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Cardiovascular and Thrombotic Events/Increased Mortality: Cardiovascular and thrombotic events such as myocardial ischaemic and infarction, cerebrovascular haemorrhage and infarction, transient ischaemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, retinal thrombosis and haemodialysis graft occlusion have been reported in patients receiving erythropoiesis stimulating agents (ESAs) such as NESP.
ESAs have been associated with an increased risk of death and serious cardiovascular events or strokes in controlled clinical trials when administered to target a haemoglobin of greater than 12 g/dL. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure, and haemodialysis graft occlusion. A rate of haemoglobin rise of greater than 1 g/dL over 2 weeks may also contribute to these risks.
To reduce cardiovascular risks, use the lowest dose of NESP that will gradually increase the haemoglobin concentration. The haemoglobin concentration should aim not to exceed a target of 12 g/dL; the rate of haemoglobin increase should not exceed 1 g/dL in any 2-week period (see DOSAGE & ADMINISTRATION).
CRF patients with relative hyporesponsiveness to ESAs may be at increased risk for mortality and cardiovascular events. These patients should be evaluated for treatable conditions (see General under PRECAUTIONS).
In a randomised prospective trial, 1432 anaemic chronic renal failure patients who were not undergoing dialysis were assigned to epoetin alfa treatment targeting a maintenance haemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalisation for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%) among the 717 patients in the lower haemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p=0.03).
Increased risk for serious cardiovascular events was also reported from a randomised, prospective trial of 1265 haemodialysis patients with clinically evident cardiac disease (ischaemic heart disease or congestive heart failure). In this trial, patients were assigned to epoetin alfa treatment targeted to a maintenance haemoglobin of either 14±1 g/dL or 10±1 g/dL. Higher mortality (35% versus 29%) was observed in the 634 patients randomised to a target haemoglobin of 14 g/dL than in the 631 patients assigned a target haemoglobin of 10 g/dL.
The reason for the increased mortality observed in this study is unknown; however, the incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomised to a target haemoglobin of 14 g/dL.
In a randomised, double-blind, placebo-controlled study of 4,038 patients called TREAT, there was an increased risk of stroke (HR 1.92, 95% CI: 1.38, 2.68) when darbepoetin alfa was administered to anaemic patients with type 2 diabetes and CRF not on dialysis to target a haemoglobin level of 13 g/dL compared with placebo-treated patients who received darbepoetin alfa when their haemoglobin levels were less than 9 g/dL.
In a post hoc subgroup analysis of TREAT, more deaths from any cause were observed in those patients who indicated a prior history of malignancy and were treated with darbepoetin alfa to target a haemoglobin level of 13 g/dL (60 deaths out of 188 patients randomised to darbepoetin alfa vs. 37 deaths out of 160 patients randomised to placebo; HR: 1.38, 95% CI: 0.91, 2.07).
An increased incidence of thrombotic events has also been observed in patients with cancer treated with ESAs such as NESP (see Adverse Events in Cancer Patients, Thrombotic Events in Cancer Patients under ADVERSE REACTIONS).
In a randomised controlled study (referred to as the 'BEST' study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anaemia (maintain haemoglobin levels between 12 and 14 g/dL or haematocrit between 36% and 42%). The trial was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% versus 3.4%) and a higher rate of fatal thrombotic events (1.1% versus 0.2%) in the first 4 months of the study were observed among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% versus 76%; HR 1.37, 95% CI: 1.07, 1.75; p=0.012).
A systematic review of 57 randomised controlled trials (including BEST and ENHANCE studies) evaluating 9353 patients with cancer compared ESAs plus RBC transfusion with RBC transfusion alone for prophylaxis or treatment of anaemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.
Growth Factor Potential/Increased Tumour Progression: NESP is a growth factor that primarily stimulates red blood cell production. Like all growth factors, there is a theoretical concern that NESP could act as a growth factor for any tumour type, particularly myeloid malignancies.
ESAs have been associated with shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to a haemoglobin between 14 to 15.5 g/dL. NESP should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy.
The ENHANCE study was a randomised controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target haemoglobins of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta, hazard ratio 1.62 (95% CI: 1.22, 2.14; p=0.0008) with a median of 406 days epoetin beta versus 745 days placebo.
The DAHANCA 10 study, conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy were randomised to darbepoetin alfa or placebo. An interim analysis in 484 patients demonstrated a 10% increase in locoregional failure rate among darbepoetin alfa-treated patients (p=0.01). At the time of study termination, there was a trend toward worse survival in the darbepoetin alfa-treated arm (p=0.08).
ESAs have been associated with shortened survival in patients with metastatic breast cancer receiving chemotherapy when administered to a target haemoglobin of greater than 12 g/dL.
The BEST study was previously described (see Cardiovascular and Thrombotic Events/Increased Mortality as previously mentioned). Mortality at 4 months (8.7% versus 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to progressive disease. Investigator assessed time to tumour progression was not different between the two groups.
Use in Cancer Patients: ESAs have been associated with an increased risk of death when administered to a haemoglobin target of 12 to 14 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. NESP is not indicated for this population. NESP should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy.
In a Phase 3, double-blind, randomised (darbepoetin alfa versus placebo), 16-week study in 989 anaemic patients with active malignant disease neither receiving nor planning to receive chemotherapy or radiation therapy, there was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. In addition, there were more deaths in the darbepoetin alfa treatment group [26% (136/515)] than the placebo group [20% (94/470)] at 16 weeks (completion of treatment phase). With a median survival follow up of 4.3 months, the absolute number of deaths was greater in the darbepoetin alfa treatment group [49% (250/515)] compared with the placebo group [46% (216/470); HR 1.29, 95% CI: 1.08, 1.55].
In a phase 3, multicentre, randomised (epoetin alfa versus placebo), double-blind study, patients with advanced non-small-cell lung cancer unsuitable for curative therapy were treated with epoetin alfa targeting haemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in median survival in favour of patients in the placebo group was observed (63 versus 129 days; HR 1.84; p=0.04).
Use in Anaemia with Myelodysplastic Syndrome: NESP should only be administered by or under supervision of a physician with extensive expertise and experience in treating haematologic diseases and only to the patients for whom the use of NESP is considered appropriate.
This product is intended for use in patients who have anaemia-associated problems in their daily activities. The purpose of the treatment should be to avoid blood transfusions, wean patients from transfusion-dependency, or reduce the dose of blood transfusion.
Patients should be carefully interviewed to assess the risk of reactions such as shock. Instruments and medicines for emergency treatment should be prepared beforehand in case of shock, etc. Patients should be kept calm and sufficiently monitored from the start through the end of administration. Especially, careful monitoring is required immediately after the start of administration. When treatment with NESP is started for the first time or restarted after temporary discontinuation, it is recommended to inject intradermally a small amount of NESP and then administer the remaining portion only after confirming that patients do not develop any abnormal reactions.
During treatment with NESP, the haemoglobin concentration should be carefully monitored at regular intervals. Attention should be paid to prevent excessive haemopoiesis (haemoglobin concentration >11 g/dL). (See Pharmacology: Pharmacodynamics: CLINICAL TRIAL under Actions.)
When starting NESP or changing the dose of NESP, measure haemoglobin concentration once a week, until haemoglobin concentration gets stable. If response of excessive haemopoiesis develops, appropriate measures such as temporary discontinuation of NESP should be taken.
Since administration of NESP may increase blood pressure and has been reported to cause hypertensive encephalopathy, parameters such as blood pressure, haemoglobin concentration, etc. should be closely monitored during the treatment.
Pure red cell aplasia associated with production of anti-erythropoietin antibodies may occur. Its occurrence should be suspected if anaemia is not improved or rather exacerbated during the treatment. When pure red cell aplasia is diagnosed, the treatment with NESP should be discontinued.
Iron is an important element for exertion of the pharmacological effect of NESP. Therefore, iron should be administered to patients with iron deficiency.
Hypertension: Patients with uncontrolled hypertension should not be treated with NESP; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anaemia with NESP. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with darbepoetin alfa or epoetin alfa.
Special care should be taken to closely monitor and control blood pressure in patients treated with NESP. During NESP therapy patients should be advised of the importance of compliance with antihypertensive therapy and dietary/fluid restriction. If blood pressure is difficult to control after initiation of appropriate antihypertensive measures, the dose of NESP should be reduced or temporarily withheld until haemoglobin begins to decrease (see DOSAGE & ADMINISTRATION). A clinically significant change in haemoglobin may occur, but may not be observed for several weeks.
Pure Red Cell Aplasia: Pure red cell aplasia (PRCA) in association with neutralising antibodies to native erythropoietin has been observed in patients treated with ESAs, including darbepoetin alfa. This has been reported predominantly in patients with chronic renal failure receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anaemia related to hepatitis C treatment (an indication for which NESP is not approved).
Any patient with loss of response to NESP should be investigated for the typical causes of loss of effect (see General as follows). NESP should be discontinued in any patient with evidence of PRCA and the patient evaluated for the presence of binding and neutralising antibodies to NESP, native erythropoietin, and any other recombinant erythropoietin administered to the patient. In patients with PRCA secondary to neutralising antibodies to any ESAs, NESP should not be administered. Patients should not be switched to other ESAs as antibodies may cross-react with other erythropoietins.
Convulsions: NESP should be used with caution in patients with a history of convulsions. Cases of convulsions have been very rarely reported in patients with CRF receiving darbepoetin alfa.
General: In order to ensure effective erythropoiesis, iron status should be evaluated for all patients before and during treatment, as the majority of patients will eventually require supplemental iron therapy. As per CARI Guidelines (Caring for Australians with Renal Impairment), supplemental iron therapy is recommended for all CRF patients whose serum ferritin is below 100 μg/L or serum transferrin saturation is below 20%.
A lack of response or failure to maintain a haemoglobin response with NESP doses within the recommended dosing range should prompt a search for causative factors. Deficiencies of folic acid or vitamin B12 should be excluded or corrected. Intercurrent infections, inflammatory or malignant processes, osteofibrosis cystica, occult blood loss, haemolysis, severe aluminium toxicity or bone marrow fibrosis may compromise an 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 and bone marrow biopsy demonstrates pure red cell aplasia, testing for anti-erythropoietin antibodies should be conducted.
The safety and efficacy of NESP therapy have not been established in patients with underlying haematologic diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassaemia and porphyria).
Allergic Reactions: There have been reports of serious allergic reactions including anaphylactic reaction, angioedema, dyspnoea, skin rash and urticaria associated with darbepoetin alfa. Symptoms have recurred with rechallenge, suggesting a causal relationship exists in some cases.
Precautions should be taken when administering NESP in case allergic or other untoward reactions occur. If a serious allergic or anaphylactic reaction occurs, NESP should be immediately discontinued and appropriate therapy administered.
Severe Cutaneous Reactions: Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN), have been reported in a small number of patients treated with darbepoetin alfa in the post-marketing environment. Discontinue darbepoetin alfa therapy immediately if a severe cutaneous reaction, such as SJS / TEN, is suspected. Because severe cutaneous adverse reactions have been seen with other ESAs and are not easily predictable, switching to another ESA is not recommended.
Effects on Fertility: No adverse effects on fertility were observed in male and female rats at IV darbepoetin alfa doses of up to 10 μg/kg 3 times weekly. Systemic exposure (plasma AUC times number of doses/week) at the highest dose was about 4 times greater than that in humans at the recommended initial SC dose of 2.25 μg/kg in cancer patients. An increase in post implantation loss was seen at darbepoetin alfa doses of 0.5 μg/kg/day and higher, but this was considered to be associated with polycythaemia in the dams and is therefore unlikely to be of clinical relevance.
Carcinogenicity: Darbepoetin alfa has not been evaluated in standard carcinogenicity bioassays, but there was no evidence from preclinical studies of a proliferative response of any tissue type, other than erythroid progenitor cells, to the drug.
Genotoxicity: Darbepoetin alfa was not mutagenic in assays for gene mutations (bacterial and CHO cell) and was not clastogenic in the mouse micronucleus assay.
Use in Pregnancy & lactation: See USE IN PREGNANCY & LACTATION section for further information.
Use in Children: The safety and efficacy of NESP in paediatric patients have not been established.
