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.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Production of erythropoietin and its regulation occur primarily in the kidneys in response to changes in tissue oxygenation. Production of endogenous erythropoietin is impaired in patients with chronic renal failure, and erythropoietin deficiency is the primary cause of anaemia in these patients. In patients with malignant neoplasms receiving chemotherapy, the aetiology of anaemia is multifactorial. In these patients, erythropoietin deficiency and a diminished 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 the 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 molecular differences, darbepoetin alfa retains 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 achieve a higher target haemoglobin level compared with a lower target level (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 anaemia correction. 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 when haemoglobin levels fell below 9 g/dl). The study did not meet either primary endpoint by demonstrating a reduction in 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 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 performed in patients with chronic renal failure (dialysis, non-dialysis, with diabetes and without diabetes). A trend towards increased estimated risk of all-cause mortality and cardiovascular and cerebrovascular events associated with higher cumulative ESA doses was observed, independent 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 receiving ESA therapy, darbepoetin alfa was administered once weekly (n = 58) or once every two weeks (n = 56) for anaemia correction. 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 a haemoglobin concentration ≥ 10.0 g/dl was first achieved, the mean (SD) weight-adjusted dose 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 epoetin alfa therapy at the current dose, schedule, and route of administration. The primary efficacy endpoint [change in haemoglobin between the baseline and evaluation periods (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 that enrolled 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) receiving darbepoetin alfa, mean haemoglobin concentrations ranged between 11.3 and 11.5 g/dl and mean weight-adjusted darbepoetin alfa doses remained relatively constant (between 2.31 μg/kg per month and 2.67 μg/kg per month) throughout the observation period in the overall 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 ). Cancer patients receiving chemotherapy A 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 designed to exclude a 15% increase in risk of tumour progression or death with epoetin alfa plus standard of care (SOC) compared with SOC alone. At the time of clinical database closure, the mean progression-free survival (PFS), based on the investigator's assessment of disease progression, was 7.4 months in each group (HR 1.09; 95% CI: 0.99; 1.20), meaning the study objective was not met. Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC group (5.8% vs. 11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC group (2.8% vs. 1.4%). At final analysis, 1,653 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07; 95% CI: 0.97; 1.18). Median time to progression (TTP) based on investigator-assessed 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). Median TTP based on PD determined by 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-based chemotherapy, the need for blood transfusion was significantly reduced (p < 0.001). Clinical studies demonstrated that darbepoetin alfa has comparable 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 to reduce the need for erythrocyte transfusions in patients receiving chemotherapy was evaluated. The study included 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., at the first reduction to 300 µg 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 over 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 the comparability of 500 µg once every three weeks dosing with once weekly dosing 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). An improvement in fatigue was also observed, assessed using 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 also be expressed on the surface of various tumour cells. In five large controlled studies involving 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 evaluated. 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 with the control groups. The overall survival outcome in the studies could not be adequately explained by differences in the incidence of thrombosis and related complications between patients treated with recombinant human erythropoietin and those in the control group. In a randomised, double-blind, placebo-controlled phase 3 study, 2,549 adult patients with anaemia being treated with 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), thereby excluding the predefined 15% increase in risk. A systematic review was also conducted, including approximately 9,000 cancer patients in 57 clinical studies. A meta-analysis of overall survival data yielded an estimated hazard ratio of approximately 1.08 in favour of the control groups (95% CI: 0.99; 1.18; 42 studies and 8,167 patients). An increased relative risk of thromboembolic events (RR 1.67; 95% CI: 1.35; 2.06; 35 studies and 6,769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence suggesting that there may be significant harm to cancer patients treated with recombinant human erythropoietin. It is unclear to what extent these findings apply to the administration of recombinant human erythropoietin to patients with malignancies receiving chemotherapy to achieve a haemoglobin concentration below 13 g/dl, as few patients with these characteristics were included in the controlled data. A patient-level data analysis was conducted involving more than 13,900 cancer patients (treated with chemotherapy, radiotherapy, both, or neither) who participated in 53 controlled clinical studies with several epoetins. The 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 treated with 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 shows a consistently and significantly increased relative risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin (see section 4.4 ).