Full Prescribing Info
Contents
Epoetin alfa (recombinant human erythropoietin).
Description
Each 1 mL contains: Recombinant Human Erythropoietin Alfa 4000 IU.
pH 6.9±0.5.
Excipients: 2.5 mg Albumin (Human), 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg citric acid in Water for injection.
Action
Pharmacology: Pharmacodynamics: Erythropoietin (EPO) is a kind of glycoprotein secreted by kidney, which can accelerate proliferation and differentiation of erythroid hemopoietic progenitor cell of bone marrow. This drug is a preparation of recombinant human erythropoietin (rhEPO) and has similar biological activity both in vivo and in vitro compared to natural EPO. Existing studies show that this drug can increase the colony generation rate of erythroid hemopoietor progenitor cell (CFU-E).
Pharmacokinetics: Plasma concentration: Healthy adults: For healthy adults with an injection of 100 IU/Kg or 200 IU/Kg, the half-life of intravenous injection is 4.76 h or 5.01 h, while plasma concentration will reach to peak (C max) (103.6 or 242.3 mIU/mL) 12 h later for hypodermic injection, then slowly decline within 2.22 or 22.4 h of half-life. The plasma concentration of hypodermic injection is higher than that of intravenous injection 36 h later.
Patients with renal anemia before dialysis: For patients with renal anemia 12-24 h after an Hypodermic injection of 6000 IU or 9000 IU previous to dialysis, plasma concentration will reach 24.6 or 19.1 h of half-life.
Urinary excretion: For healthy adult men, 48 h after an injection of 100 IU/kg or 200 IU/kg, 1.80% or 2.13% of the dosage of intravenous injection will be excreted, while 0.15% or 1.41% of the dosage of hypodermic injection will be excreted.
Toxicology: Repeated dose toxicity: hematopoiesis hyperfunction was found for intravenous injection or intraperitoneal injection to rat for continuous 4 weeks, 13 weeks and 52 weeks with dosages higher than 80, 20 and 10 IU/Kg/day respectively, and myelofibrosis was found for long term administration. Hematopoiesis hyperfunction was found for hypodermic injection to rat born 4 days later for continuous 28 days with a dosage higher that 80 IU/Kg/day, and myelofibrosis and structural change of osteogenesis were found for a dosage of 400 IU/Kg/day. Hematopoiesis hyperfunction was found for intravenous injection to dog for continuous 4 weeks, 13 weeks, and 52 weeks with dosages higher than 200, 100 and 20 IU/Kg/day respectively, and myelofibrosis and structural change of kidney was found for long term administration.
Genetic Toxicity: All results of Ames test, mammalian chromosomal aberration test, micronucleus test and HGPRT locus gene mutation test were negative.
Reproduction toxicity: slight increase in rate of abortion was found for intravenous injection to female rat at 100 and 500 IU/Kg (5.4 and 27 fold of maximum recommended dosage, respectively, calculated on body surface area); the following were found for 500 IU/Kg group; lower increase in weight for F1 (first filial generation) fetuses. Delay in generation of ventrals, opening eyelids and ossification, and reduction in number of caudal vertebras. But no adverse reaction was found in rabbits administered with 500 IU/Kg from 8 to 18 days after becoming pregnant. There is no sufficient and strict controlled clinical study data about pregnant women. It can be used for pregnant women only when the potential benefits is more than the potential harm to fetuses. No drug related adverse reaction was found for F1 and F2 (second filial generation) fetuses when 500 IU/Kg was administered to female rat during perinatal period. It is not sure whether this drug is excreted through human milk. Pregnant women should use carefully considering that many drugs can be excreted through human milk.
Indications/Uses
In the management of anemia of chronic renal failure; In adults receiving chemotherapy for non-myeloid malignant disease; In adult HIV-positive patient in zidovudine therapy; and to increase the yield of autologous blood.
Dosage/Direction for Use
Erythropoietin is a glycosylated protein hormone and a haematopoietic growth factor. It is secreted primarily by the kidneys, although a small amount is produced in extrarenal sites such as the liver. Erythropoietin regulates erythropoiesis by stimulating the differentiation and proliferation of erythroid precursors, the release of reticulocytes into the circulation, and the synthesis of cellular haemoglobin. The release of erythropoietin is promoted by hypoxia or anaemia, and up to 1000 times the normal serum-erythropoietin concentration may be reached under these conditions; this response may be impaired in some disease states such as chronic renal failure.
The haematological response to erythropoietin is reduced if there is an inadequate supply of iron. For an outline of blood cell formation in general and average cell counts in adults.
Epoetin alfa and epoetin beta are recombinant human erythropoietins available for clinical use that have the same pharmacological actions as endogenous erythropoietin. They are used in the management of anaemia associated with chronic renal failure in dialysis and predialysis patients; they may reduce or obviate the need or blood transfusions in these patients. Epoetin delta is under investigation for anaemia in chronic renal failure. Epoetin Alfa and epoetin beta are also used in the management of chemotherapy-induced anaemia in patients with non-myeloid malignant disease. Epoetin alfa is used in zidovudine-related anaemia in HIV-positive patients. Epoetin beta is used in the management of anaemia of prematurity. Recombinant human erythropoietin is also being evaluated in the management of other types of normocytic-normochromic anaemias, including that associated with inflammatory disorders such as rheumatoid arthritis. In all patients, iron status should be monitored and supplementation provided if necessary.
Epoetin alfa and epoetin beta may also be used in patients with moderate anaemia (but no iron deficiency) before elective surgery to increase the yield of blood collected for autologous blood transfusions. Epoetin alfa may also be used in such patients to reduce the need for allogenic blood transfusions.
In the management of anaemia of chronic renal failure epoetin alfa or epoetin beta may be given subcutaneously or intravenously, depending on the formulation. The intravenous route is recommended for patients on haemodialysis. The aim of treatment is to increase the haemoglobin concentration to 10 to 12 g per 100 mL or to increase the haematocrit to 30 to 36%. The rate of rise in haemoglobin should be gradual to minimise adverse effects such as hypertension, a rate not exceeding 2 g per 100 mL per month is suggested.
Epoetin alfa may be given by intravenous injection over at least 1 minute; slow intravenous injection over 5 minutes may be used in patients who experience flu-like symptoms as adverse effects. Epoetin alfa may also be given subcutaneously, but preparations that contain polysorbate 80 should only be given intravenously in this group of patients.
In predialysis and haemodialysis patients, a Recommended initial close epoetin alfa is 50 international units/kg three times weekly; a higher initial dose of 50 to 100 units/kg three times weekly has been suggested in the USA.
Doses may be increased at 4-week intervals in increment of 25 units/kg three times weekly until the target is reached.
In patients on peritoneal an initial dose of 50 units/kg given intravenously twice weekly may be used.
Once the target is reached doses may need to be adjusted, and even decreased, for maintenance therapy.
The usual total weekly maintenance dose of epoetin alfa in predialysis patients is 50 to 100 units/kg given in three divided doses, and in haemodialysis patients it is about 75 to 300 units/kg given in three divided doses. In predialysis patients a total weekly dose of 600 units/kg should not be exceeded. In patients on peritoneal dialysis, the usual total weekly maintenance dose is 50 to 100 units/kg given intravenously in two divided doses.
In children, epoetin alfa may be given intravenously to those on haemodialysis.
The initial dose is 50 units/kg three times weekly. The dose may be increase at 4-week intervals in increments of 25 units/kg three times weekly until a target haemoglobin concentration of 9.5 to 11 g per 100 mL is reached.
The total weekly maintenance dose given in three divided doses is: 225 to 450 units/kg for those weighing less than 10 kg; 180 to 450 units/kg for those weighing 10 to 30 kg; 90 to 300 units/kg for those weighing over 30 kg.
In patients with non-myeloid malignant disease receiving chemotherapy, epoetin alfa or epoetin beta may be given by subcutaneously injection in an initial dose of 150 units/kg three times weekly. The dose may be increased after 4 or 8 weeks, if necessary, to 300 units/kg three times weekly. If the response is still inadequate after 4 weeks at this higher dose, treatment should be stopped. As alternative regiments, the total weekly dose of epoetin beta may be given as a single dose or divided into 3 to 7 doses. Epoetin alfa may also be given in once-weekly doses of 450 units/kg or 40,000 units; the dose may be increased 60,000 units after 4 weeks if necessary. The rise in haemoglobin should be gradual; a rate not exceeding 2 g per 100 mL per month, and a target haemoglobin concentration of not more than 12 g per 100 mL, are suggested. After the end of chemotherapy, epoetin alfa or epoetin beta may be continued for up to one month.
In HIV-positive patients on zidovudine therapy, epoetin alfa may be beneficial if the endogenous serum-erythropoietin concentration is 500 milliunits/mL or Less. Epoetin alfa is given by subcutaneously or Intravenous injection in an initial dose of 100 units/kg three times weekly for 8 weeks. The dose may then be increased every 4 to 8 weeks by 50 to 100 units/kg three times weekly according to response. However, patients are unlikely to benefit from dose above 300 units/kg three times weekly if this dose has failed to elicit a satisfactory response.
To increase the yield of autologous blood, epoetin alfa or epoetin beta may be used with iron supplementation. The dose depends on the volume of blood required for collection and on factors such as the patients' whole blood volume and haematocrit. Suggested regimens are; epoetin alfa 600 units/kg given intravenously twice weekly starting 3 weeks before surgery up to 800 units/kg of epoetin beta intravenously, or up to 600 units/kg subcutaneously, twice weekly for 4 weeks before surgery.
To reduce the need for allogenic blood transfusion epoetin Alfa may be given in a dose of 600 units/kg subcutaneously once weekly starting 3 weeks before surgery, with a fourth dose given on the day of surgery, alternatively, when the time before surgery is short, 300 units/kg subcutaneously daily may be given for 10 days before surgery, on the day of surgery, and for 4 days after.
Administration in neonates: Recombinant human erythropoietin may be given to neonates for anaemia of prematurity. It is usually given by subcutaneous injection. Intravenous infusion in total parenteral nutrition solutions produced satisfactory results in a group of 20 neonates. Enteral dosage in one small study increased plasma-erythropoietin concentrations and peak reticulocyte counts, but in another larger study it had no effect.
Overdosage
May cause elevation in hematocrit and various vital complications of cardiovascular system.
Contraindications
Uncontrolled severe hypertension patients.
Patients' hypersensitive to the drug and other materials derived from mammalian cells, as well as human serum albumin.
It's suitable to control infections before use for patients with complicated infections.
Special Precautions
Hematocrit should be checked periodically during treatment (once a week during the primary period, once every two weeks during maintenance phase) to avoid formation of excessive red cells (ensure which to be less than 36 vol %). Administration shall be discontinued provisionally, if excessive red cells are formed.
Diet shall be adjusted because application of this drug may cause slight elevation of serum potassium sometimes. Dosage shall be adjusted under the guidance of doctors if elevation of serum potassium occurs.
For patients with myocardial infarction, pulmonary infarction and cerebral infarction, and patients with allergic history and allergic tendency, use of the drug shall be careful.
During the treatment, demand of iron will increase because of effective hemopoiesis. Usually, the concentration of serum iron will decrease. Iron preparation shall be supplied everyday if serum ferritin is lower than 100 mg/mL or transferrin saturation is lower than 20%.
Deficiency of folic acid or vitamin B12 will lower curative effect of the drug, so does serious excessive aluminum.
Athlete shall use carefully.
Use in Children: No data to support the medication security for prematures, newborns and infants.
Use in Elderly: Elderly patients shall monitor blood pressure and hematocrit, and adjust dosage and frequency appropriately.
Use In Pregnancy & Lactation
Pregnancy and Nursing Mothers: No data to support the medication security for pregnancy and nursing mothers.
Adverse Reactions
Adverse Effects and Treatment: Adverse effects of epoetins include flu-like symptoms such as fever, chills, headache, arthralgias, myalgias, asthenia, dizziness, and tiredness, which occur especially at the start of treatment. Other effects include rashes, urticaria, nausea and vomiting, diarrhea, hyperkalaemia, and reactions at the injection site. Severe hypersensitivity reactions have been reported rarely. Pure red cell aplasia associated with neutralising antibodies has also been reported rarely in patients with chronic renal failure. Modest increases in the platelet count within the normal range may occur during epoetin therapy.
Hypertension is common with the use of epoetins, particularly in patients with renal failure, and is associated with a rapid rise in haematocrit. Hypertension crisis with encephalopathy and seizures has been reported, even in patients with initially normal or low blood pressure.
Reports of thromboembolism include myocardial ischaemia and infarction, transient ischaemic attacks and cerebrovascular accidents, deep-vein thrombosis, and pulmonary embolism. Shunt thromboses may occur in the arteriovenous fistulae of dialysis patients, and occlusion of the dialysis system is possible, due to an increased haematocrit.
Drug Interactions
Not clear.
Storage
Store at 2-8°C, protect from light.
Shelf-Life: 24 months.
ATC Classification
B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Presentation/Packing
Soln for inj (vial) 4,000 IU/mL (single-dose; colorless and clear liquid) x 1 mL x 10's.
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