Careful Administration (NESP should be administered with care in the following patients.): (1) Patients with myocardial infarction, pulmonary infarction, cerebral infarction, or those with history of these conditions who may experience thromboembolism [It has been reported that the administration of erythropoietic proteins increased the viscosity of the blood, and may potentially aggravate or induce thromboembolism. Therefore, if NESP is used in these patients, sufficient monitoring is required].
(2) Patients with hypertension [As the administration of NESP may increase blood pressure and induce hypertensive encephalopathy, sufficient monitoring is required].
(3) Patients with a history of hypersensitivity to any drug.
(4) Patients with an allergic predisposition.
Important Precautions: (1) This product is intended for use in patients with renal anemia who have anemia-associated problems in their daily activities. An approximate hemoglobin concentration to start the therapy with this product is less than 10 g/dL (30 % as hematocrit level) for hemodialysis patients, and less than 11 g/dL (33 % as hematocrit level) for the relatively young hemodialysis patients with high activities of daily living, peritoneal dialysis patients, and patients with chronic kidney disease not on dialysis.
(2) Prior to use of NESP, the diagnosis of renal anemia should be confirmed. NESP should not be used in patients with other types of anemia (hemorrhagic anemia, pancytopenia, etc.).
(3) 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 intravenously or intradermally a small amount of NESP and then administer the remaining portion only after confirming that patients do not develop any abnormal reactions.
(4) Regarding hemoglobin concentration in the treatment for renal anemia, clinical studies have shown the following results. During treatment with NESP, the hemoglobin concentration or the hematocrit level should be carefully monitored at regular intervals. Attention should be paid to prevent excessive hemopoiesis (hemoglobin concentration ≥12 g/dL, or hematocrit level ≥36 % for hemodialysis patients) with making reference to the guidelines and other relevant updates.
In hemodialysis patients with ischemic heart disease or heart failure, mortality tended to be higher in patients targeted to a maintenance hemoglobin of 14 g/dL (42 % as hematocrit level) than in patients targeted to a maintenance hemoglobin of 10 g/dL (30 % as hematocrit level).
In treatment with erythropoiesis stimulating agents for renal anemia in patients with chronic kidney disease not on dialysis, significantly higher incidences of death and cardiovascular disorder have been reported in patients with the target hemoglobin concentration set at 13.5 g/dL than in those with the target hemoglobin concentration set at 11.3 g/dL.
In patients with renal anemia, type 2 diabetes, and chronic kidney disease who were not on dialysis, event rate of stroke was higher in patients receiving an erythropoiesis stimulating agent targeted to a hemoglobin level of 13 g/dL than in patients receiving placebo (placebo patients received an erythropoiesis stimulating agent only if their hemoglobin levels were less than 9 g/dL.).
(5) When starting NESP or changing the dose of NESP, measure hemoglobin concentration or hematocrit level once a week or once every two weeks, until hemoglobin concentration or hematocrit level reach the target range and get stable. If response of excessive hemopoiesis develops, appropriate measures such as temporary discontinuation of NESP should be taken.
(6) Since administration of NESP may increase blood pressure and has been reported to cause hypertensive encephalopathy, parameters such as blood pressure, hemoglobin concentration, hematocrit level, etc. should be closely monitored during the treatment. In particular, caution should be exercised to ensure that the hemoglobin concentration or the hematocrit level increases gradually. As NESP is a long-acting drug, its hematopoietic action lasts longer than that of erythropoietin preparations. According to the reports from clinical trials, it took long time for the hemoglobin concentration or the hematocrit level to decrease even after discontinuation of the treatment in some cases. Therefore, patients should be carefully monitored until the hemoglobin concentration or the hematocrit level recovers.
(7) Pure red cell aplasia associated with production of anti-erythropoietin antibodies may occur. Its occurrence should be suspected if anemia is not improved or rather exacerbated during the treatment. When pure red cell aplasia is diagnosed, the treatment with NESP should be discontinued and appropriate measures, excluding switching to erythropoietin preparations, should be taken.
(8) Since the administration of NESP may cause hyperkalemia, appropriate dietary control is required.
(9) Iron is an important element for exertion of the pharmacological effect of NESP. Therefore, iron should be administered to patients with iron deficiency.
(10) Since the administration of NESP may cause shunt occlusion or residual blood in hemodialyzers, the flow of blood through shunts and hemodialyzers should be carefully monitored in hemodialysis patients. If such problems occur, appropriate measures, such as reconstructing a shunt or increasing the dose of an inti-coagulant, should be taken.
(11) Special attention should be paid to the following points when the product is used in patients with chronic kidney disease not on dialysis.
Body fluid balance is difficult to control in patients with chronic kidney disease not on dialysis. Therefore, closely monitor body fluid and electrolyte balance, renal function, and blood pressure.
The effect of this product in improving anemia may weaken with progress of chronic kidney disease. Serum creatinine concentrations and creatinine clearance must be monitored during treatment with this product, and appropriate measures such as increasing the dose or temporary discontinuation of NESP should be taken.
(12) Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Darbepoetin Alfa) in the post-marketing setting. 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.
Precautions Concerning Use: Do not inject NESP with other products.
Before using NESP Syringe, remove the Tip Cap. Attach an appropriate needle, etc., if necessary, and then administer the drug.
Be sure to discard residual solution after use.
Other Precautions: In treatment with erythropoiesis stimulating agents in patientsNote) with anemia caused by cancer chemotherapy or radiotherapy, reduced survival time has been reported.
In treatment with erythropoiesis stimulating agents in patientsNote) with anemia caused by radiotherapy, increased risk of tumor progression and local recurrence has been reported.
It has been reported, in clinical studies in patientsNote) with anemia caused by cancer chemotherapy, that a higher incidence of thromboembolism was noted in patients treated with erythropoiesis stimulating agents than in those treated with placebo.
It has been reported, in clinical studies in patientsNote) with cancer-related anemia who had not received cancer chemotherapy or radiotherapy, that a higher incidence of death was noted in patients treated with erythropoiesis stimulating agents than in those treated with placebo.
Note: Administration of erythropoiesis stimulating agents to these patients has not been approved in Japan.
Use in Children: The safety of NESP in babies with low birthweight, neonates, suckling babies, infants or children has not been established. (NESP has never been used in such patients.)
Use in the Elderly: When NESP is used in elderly patients, parameters such as the blood pressure, hemoglobin concentration and hematocrit level should be frequently measured so that the dosage and the frequency of administration can be appropriately adjusted. [The elderly generally have reduced physiological function and are likely to have cardiovascular complications such as hypertension.]