[LU1]
Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients
Retacrit should be administered either subcutaneously or intravenously.
The haemoglobin concentration aimed for is between 10 and 12 g/dl (6.2‑7.5 mmol/l), except in paediatric patients in whom the haemoglobin concentration should be between 9.5 and 11 g/dl (5.9‑6.8 mmol/l). The upper limit of the target haemoglobin concentration should not be exceeded.
Anemia symptoms and sequaelea may vary with age, gender and overall burden of disesase; a physician´s evaluation of the individual patient´s clinical course and condition is necessary. Retacrit should be administered either subcutaneously or intravenously in order to increase haemoglobin to not greater than 12 g/dL (7.5 mmol/L) 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 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.
Patients should be monitored closely to ensure that the lowest approved dose of Retacrit is used to provide adequate control of the symptoms of anemia.
In patients with chronic renal failure and clinically evident ischemic heart disease or congestive heart failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration.
Adult patients on haemodialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two stages:
1. Correction phase: 50 IU/kg 3 times per week. When a dose adjustment is necessary, this should be done in steps of at least four weeks. At each step, the increase or reduction in dose should be of 25 IU/kg 3 times per week.
2. Maintenance phase: Dose adjustment in order to maintain haemoglobin (Hb) values at the desired level: Hb between 10 and 12 g/dl (6.2‑7.5 mmol/l). The recommended total weekly dose is between 75 and 300 IU/kg.
The clinical data available suggest that those patients whose initial haemoglobin is very low (< 6 g/dl or < 3.75 mmol/l) may require higher maintenance doses than those whose initial anaemia is less severe (Hb > 8 g/dl or > 5 mmol/l).
Paediatric patients on haemodialysis
The treatment is divided into two stages:
1. Correction phase 50 IU/kg, 3 times per week by the intravenous route. When a dose adjustment is necessary, this should be done in steps of 25 IU/kg, 3 times per week at intervals of at least 4 weeks until the desired goal is achieved.
2. Maintenance phase: Dose adjustment in order to maintain haemoglobin (Hb) values at the desired level: Hb between 9.5 and 11 g/dl (5.9‑6.8 mmol/l).
Generally, children and adolescents under 30 kg body weight require higher maintenance doses than adults and children over 30 kg. The following maintenance doses were observed in clinical trials after 6 months of treatment.
|
|
Dose (IU/kg given 3x week)
|
|
Weight (kg)
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Median
|
Usual maintenance dose
|
|
< 10
|
100
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75-150
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10-30
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75
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60-150
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> 30
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33
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30-100
|
The clinical data available suggest that those patients whose initial haemoglobin is very low (< 6.8 g/dl or < 4.25 mmol/l) may require higher maintenance doses than those whose initial haemoglobin is higher > 6.8 g/dl or> 4.25 mmol/l).
Adult patients on peritoneal dialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two stages:
1. Correction phase: Starting dose of 50 IU/kg 2 times per week.
2. Maintenance phase: Dose adjustment in order to maintain haemoglobin (Hb) values at the desired level: Hb between 10 and 12 g/dl (6.2‑7.5 mmol/l). Maintenance dose between 25 and 50 IU/kg 2 times per week into 2 equal doses.
Adult patients with renal insufficiency not yet undergoing dialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two stages:
1. Correction phase: Starting dose of 50 IU/kg 3 times per week, followed if necessary by a dose increase with 25 IU/kg increments (3 times per week) until the desired goal is achieved (this should be done in steps of at least four weeks).
2. Maintenance phase: Dose adjustment in order to maintain haemoglobin (Hb) values at the desired level: Hb between 10 and 12 g/dl (6.2‑7.5 mmol/l). Maintenance dose between 17 and 33 IU/kg 3 times per week.
The maximum dose should not exceed 200 IU/kg 3 times per week.
- Treatment of patients with chemotherapy induced anaemia..
Retacrit should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration ≤ 10 g/dl (6.2 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 adjustment for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.
Patients should be monitored closely to ensure that the lowest approved dose of Retacrit is used to provide adequate control of the symptoms of anaemia.
Retacrit therapy should continue until one month after the end of chemotherapy.
The initial dose is 150 IU/kg given subcutaneously 3 times per week. Alternatively, Retacrit can be administered at an initial dose of 450 IU/kg subcutaneously once weekly.
If the haemoglobin has increased by at least 1 g/dl (0.62 mmol/l) or the reticulocyte count has increased ≥ 40,000 cells/µl above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg 3 times per week or 450 IU/kg once weekly. If the haemoglobin increase is < 1 g/dl (< 0.62 mmol/l) and the reticulocyte count has increased < 40,000 cells/µl above baseline, increase the dose to 300 IU/kg 3 times per week. If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week, the haemoglobin has increased ≥ 1 g/dl (0.62 mmol/l) or the reticulocyte count has increased ≥ 40,000 cells/µl the dose should remain at 300 IU/kg 3 times per week. However, if the haemoglobin has increased < 1 g/dl (< 0.62 mmol/l) and the reticulocyte count has increased < 40,000 cells/µl above baseline, response is unlikely and treatment should be discontinued.
The recommended dosing regimen is described in the following diagram:
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to maintain haemoglobin at that level. Appropriate dose titration should be considered.
Dose adjustment
At a rate of rise in haemoglobin of > 2 g/dl (> 1.25 mmol/l) per month the Retacrit dose should be reduced by about 25‑50%. If haemoglobin level exceeds 12 g/dl (7.5 mmol/l), discontinue therapy until it falls to 12 g/dl (7.5 mmol/l) or lower and then reinstitute Retacrit therapy at a dose 25% below the previous dose.
- Adult surgery patients in an autologous predonation programme.
Retacrit should be given by the intravenous route.
At the time of donating blood, Retacrit should be administered after the completion of the blood donation procedure.
Mildly anaemic patients (haematocrit of 33‑39%) requiring predeposit of ≥ 4 units of blood should be treated with Retacrit at a dose of 600 IU/kg body weight 2 times weekly for 3 weeks prior to surgery.
All patients being treated with Retacrit should receive adequate iron supplementation (e.g. 200 mg oral elemental iron daily) throughout the course of treatment. Iron supplementation should be started as soon as possible, even several weeks prior to initiating the autologous predeposit, in order to achieve high iron stores prior to starting Retacrit therapy.
Method of administration
For instructions on handling of the medicinal product before administration, see section 6.6.[LU2]
Intravenous injection
The dose should be administered over at least 1‑5 minutes, depending on the total dose. In haemodialysed patients, a bolus injection may be given during the dialysis session through a suitable venous port in the dialysis line. Alternatively, the injection can be given at the end of the dialysis session via the fistula needle tubing, followed by 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to rinse the tubing and ensure satisfactory injection of the medicinal product into the circulation.
A slower injection is preferable in patients who react to the treatment with “flu‑like” symptoms.
Retacrit should not be administered by intravenous infusion.
Retacrit must not be mixed with other medicinal products (see section 6.2).
4.4 Special warnings and precautions for use
Paragraph has been amended as requested by EMA
Haemoglobin concentration
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 trials, an increased risk of death, serious cardiovascular events or cerebrovascular events including stroke were observed when ESAs were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).[LU1]
4.6 Fertility, pregnancy and lactation
Implementation of new QRD format/new SPC guideline.
There are no adequate and well‑controlled studies in pregnant women. Studies in animals have shown reproduction toxicity (see section 5.3). Consequently, erythropoietin should generally be used during pregnancy and lactation only if the potential benefit outweighs the potential risk to the foetus.
4.8 Undesirable effects
Implementation of new QRD format/new SPC guideline.
Retacrit is a biological medicinal product. Data from clinical studies with Retacrit are in line with the safety profile of other authorized erythropoietins. Based on the results from clinical trials with other authorized erythropoietins approximately 8% of patients treated with erythropoietin are expected to experience adverse reactions. Undesirable effects during treatment with erythropoietin are observed predominantly in patients with chronic renal failure or underlying malignancies. These undesirable effects are most commonly headache and a dose dependent increase in blood pressure. Hypertensive crisis with encephalopathy-like symptoms can occur. Attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal.
Thrombotic/vascular events, such as myocardial ischaemia, myocardial infarction, cerebrovascular accidents (cerebral haemorrhage and cerebral infarction), transient ischaemic attacks, deep vein thrombosis, arterial thrombosis, pulmonary emboli, aneurysms, retinal thrombosis, and clotting of an artificial kidney have been reported in patients receiving erythropoietic agents.
Antibody-mediated erythroblastopenia (PRCA) has been reported after months to years of treatment with epoetin alfa. In most of these patients, antibodies to erythropoietins have been observed (see sections 4.3 and 4.4).
In this section frequencies of undesirable effects are defined as follows: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (frequency cannot be estimated from the available data).
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SOC
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Frequency
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ADR
|
|
Blood and lymphatic system disorders
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very rare
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Thrombocytosis (see section 4.4)
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Frequency not known
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Antibody-mediated erythroblastopenia (PRCA)
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Immune system disorders
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rare
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Hypersensitivity reactions
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very rare
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anaphylactic reaction
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|
Nervous system disorders
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very common
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dizziness (chronic renal failure patients)
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|
headache (cancer patients)
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|
common
|
dizziness (cancer patients)
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|
headache (chronic renal failure patients)
|
|
stroke[LU2]
|
|
uncommon
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cerebral haemorrhage
|
|
Frequency not known
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cerebral infarction
|
|
transient ischaemic attacks
|
|
hypertensive encephalopathy
|
|
Eye disorders
|
Frequency not known
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retinal thrombosis
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|
Cardiac disorders
|
Frequency not known
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myocardial infarction
|
|
myocardial ischaemia
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|
Vascular disorders
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common
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deep vein thrombosis (cancer patients)
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|
increase in blood pressure
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|
Frequency not known
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aneurysms
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|
arterial thrombosis
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|
deep vein thrombosis (chronic renal failure patients)
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hypertensive crisis
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|
Respiratory, thoracic and mediastinal disorders
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common
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pulmonary embolism (cancer patients)
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|
Frequency not known
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pulmonary embolism (chronic renal failure patients)
|
|
Skin and subcutaneous tissue disorders
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common
|
Non-specific skin rashes
|
|
very rare
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angioedema
|
|
|
Frequency not known
|
pruritus[LU3]
|
|
Musculoskeletal and connective tissue disorders
|
very common
|
joint pains (chronic renal failure patients)
|
|
common
|
joint pains (cancer patients)
|
|
General disorders and administration site conditions
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very common
|
"Flu-like" symptoms (chronic renal failure patients)
|
|
feelings of weakness (chronic renal failure patients)
|
|
tiredness (chronic renal failure patients)
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|
common
|
"Flu-like" symptoms (cancer patients)
|
|
feelings of weakness (cancer patients)
|
|
tiredness (cancer patients)
|
|
Injury, poisoning and procedural complications
|
common
|
clotting of an artificial kidney
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Adult and paediatric haemodialysis patients, adult peritoneal dialysis patients and adult patients with renal insufficiency not yet undergoing dialysis
The most frequent adverse reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. These increases in blood pressure can be treated with medicinal products. Moreover, monitoring of the blood pressure is recommended particularly at the start of therapy. The following reactions have also occurred in isolated patients with normal or low blood pressure: hypertensive crisis with encephalopathy-like symptoms (e.g. headaches and confused state) and generalised tonoclonal seizures, requiring the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning signal.
Shunt thromboses may occur, especially in patients who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.). Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.
Adult cancer patients with symptomatic anaemia receiving chemotherapy
Hypertension may occur in epoetin alfa treated patients. Consequently, haemoglobin and blood pressure should be closely monitored.
An increased incidence of thrombotic vascular events (see section 4.4 and section 4.8 - General) has been observed in patients receiving erythropoietic agents.
Surgery patients in autologous predonation programmes
Independent of erythropoietin treatment, thrombotic and vascular events may occur in surgical patients with underlying cardiovascular disease following repeated phlebotomy. Therefore, routine volume replacement should be performed in such patients.
5.1 Pharmacodynamic properties
Implementation of new QRD format/new SPC guideline.
Pharmacotherapeutic group: Antianaemic preparations, erythropoietin
ATC code: B03XA01
Retacrit is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.[LU1]
Erythropoietin is a glycoprotein that stimulates, as a mitosis‑stimulating factor and differentiating hormone, the formation of erythrocytes from precursors of the stem cell compartment.
The apparent molecular weight of erythropoietin is 32,000‑40,000 Dalton. The protein moiety of the molecule contributes about 58% of total molecular weight and consists of 165 amino acids. The four carbohydrate chains are attached via three N‑glycosidic bonds and one O‑glycosidic bond to the protein. Epoetin zeta is identical in its amino acid sequence and similar in carbohydrate composition to endogenous human erythropoietin that has been isolated from the urine of anaemic patients.
The biological efficacy of erythropoietin has been demonstrated in various animal models in vivo (normal and anaemic rats, polycythaemic mice). After administration of erythropoietin, the number of erythrocytes, the Hb values and reticulocyte counts increase as well as the 59Fe‑incorporation rate.
An increased 3H‑thymidine incorporation in the erythroid nucleated spleen cells has been found in vitro (mouse spleen cell culture) after incubation with erythropoietin. It could be shown with the aid of cell cultures of human bone marrow cells that erythropoietin stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of erythropoietin on bone marrow cells could not be detected.
As with other haematopoietic growth factors, erythropoietin has shown in vitro stimulating properties on human endothelial cells.
721 cancer patients receiving non‑platinum chemotherapy were included in three placebo‑controlled studies, 389 patients with haematological malignancies (221 multiple myeloma, 144 non‑Hodgkin's lymphoma, and 24 other haematological malignancies) and 332 with solid tumours (172 breast, 64 gynaecological, 23 lung, 22 prostate, 21 gastrointestinal, and 30 other tumour types). In two large, open‑label studies, 2697 cancer patients receiving non‑platinum chemotherapy were included, 1895 with solid tumours (683 breast, 260 lung, 174 gynaecological, 300 gastrointestinal, and 478 other tumour types) and 802 with haematological malignancies.
In a prospective, randomised, double‑blind, placebo‑controlled trial conducted in 375 anaemic patients with various non‑myeloid malignancies receiving non‑platinum chemotherapy, there was a significant reduction of anaemia‑related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy‑Anaemia (FACT‑An) general scale, FACT‑An fatigue scale, and Cancer Linear Analogue Scale (CLAS). Two other smaller, randomized, placebo‑controlled trials failed to show a significant improvement in quality of life parameters on the EORTC‑QLQ‑C30 scale or CLAS, respectively.
Erythropoietin is a growth factor that primarily stimulates red 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. The studies either recruited patients who were being treated with chemotherapy (two studies) or used patient populations in which erythropoiesis stimulating agents are not indicated: anaemia in patients with cancer not receiving chemotherapy, and head and neck cancer patients receiving radiotherapy. 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 statisfactorily 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 an increased risk for thromboembolic events in patients with cancer treated with recombinant human erythropoietin and a negative impact on overall survival cannot be excluded. 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.
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).
This paragraph has been added as requested by EMA
In a randomised, double-blind, placebo-controlled study 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 (see section 4.4). The study did not meet either primary objective of demonstrating a reduction in risk for all-cause mortality, cardiovascular morbidity, or end stage renal disease (ESRD). Analysis of the individual components of the composite endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68), congestive heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).[LU2]
10. DATE OF REVISION OF THE TEXT
DATE AMMENDED
17th January 2011
