ARANESP 100MCG Solution for injection in vial

Pharmacotherapeutic group: Antianemic agents, other antianemic agents, ATC code: B03XA02. Mechanism of action Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of erythropoiesis through specific interaction with the erythropoietin receptor on erythroid progenitor cells in the bone marrow.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Erythropoietin production and its regulation occur primarily in the kidneys in response to changes in tissue oxygenation. Endogenous erythropoietin production is impaired in patients with chronic renal failure, and erythropoietin deficiency is the primary cause of anaemia in these patients. In patients with malignant disease receiving chemotherapy, the aetiology of anaemia is multifactorial. In these patients, erythropoietin deficiency and a decreased response of erythroid progenitor cells to endogenous erythropoietin contribute significantly to the development of anaemia. Pharmacodynamic effects Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous hormone. Darbepoetin alfa has five nitrogen-linked carbohydrate chains, whereas endogenous hormone and recombinant human erythropoietins (r-HuEPO) have three. The additional sugar residues are molecularly indistinguishable 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 greater in vivo activity. Despite the molecular differences, darbepoetin alfa retains a very narrow specificity for the erythropoietin receptor. Clinical efficacy and safety Patients with chronic renal failure In patients with chronic renal failure, two clinical studies demonstrated a higher risk of death and serious cardiovascular events when ESAs were administered to target higher haemoglobin levels compared to lower target 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 a randomised, double-blind correction study (n = 358) comparing once every two weeks and once monthly dosing regimens in non-dialysis patients with chronic renal failure, once monthly dosing of darbepoetin alfa was non-inferior to once every two weeks dosing for correction of anaemia. The median (interquartile range Q1–Q3) time to haemoglobin correction (≥ 10.0 g/dl and increase ≥ 1.0 g/dl from baseline) was 5 weeks for both dosing regimens, once every two weeks (Q1, Q3 – 3, 7 weeks) and once monthly (Q1, Q3 – 3, 9 weeks). During the evaluation period (weeks 29–33), the mean (95% CI) weekly equivalent dose was 0.20 (0.17; 0.24) μg/kg in the once every two weeks arm and 0.27 (0.23; 0.32) μg/kg in the once monthly arm. In a randomised, double-blind, placebo-controlled study (TREAT) involving 4,038 non-dialysis patients with chronic renal failure with type II diabetes and haemoglobin levels ≤ 11 g/dl, patients received either darbepoetin alfa to achieve a haemoglobin level of 13 g/dl or placebo (with rescue darbepoetin alfa administration for haemoglobin levels below 9 g/dl). The study did not meet either primary endpoint of demonstrating a reduction in the risk of all-cause mortality or cardiovascular morbidity (darbepoetin alfa vs placebo; Hazard Ratio 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 HRs (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). Pooled post-hoc analyses of clinical studies with ESAs were conducted in patients with chronic renal failure (dialysis, non-dialysis, with and without diabetes). A trend towards increased estimated risk of all-cause mortality, cardiovascular and cerebrovascular events associated with higher cumulative ESA doses was observed regardless of diabetes or dialysis status (see sections 4.2 and 4.4). Paediatric population In a randomised clinical study involving 114 dialysis and non-dialysis paediatric patients aged 2–18 years with chronic kidney disease who had anaemia (haemoglobin below 10.0 g/dl) and were not treated with ESAs, darbepoetin alfa was administered once weekly (n = 58) or once every two weeks (n = 56) for correction of anaemia. Haemoglobin concentrations were corrected to ≥ 10 g/dl in more than 98% (p < 0.001) of paediatric patients receiving darbepoetin alfa once weekly and in 84% (p = 0.293) receiving it once every two weeks. At the time when haemoglobin concentration ≥ 10.0 g/dl was first achieved, the mean dose (SD) based on body weight was 0.48 (0.24) μg/kg (range: 0.0 to 1.7 μg/kg) weekly for the once weekly group and 0.76 (0.21) μg/kg (range: 0.3 to 1.5 μg/kg) every two weeks for the once every two weeks group. In a clinical study involving 124 dialysis and non-dialysis paediatric patients aged 1–18 years with chronic kidney disease who were stable on epoetin alfa therapy, patients were randomised either to receive darbepoetin alfa once weekly (subcutaneously or intravenously) using a conversion ratio of 238:1, or to continue treatment with epoetin alfa at the current dose, schedule and route of administration. The primary efficacy endpoint [change in haemoglobin between the baseline and evaluation period (weeks 21–28)] was comparable between the two groups. Mean baseline haemoglobin levels were 11.1 (SD 0.7) g/dl for r-HuEPO and 11.3 (SD 0.6) g/dl for darbepoetin alfa. Mean haemoglobin levels at week 28 were 11.1 (SD 1.4) g/dl for r-HuEPO and 11.1 (SD 1.1) g/dl for darbepoetin alfa. In a European Observational Registry study enrolling 319 paediatric patients with chronic kidney disease (13 (4.1%) patients under 1 year of age, 83 (26.0%) patients aged 1 to 6 years, 90 (28.2%) patients aged 6 to 12 years and 133 (41.7%) patients aged 12 years and older) who received darbepoetin alfa, mean haemoglobin concentrations ranged between 11.3 and 11.5 g/dl and mean weight-based darbepoetin alfa doses remained relatively constant (between 2.31 μg/kg per month and 2.67 μg/kg per month) throughout the observation period for the entire study population. In these studies, no significant differences were identified between the safety profile in paediatric patients and the previously reported safety profile in adult patients (see section 4.8). Patients with malignant disease receiving chemotherapy The randomised, open-label, multicentre study EPO-ANE-3010 was conducted in 2,098 anaemic women with metastatic breast cancer receiving first- or second-line chemotherapy. This was a non-inferiority study aiming to exclude a 15% increase in the risk of tumour progression or death with epoetin alfa plus standard of care (SOC) compared to SOC alone. At the time of clinical database closure, the mean progression-free survival (PFS), based on investigator assessment of disease progression, was 7.4 months in each group (HR 1.09; 95% CI: 0.99; 1.20), indicating that the study objective was not met. Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC group (5.8% versus 11.4%); however, significantly more patients in the epoetin alfa plus SOC group experienced thrombotic vascular events (2.8% versus 1.4%). At the final analysis, 1,653 deaths were reported. The median overall survival in the epoetin alfa plus SOC group was 17.8 months compared to 18.0 months in the SOC alone group (HR 1.07; 95% CI: 0.97; 1.18). The median time to progression (TTP) based on investigator assessment of disease progression (PD) was 7.5 months in the epoetin alfa plus SOC group and 7.5 months in the SOC group (HR 1.099; 95% CI: 0.998; 1.210). The median TTP based on PD determined by the independent review committee (IRC) was 8 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group (HR 1.033; 95% CI: 0.924; 1.156). In a prospective, randomised, double-blind, placebo-controlled study conducted in 314 patients with lung cancer receiving platinum-containing chemotherapy, the need for blood transfusion was significantly reduced (p < 0.001). Clinical studies have demonstrated that darbepoetin alfa has similar efficacy when administered as a single injection once every three weeks, once every two weeks, or once weekly, without the need to increase the total dose. In a randomised, double-blind international study, the safety and efficacy of Aranesp administered once every three weeks for reducing the need for erythrocyte transfusions in patients receiving chemotherapy were assessed. The study involved 705 anaemic patients with non-myeloid malignancies receiving multiple cycles of chemotherapy. Patients were randomised to receive either 500 µg of Aranesp once every three weeks or 2.25 µg/kg once weekly. In both groups, the dose was reduced by 40% (e.g. to 300 µg at the first reduction for the once every three weeks group and to 1.35 µg/kg for the once weekly group) if haemoglobin increased by more than 1 g/dl within 14 days. In the once every three weeks group, 72% of patients required dose reduction. In the once weekly group, 75% of patients required dose reduction. This study supports once every three weeks dosing of 500 µg as comparable to once weekly administration with respect to the incidence of subjects receiving at least one erythrocyte transfusion from week 5 to the end of the treatment phase. In a prospective, randomised, double-blind, placebo-controlled study conducted in 344 anaemic patients with lymphoproliferative malignancies receiving chemotherapy, the need for blood transfusion was significantly reduced and haemoglobin response was improved (p < 0.001). Improvement in patient fatigue was also observed as assessed by the Functional Assessment of Cancer Therapy-Fatigue (FACT-Fatigue) scale. Erythropoietin is a growth factor that primarily stimulates red blood cell production. However, erythropoietin receptors may be expressed on the surface of a variety of tumour cells. In five large controlled studies with a total of 2,833 patients, of which four were double-blind and placebo-controlled and one was open-label, survival and tumour progression were assessed. Two of these studies included patients receiving chemotherapy. The target haemoglobin concentration was > 13 g/dl in two studies; 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 the control group. In the four placebo-controlled studies, the hazard ratios for overall survival ranged from 1.25 to 2.47 in favour of the control groups. These studies showed a consistent, unexplained, statistically significant increase in mortality in patients with anaemia associated with various common malignancies who received recombinant human erythropoietin compared to controls. The overall survival outcome in the studies could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between patients treated with recombinant human erythropoietin and those in the control groups. In a randomised, double-blind, placebo-controlled phase 3 study, 2,549 adult patients with anaemia receiving chemotherapy for advanced non-small cell lung cancer (NSCLC) were randomised 2:1 to darbepoetin alfa or placebo and treated to a maximum Hb of 12 g/dl. Results demonstrated non-inferiority for the primary endpoint of overall survival with a median survival for darbepoetin alfa versus placebo of 9.5 and 9.3 months, respectively (stratified HR 0.92; 95% CI: 0.83–1.01). The secondary endpoint of progression-free survival was 4.8 and 4.3 months, respectively (stratified HR 0.95; 95% CI: 0.87–1.04), thus excluding the pre-defined 15% increase in risk. A systematic review was also conducted including 9,000 patients with malignant disease in 57 clinical studies. A meta-analysis of overall survival data yielded an estimated survival hazard ratio of approximately 1.08 in favour of controls (95% CI: 0.99; 1.18; 42 studies and 8,167 patients). An increased relative risk of thromboembolic events was observed in patients treated with recombinant human erythropoietin (RR 1.67; 95% CI: 1.35; 2.06; 35 studies and 6,769 patients). There is therefore consistent evidence suggesting that there may be significant harm in patients with malignant disease who are treated with recombinant human erythropoietin. It is not clear to what extent these findings apply to the administration of recombinant human erythropoietin to patients with malignant disease receiving chemotherapy to achieve haemoglobin concentrations of less than 13 g/dl, as few patients with these characteristics were included in the controlled data. A patient-level data analysis of more than 13,900 cancer patients (receiving chemotherapy, radiotherapy, both, or neither treatment) who participated in 53 controlled clinical studies with several epoetins was conducted. A meta-analysis of overall survival data showed a hazard ratio of approximately 1.06 in favour of controls (95% CI: 1.00; 1.12; 53 studies and 13,933 patients), and for cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97; 1.11; 38 studies and 10,441 patients). The meta-analysis also indicates a consistently and significantly increased relative risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin (see section 4.4).