Nesp

Nesp

darbepoetin alfa

Manufacturer:

Dexa Medica
Full Prescribing Info
Contents
Darbepoetin alfa.
Description
NESP 20: Each NESP 20 prefilled syringe injection contains Darbepoetin alfa 20 μg/0.5 ml.
NESP 30: Each NESP 30 prefilled syringe injection contains Darbepoetin alfa 30 μg/0.5 ml.
NESP 40: Each NESP 40 prefilled syringe injection contains Darbepoetin alfa 40 μg/0.5 ml.
NESP 60: Each NESP 60 prefilled syringe injection contains Darbepoetin alfa 60 μg/0.5 ml.
NESP 120: Each NESP 120 prefilled syringe injection contains Darbepoetin alfa 120 μg/0.5 ml.
Excipients/Inactive Ingredients: Sodium dihydrogen phosphate dihydrate, dibasic sodium phosphate hydrate, sodium chloride, polysorbate 80, l-methionine, water for injection.
Action
Pharmacology: NESP exerts an erythropoietic effect by acting on erythroid progenitor cells directly.
Erythropoietic action: When intravenously administered NESP showed an erythropoietic effect (increasing the hemoglobin concentration and the reticulocyte count) more sustained than that of epoetin alfa. Moreover, when intravenously or subcutaneously administered, NESP brought about a marked improvement in anemia. NESP showed an effect of improving anemia equivalent to that of epoetin alfa in a lower administration frequency.
Mechanism of action: By binding with erythropoietin receptors, NESP acted on human hematopoietic progenitor cells to promote colony formation of late erythroid progenitor cells (CFU-E) and early erythroid progenitor cells (BFU-E) in a concentration-dependent manner (in vitro).
Pharmacokinetics: Serum concentration: Single administration: Intravenous administration: Following a single intravenous administration of NESP at a dose of 10-180 μg to patients with renal anemia receiving hemodialysis, the serum concentration increased almost dose proportionally and its time-course changes showed biphasic elimination. AUC also increased almost in proportion to the dose.
Subcutaneous administration: Following a single subcutaneous administration of NESP at a dose of 20-180 μg to patients with chronic kidney disease not on dialysis, the serum concentration increased almost dose proportionally. AUC also increased almost in proportion to the dose.
Repeated administration: Following repeated intravenous administration of NESP at a dose of 10-60 μg to patients with renal anemia receiving hemodialysis for 28 weeks, no change was found in the pharmacokinetics at the final administration when compared to the initial administration. Following repeated intravenous administration of NESP at a dose of 10-180 μg to patients with renal anemia receiving hemodialysis, no major change was found in the serum trough concentration.
Following repeated subcutaneous administration of NESP at a dose of 15-180 μg to patients with chronic kidney disease not on dialysis, no major change was found in the serum trough concentration.
Toxicology: Preclinical safety data: The minimum lethal dose of darbepoetin alfa after single intravenous administration was >1,000 μg/kg in rats and >150 μg/kg in dogs.
Repeat dose toxicity studies of darbepoetin alfa were conducted in rats and dogs. Darbepoetin alfa was administered up to 26 weeks in rats (NOAEL: <1.8 μg/kg) and up to 39 weeks in dogs (NOAEL: 0.1 μg/kg) at intervals of once or 3 times weekly via an intravenous or subcutaneous route. Also, the changes observed in the toxicity studies of darbepoetin alfa were secondary to the erythropoietic activity, excess hematopoietic activity and persistent polycythemia and were similar to those observed for recombinant human erythropoietin.
In the general and safety pharmacology studies (in current regulation "Safety Pharmacology"), darbepoetin alfa, like recombinant human erythropoietin, had no clinically significant effects on the central nervous system, cardiovascular or respiratory system.
No genotoxicity of darbepoetin alfa was observed. In the reproductive and developmental toxicity studies, darbepoetin alfa had no effect on the reproductive function of parent animals and had no teratogenic potential.
Indications/Uses
Anemia associated with chronic kidney disease (CKD) in patients on hemodialysis or not on dialysis.
Dosage/Direction for Use
Hemodialysis patients: Initial dose: The usual dose of NESP in adult patients is 20 μg as darbepoetin alfa (genetical recombination), to be administered as a single intravenous injection once weekly.
Initial dose at the switching from erythropoietin preparations (epoetin alfa (genetical recombination), epoetin beta (genetical recombination), etc): The usual dose of NESP in adult patients is 15-60 μg as darbepoetin alfa (genetical recombination), to be administered as a single intravenous injection once weekly.
Maintenance dose: When correction of anemia is achieved, the usual dose of NESP in adult patients is 15-60 μg as darbepoetin alfa (genetical recombination), to be administered as a single intravenous injection once weekly. If alleviation of anemia is maintained by once weekly injection, the frequency of administration can be changed to once every two weeks with an initial dose set to be two-fold of the dose in the once weekly injection. In this case, the usual dose in adult patients is 30-120 μg administered as a single intravenous injection once every two weeks.
In all cases, the dose should be adjusted in view of the degree of anemic symptoms and the patient's age, and should not exceed 180 μg as a single injection.
Initiate treatment when the hemoglobin level is less than 10 g/dl. If the hemoglobin level approaches or exceeds 11 g/dl, reduce or interrupt the dose of darbepoetin alfa (genetical recombinant).
Patients with chronic kidney disease not on dialysis: Initial dose: The usual dose of NESP in adult patients is 30 μg as darbepoetin alfa (genetical recombination), to be administered as a single injection once every two weeks subcutaneously or intravenously.
Initial dose at the switching from erythropoietin preparations (epoetin alfa (genetical recombination), epoetin beta (genetical recombination), etc): The usual dose of NESP in adult patients is 30-120 μg as darbepoetin alfa (genetical recombination), to be administered as a single injection once every two weeks subcutaneously or intravenously.
Maintenance dose: When correction of anemia is achieved, the usual dose of NESP in adult patients is 30-120 μg as darbepoetin alfa (genetical recombination), to be administered as a single injection once every two weeks subcutaneously or intravenously. If alleviation of anemia is maintained by once every two weeks injection, the frequency of administration can be changed to once every four weeks with an initial dose set to be two-fold of the dose in the once every two weeks injection. In this case, the usual dose in adult patients is 60-180 μg administered as a single injection once every four weeks subcutaneously or intravenously.
In all cases, the dose should be adjusted in view of the degree of anemic symptoms and the patient's age, and should not exceed 180 μg as a single injection.
Consider initiating darbepoetin alfa treatment only when the hemoglobin level is less than 10 g/dl and the following consideration apply: the rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. If the hemoglobin level exceeds 10 g/dl, reduce or interrupt the dose of darbepoetin alfa, and use the lowest dose of darbepoetin alfa sufficient to reduce the need for RBC transfusions.
Precautions related to Dosage and administration: Initial dose at the switching from an erythropoietin preparation: When NESP is started in substitution for an erythropoietin preparation, the dose and the frequency of administration should be determined on the basis of the dose of the erythropoietin preparation that has been used. See table as follows.
Patients who have been treated with an erythropoietin preparation twice weekly or three times weekly: Calculate the total dose of the erythropoietin preparation administered during the week before the switching, and then determine the initial dose of NESP according to the table as follows. The treatment should be started on once weekly basis.
Patients who have been treated with an erythropoietin preparation once weekly or once every two weeks: Calculate the total dose of the erythropoietin preparation administered during the two weeks before the switching, and then determine the initial dose of NESP according to the table as follows. The treatment should be started on once every two weeks basis. (See Table 1.)


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Dose adjustments: If dose adjustment is required (for example, when the appropriate increase in the hemoglobin concentration or the hematocrit levels can not be achieved in correction phase, or when the hemoglobin concentration or the hematocrit level deviates from the target range for successive two weeks in maintenance phase), the dose should be increased or decreased according to the table as follows. Any dose increase should be performed stage by stage in principle.
Table for dose adjustment in the intravenous administration (hemodialysis patients and patients with chronic kidney disease not on dialysis). (See Table 2.)


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Table for dose adjustment in the subcutaneous administration (patients with chronic kidney disease not on dialysis). (See Table 3.)


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Change of the frequency of administration: When changing the frequency of administration, the hemoglobin concentration or the hematocrit level should be sufficiently monitored before expanding the interval of administration. Be sure that the hemoglobin concentration or the hematocrit level have been kept stable at a certain dose of NESP and then change the frequency of administration from once weekly to once every two weeks, or from once every two weeks to once every four weeks. The hemoglobin concentration or the hematocrit level should be monitored after the change as well, and adjustment should be made as needed.
If the hemoglobin concentration or the hematocrit level fails to reach the target range even with the dose of 180 μg, the dose should be reduced by half and the frequency of administration should be changed from once every two weeks to once weekly, or from once every four weeks to once every two weeks.
Overdosage
In clinical pharmacology studies, there is no clinical experience of use at higher doses.
The maximum amount of NESP that can be safely administered in single or multiple doses has not been determined. Therapy with NESP can result in polycythemia if the hemoglobin is not carefully monitored and the dose appropriately adjusted. Cases of severe hypertension have been observed following overdose with darbepoetin alfa.
In the event of polycythemia, NESP should be temporarily withheld. If clinically indicated, phlebotomy may be performed.
Contraindications
Patient with a history of hypersensitivity to any of the ingredients in the product or to other erythropoietin preparations.
Uncontrolled hypertension.
Special Precautions
NESP should be administered with care in the following patients: Patients with myocardial infarction, pulmonary infarction, or those with history of these condition who may experience thromboembolism. 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.
Patients with hypertension. As the administration of NESP may increase blood pressure and induce hypertensive encephalopathy, sufficient monitoring is required.
Patients with a history of hypersensitivity to any drug.
Patients with an allergic predisposition.
Patients with cancer. As the administration of NESP may increase risk of tumor progression or recurrence.
Patients with chronic kidney disease. As the administration of NESP may increase risk for seizures.
Important precautions: 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).
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.).
Patients should be carefully interviewed to assess the risk of reaction 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.
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 high in patients receiving an erythropoiesis stimulating agent targeted to a hemoglobin level of 13 g/dl.
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.
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. 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.
Pure red cell aplasia associated with production of antierythropoietin 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.
Since the administration of NESP may cause hyperkalemia, appropriate dietary control is required.
Iron is an important element for exertion of the pharmacological effect of NESP. Therefore, iron should be administered to patients with iron deficiency.
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 anticoagulant, should be taken.
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.
Effects on ability to drive and use machines: NESP has no or negligible influence on the ability to drive and use machines. There are no reports of adverse effects that would have effects on ability to drive or operate machinery or that would impair mental ability.
Use in Pregnancy: Use of NESP in pregnant women or women who may possibly be pregnant is not recommended. When the use is necessary in such women, it should be limited to cases where expected therapeutic benefits outweigh possible risks associated with the treatment. The safety of NESP in pregnant women has not been established.
Use in Lactation: Use of NESP in lactating women is not recommended. When the use is necessary in such women, the patients should avoid lactation during the treatment. The safety of NESP in lactating women has not been established.
Use in Children: The safety of NESP in babies with low birthweight, neonates, suckling babies, infants or children has not been established.
Use in 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.
Use In Pregnancy & Lactation
Pregnancy: Use of NESP in pregnant women or women who may possibly be pregnant is not recommended. When the use is necessary in such women, it should be limited to cases where expected therapeutic benefits outweigh possible risks associated with the treatment. The safety of NESP in pregnant women has not been established.
Lactation: Use of NESP in lactating women is not recommended. When the use is necessary in such women, the patients should avoid lactation during the treatment. The safety of NESP in lactating women has not been established.
Adverse Reactions
Adverse reactions were reported in 472 (32.3%) of 1,462 patients treated with NESP. The major adverse reactions were increased blood pressure in 248 cases (17.0%), shunt thrombosis/occlusion in 44 cases (3.0%), headache in 29 cases (2.0%) and malaise in 20 cases (1.4%).
Clinically significant adverse reaction: Cerebral infarction: Since cerebral infarction may occur, patients should be closely monitored. If any abnormalities are observed, appropriate measures such as discontinuation of NESP should be taken.
Cerebral hemorrhage: Since cerebral hemorrhage may occur, patients should be closely monitored. If any abnormalities are observed, appropriate measures such as discontinuation of NESP should be taken.
Hepatic function disorder, jaundice: Since hepatic function disorder and/or jaundice accompanied by increased ALT (GPT), γ-GPT, etc. may occur, patients should be closely monitored. If any adnormalities are observed, appropriate measures such as discontinuation of NESP should be taken.
Hypertensive encephalopathy: Since hypertensive encephalopathy may occur, patients should be closely monitored for changes in the blood pressure, etc. during the treatment.
Shock and anaphylactoid reactions: Since shock and/or anaphylactoid reactions (urticaria, dyspnea, lip edema, pharyngeal edema, etc.) may occur, patients should be closely monitored. If any abnormalities are observed, NESP should be discontinued and appropriate measures should be taken.
Pure red cell aplasia: Pure red cell aplasia accompanied by production of anti-erythropoietin antibodies may occur. If such a problem is observed, NESP should be discontinued and appropriate measures should be taken.
Myocardial infarction, pulmonary infarction: Since myocardial infarction and/or pulmonary infarction may occur, patients should be closely monitored. If any abnormalities are observed, appropriate measures such as discontinuation of NESP should be taken.
Other adverse reactions: Incidence of adverse reactions is listed by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated). (See Table 4.)


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Drug Interactions
The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other substances. However, there is potential for an interaction with substances that are highly bound to red blood cells e.g. cyclosporine and tacrolimus. If NESP is given concomitantly with any of these treatments, blood levels of these substances should be monitored and the dosage adjusted as the haemoglobin rises.
Caution For Usage
Instruction for use and handling: Do not inject NESP with other products.
Before using NESP prefilled-syringe injection, remove the tip cap. Attach an appropriate needle, if necessary, and then administer the drug.
Be sure to discard residual solution after use.
Storage
Store at temperature between 2-8°C.
Protect from light.
Do not freeze.
Avoid shaking.
Shelf-life: 24 months.
ATC Classification
B03XA02 - darbepoetin alfa ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Presentation/Packing
Soln for inj (prefilled syringe) 20 mcg/0.5 mL x 1's. 30 mcg/0.5 mL x 1's. 40 mcg/0.5 mL x 1's. 60 mcg/0.5 mL x 1's. 120 mcg/0.5 mL x 1's.
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