
darbepoetin alfa to target haemoglobin levels of 13 g/dl or placebo (with darbepoetin alfa rescue at
haemoglobin less than 9 g/dl). The study did not meet either primary objective of demonstrating a
reduction in risk for all-cause mortality or cardiovascular morbidity (darbepoetin alfa vs placebo;
HR
1.05, 95% CI (0.94, 1.17)), or all-cause mortality or end stage renal disease (ESRD) (darbepoetin alfa
vs placebo;
HR 1.06, 95% CI (0.95, 1.19)). Analysis of the individual components of the composite
endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), congestive heart failure (CHF)
0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), stroke 1.92 (1.38, 2.68), hospitalisation
for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).
23
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 Aranesp 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
Aranesp 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
chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients
with these characteristics were included in the data reviewed.
24
A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-,
radio-,chemoradio-, or no therapy) participating in 53 controlled clinical trials involving several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4).
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 (V
ss
) 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 Aranesp 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
25
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 darbepoetin alfa 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.
Darbepoetin alfa 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.
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, Aranesp 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 pre-filled syringe in the outer carton in order to protect from light.
For the purpose of ambulatory use, Aranesp may be removed from storage once for a maximum 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
0.375 ml solution for injection (40 µg/ml darbepoetin alfa) in a type 1 glass pre-filled syringe with
stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.
26
The syringes may be presented in either blistered (1- & 4-pack), with or without an automatic needle
guard or non-blistered packaging (1-pack only).
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex). See
section 4.4.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Aranesp 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 Aranesp 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
The Netherlands
8.
EU/1/01/185/003 1 Pack Blister
EU/1/01/185/004 4 Pack Blister
EU/1/01/185/034 1 Pack Unblistered
EU/1/01/185/076 1 blister pack with needle guard
EU/1/01/185/077 4 blister pack with needle guard
9.
Date of first authorisation: 8 June 2001
Date of last renewal: 19 May 2006
Detailed information on this product is available on the website of the European Medicines Agency
27
1.
Aranesp 20 micrograms solution for injection in a pre-filled syringe.
2.
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).
Excipients:
Each pre-filled syringe contains 1.90 mg of sodium in 0.5 ml.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection) in a pre-filled syringe.
Clear, colourless solution.
4.
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.
Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.
Posology
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. Aranesp
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.
28
Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is
given separately for adult and paediatric patients.
Adult patients with chronic renal failure
Correction phase:
The initial dose by subcutaneous or intravenous administration is 0.45 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, Aranesp may continue to be administered as a single injection once weekly
or once every two weeks. Dialysis patients converting from once weekly to once every other week
dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose.
In patients not on dialysis, once the target haemoglobin has been achieved with once every two week
dosing, Aranesp 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 Aranesp 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 Aranesp. The initial weekly dose
29
of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by
200. The initial every other week dose of Aranesp (μg/every other week) can be determined by
dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because
of individual variability, titration to optimal therapeutic doses is expected for individual patients.
When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two
weeks and the same route of administration should be used.
Paediatric population with chronic renal failure
Treatment of paediatric patients younger than 1 year of age has not been studied.
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, Aranesp may continue to be
administered as a single injection once weekly or once every two weeks. Dialysis patients converting
from once weekly to once every other week dosing with Aranesp should initially receive a dose
equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target
haemoglobin has been achieved with once every two week dosing, Aranesp may be administered
subcutaneously once monthly using an initial dose equal to twice the previous once every two week
dose.
For paediatric 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 Aranesp, and
those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The
initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly
dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other
week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a
two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is
expected for individual patients. When substituting Aranesp for r-HuEPO the 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%.
30
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 Aranesp 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
Aranesp 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.
Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced
by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain
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 Aranesp 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%.
Method of administration
Aranesp is administered either subcutaneously or intravenously as described in the posology.
31
Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.
Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and
disposal are given in section 6.6.
Hypersensitivity to darbepoetin alfa, r-HuEPO or to any of the excipients.
Poorly controlled hypertension.
General
In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the
administered ESA should be clearly recorded (or stated) in the patient file.
Blood pressure should be monitored in all patients, particularly during initiation of Aranesp therapy. If
blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be
reduced by decreasing or withholding the dose of Aranesp (see section 4.2). Cases of severe
hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been
observed in CRF patients treated with Aranesp.
In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and
during treatment and supplementary iron therapy may be necessary.
Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies of
iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.
Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, 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 ESAs, including Aranesp. This has been predominantly reported in patients with CRF
treated subcutaneously. These antibodies have been shown to cross-react with all erythropoietic
proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should
not be switched to Aranesp (see section 4.8).
A paradoxical decrease in haemoglobin and development of severe anaemia associated with low
reticulocyte counts should prompt to discontinue treatment with epoetin and perform
anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with
interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the
management of anaemia associated with hepatitis C.
Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are available
from patients with impaired liver function. Since the liver is thought to be the principal route of
elimination of darbepoetin alfa Aranesp and r-HuEPO, Aranesp should be used with caution in
patients with liver disease.
Aranesp should also be used with caution in those patients with sickle cell anaemia.
Misuse of Aranesp by healthy persons may lead to an excessive increase in packed cell volume. This
may be associated with life-threatening complications of the cardiovascular system.
32
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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported in
patients receiving Aranesp.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-
free’.
Chronic renal failure patients
In patients with chronic renal failure, maintenance 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 or cerebrovascular events including stroke, and vascular
access thrombosis was observed when 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.
Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l
or whose transferrin saturation is below 20%.
Serum potassium levels should be monitored regularly during Aranesp therapy. Potassium elevation
has been reported in a few patients receiving Aranesp, though causality has not been established. If an
elevated or rising potassium level is observed then consideration should be given to ceasing Aranesp
administration until the level has been corrected.
Cancer patients
Effect on 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 Aranesp and other 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.
33
•
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.
The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other
substances. However, there is potential for an interaction with substances that are highly bound to red
blood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of these
treatments, blood levels of these substances should be monitored and the dosage adjusted as the
haemoglobin rises.
For Aranesp 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 Aranesp should not be administered to women
who are breast-feeding. When Aranesp therapy is absolutely indicated women must stop
breast-feeding.
Aranesp has no or negligible influence on the ability to drive and use machines.
General
There have been reports of serious allergic reactions including anaphylactic reaction, angioedema,
allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.
Clinical trial experience
34
Chronic renal failure patients
Data presented from controlled studies included 1357 patients, 766 who received Aranesp and 591
patients who received r-HuEPO. In the Aranesp group, 83% were receiving dialysis and 17% were not
receiving dialysis.
Injection site pain was reported as attributable to treatment in studies where Aranesp 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 adverse reactions 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
Nervous system disorders
Common (≥ 1/100 to
< 1/10)
Stroke
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 Aranesp with a total of 2112 patients (Aranesp 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 adverse reactions 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 Aranesp:
•
Pure Red Cell Aplasia. In isolated cases, neutralising anti-erythropoietin antibody mediated pure
red cell aplasia (PRCA) associated with Aranesp therapy have been reported predominantly in
patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Aranesp
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.
Frequency is not known (cannot be estimated from the available data).
35
•
Convulsions. Frequency is not known (cannot be estimated from the available data).
•
Hypertension. Frequency is not known (cannot be estimated from the available data).
The therapeutic margin of darbepoetin alfa is very wide. Even at very high serum levels, no symptoms
of overdose have been observed.
In the event of polycythaemia, Aranesp should be temporarily withheld (see section 4.2). If clinically
indicated, phlebotomy may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-anemic preparations, other Antianemic preparations. 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.
Chronic renal failure patients
Patients with CRF experienced greater risks for death and serious cardiovascular events when
administered ESAs to target higher versus lower haemoglobin levels (13.5 g/dl (8.4 mmol/l) versus
11.3 g/dl (7.1 mmol/l); 14 g/dl (8.7 mmol/l) versus 10 g/dl (6.2 mmol/l) in two clinical studies.
In a randomised, double-blind, placebo-controlled study (TREAT) of 4,038 CRF patients not on
dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dl, patients received either treatment with
darbepoetin alfa to target haemoglobin levels of 13 g/dl or placebo (with darbepoetin alfa rescue at
haemoglobin less than 9 g/dl). The study did not meet either primary objective of demonstrating a
reduction in risk for all-cause mortality or cardiovascular morbidity (darbepoetin alfa vs placebo;
HR
1.05, 95% CI (0.94, 1.17)), or all-cause mortality or end stage renal disease (ESRD) (darbepoetin alfa
vs placebo;
HR 1.06, 95% CI (0.95, 1.19)). Analysis of the individual components of the composite
endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), congestive heart failure (CHF)
0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), stroke 1.92 (1.38, 2.68), hospitalisation
for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).
36
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 Aranesp 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
Aranesp 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
chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients
with these characteristics were included in the data reviewed.
37
A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-,
radio-,chemoradio-, or no therapy) participating in 53 controlled clinical trials involving several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4).
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 (V
ss
) 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 Aranesp 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
38
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 darbepoetin alfa 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.
Darbepoetin alfa 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.
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, Aranesp 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 pre-filled syringe in the outer carton in order to protect from light.
For the purpose of ambulatory use, Aranesp may be removed from storage once for a maximum 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
0.5 ml solution for injection (40 µg/ml darbepoetin alfa) in a type 1 glass pre-filled syringe with
stainless steel 27 gauge needle. Pack size of 1 or 4 pre-filled syringes.
39
The syringes may be presented in either blistered (1- & 4-pack), with or without an automatic needle
guard or non-blistered packaging (1-pack only).
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex). See
section 4.4.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Aranesp 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 Aranesp 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
The Netherlands
8.
EU/1/01/185/005 1 Pack Blister
EU/1/01/185/006 4 Pack Blister
EU/1/01/185/035 1 Pack Unblistered
EU/1/01/185/078 1 blister pack with needle guard
EU/1/01/185/079 4 blister pack with needle guard
9.
Date of first authorisation: 8 June 2001
Date of last renewal: 19 May 2006
Detailed information on this product is available on the website of the European Medicines Agency
40
1.
FURTHER INFORMATION
What Aranesp contains
-
The active substance is darbepoetin alfa.
The vial contains either 25, 40, 60, 100, 200 or 300 micrograms of darbepoetin alfa.
-
The other ingredients are sodium phosphate monobasic, sodium phosphate dibasic, sodium
chloride, polysorbate 80 and water for injections.
What Aranesp looks like and contents of the pack
Aranesp is a clear, colourless or slightly pearly solution for injection in vial.
Aranesp is available in packs of 1 or 4 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder and 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 Aranesp.
België/Belgique/Belgien
s.a. Amgen n.v.
Tel/Tél: +32 (0)2 7752711
Luxembourg/Luxemburg
s.a. Amgen
Belgique/Belgien
Tel/Tél: +32 (0)2 7752711
България
Амджен България ЕООД
Тел: +359 (0)2 805 7020
Magyarország
Amgen Kft.
Tel.: +36 1 35 44 700
Česká republika
Amgen s.r.o.
Tel: +420 2 21 773 500
Malta
Amgen B.V.
The Netherlands
Tel: +31 (0)76 5732500
Danmark
Amgen filial af Amgen AB, Sverige
Tlf: +45 39617500
Nederland
Amgen B.V.
Tel: +31 (0)76 5732500
Deutschland
AMGEN GmbH
Tel.: +49 (0)89 1490960
Norge
Amgen AB
Tel: +47 23308000
Eesti
Amgen Switzerland AG Eesti filiaal
Tel: +372 512 5501
Österreich
Amgen GmbH
Tel: +43 (0)1 50 217
Ελλάδα
Genesis Pharma S.A.
Τηλ: +30 210 8771500
Polska
Amgen Sp. z o.o.
Tel.: +48 22 581 3000
612
España
Amgen S.A.
Tel: +34 93 600 19 00
Portugal
AMGEN Biofarmacêutica, Lda.
Tel: +351 21 4220550
France
Amgen S.A.S.
Tél: +33 (0)1 40 88 27 00
România
Amgen România SRL
Tel.: +4021 527 30 00
Ireland
Amgen Limited
United Kingdom
Tel: +44 (0)1223 420305
Slovenija
AMGEN zdravila d.o.o.
Tel: +386 1 585 1767
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Amgen Switzerland AG, Slovakia
Tel: +421 33 321 13 22
Italia
Amgen Dompé S.p.A.
Tel: +39 02 6241121
Suomi/Finland
Amgen AB, sivuliike Suomessa/Amgen AB, filial
i Finland
Puh/Tel: +358 (0)9 54900500
Kύπρος
Genesis Pharma (Cyprus) Ltd
Τηλ: +357 22 76 99 46
Sverige
Amgen AB
Tel: +46 (0)8 6951100
Latvija
Amgen Switzerland AG Rīgas filiāle
Tel: +371 29284 807
United Kingdom
Amgen Limited
Tel: +44 (0)1223 420305
Lietuva
Amgen Switzerland AG Vilniaus filialas
Tel: +370 6983 6600
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
613
Source: European Medicines Agency
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