epoetin alfa


LG Chem Life Sciences




LG Chem Life Sciences
Full Prescribing Info
Recombinant human erythropoietin α.
Epotiv Prefilled lnj. contains Recombinant Human Erythropoietin Alpha 4,000 and 10,000 IU.
Pharmacology: Pharmacodynamics: Epotiv Prefilled Inj. is a glycoprotein that stimulates RBC production. It is produced mainly in the kidney and stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. Epotiv Prefilled Inj. consists of a single 165 amino acid peptide chain with a total molecular weight of approximately 30,400 daltons when fully glycosylated. Epotiv Prefilled lnj. is produced by mammalian cells into which the human erythropoietin gene has been introduced. As a product of this recombinant DNA technology, Epotiv Prefilled lnj. has the same amino acid sequence as the naturally occurring hormone, and is functionally and immunologically similar to the endogenous form.
Mechanism of action: Epotiv Prefilled Inj. stimulates the proliferation, maturation, and differentiation of erythroid precursor cells in the bone marrow. The most primitive erythroid progenitor that responds to erythropoietin is called the burst-forming unit-erythroid (BFU-E) because it produces multiclustered colonies of Hb-synthesizing cells in response to increased concentrations of erythropoietin. The colony-forming unit-erythroid (CFU-E) has a lower proliferative potential than the BFU-E, and is absolutely dependent on erythropoietin for its ability to proliferate and differentiate. As differentiation of the erythroid cell line proceeds, erythropoietin dependence declines – a response associated with a loss of erythropoietin receptors.
The maturation time for red blood cell formation is approximately 7 days. During the first 4 days, cell proliferation and differentiation occur. During the remaining 3 days, maturation, including completion of Hb synthesis and nuclear extrusion, occurs. Erythropoietin production in the kidney is controlled by the oxygen-mediated feedback loop. The feedback loop is triggered by a reduction in erythrocyte-carried oxygen, and suppressed by restoration of adequate tissue oxygenation.
Pharmacokinetics: rhEPO is administered by IV or SC injection. Intravenously administered rhEPO is eliminated at a rate consistent with first order kinetics with a circulating half-life ranging from approximately 4 to 13 hours in patients with chronic renal failure (CRF). Within the therapeutic dose range, detectable levels of plasma erythropoietin are maintained for at least for 24 hours. After subcutaneous administration of rhEPO to patients with CRF, peak serum levels are achieved within 5-24 hours after administration and decline slowly thereafter. There is no apparent difference in half-life between patients not on dialysis whose serum creatinine levels were greater than 3, and patients maintained on dialysis. In normal volunteers, the half-life of intravenously administered rhEPO is approximately 20% shorter than the half-life in CRF patients. The pharmacokinetics of rhEPO has not been studied in HIV-infected patients.
Treatment of anemia of chronic renal failure (CRF) patients: Symptomatic anemia; Anemia requiring transfusion.
Dosage/Direction for Use
Recommended Dose: Chronic renal failure patients: Starting dose of Epotiv Prefilled Inj. therapy is 50 U/kg, 3 times per week by slow s.c. or i.v. injection over 1~2 minutes. Further dose increase should be determined according to initial response. Dose may be increased by 25U/kg every four weeks, if needed.
Mode of Administration: Dose may be increased by 25U/kg every four weeks, if needed. Also, when the increasing rate of hemoglobin is more than 2g/dl after 50U/kg is administered, dose should be adjusted by omitting one of the three doses per week. The target range of the treatment is about 10g/dl as hemoglobin concentration (30% hematocrit). If therapeutic effect of Epotiv Prefilled lnj. Inj. in anemia is achieved, 25-50U/kg as a maintenance dose is generally administered 2~3 times per week. It is known that the target range of hemoglobin is 10-12g/dl. The patients who started the therapy at a low level of hemoglobin (6g/dl) need higher maintenance dose than those who didn't start the therapy at less than 8g/dl of hemoglobin and dose should be adjusted depending on age. In any case, maximum dose should not exceed 200U/kg in a single day 3 times per week. Iron stores should be evaluated prior to or during the therapy and iron should be administered, if necessary. In case of aluminum poisoning or infectious disease patients, response may be diminished. Even in case of patients not requiring dialysis, maintenance dose should be determined depending on the severity of anemic symptoms or age, however, it has been reported that 36-38% of hematocrit was sustained for more than 6 months.
In case of patients on hemodialysis, it is recommendable erythropoietin is injected after hemodialysis. And it is desirable erythropoietin be injected slowly over more than 5 minutes to the patients with flu-like symptoms.
Epotiv Prefilled lnj. should not be administered by intravenous infusion.
Responses to Epotiv Prefilled lnj. are individualized according to the dose. In case of over dosage, hypertensive symptoms may occur. If hemoglobin increases excessively, phlebotomy can be indicated.
Epotiv Prefilled lnj. should not be administered to following patients: Patients with history of pure red cell anemia (PRCA) after treatment of erythropoietin preparations.
Patients with hypersensitivity to this product or other erythropoietin preparations.
Patients with uncontrolled hypertension.
Epotiv Prefilled lnj. should be cautiously administered to following patients: Patients with hypertension (Rise in blood pressure caused by erythropoietin administration has been recognized and hypertensive encephalopathy may rise).
Patients with history of hypersensitivity to drug.
Patients with predisposition to allergy.
Patients with myocardial infarction, pulmonary infarction, cerebral infarction and so on, on patients with a chance of thromboembolism by the history of these (It has been reported that the blood viscosity increases with erythropoietin and thromboembolism may be exacerbated or induced. Also since there is a chance of acceleration in blood coagulation, especially in case erythropoietin is administered in order to store autologous blood and after operation, sufficient monitoring is required).
Premature with ventricular hemorrhage and intracerebral hemorrhage (Cerebral hemorrhage may be exacerbated by erythropoietin administration).
Special Precautions
Administration of erythropoietin should be limited to patients with renal anemia who are causing inconvenience in daily lives by being accompanied during anemia. Moreover, erythropoietin should be intended for patients with less than 10g/dl of hemoglobin (30% as hematocrit) in case of renal anemia.
Erythropoietin should not be administered to the other anemia.
Sufficient examination by asking should be made to estimate responses. Moreover, in case administration is initiated or the first dose after discontinuation is administered, it is desirable that total volume be administered after confirming that abnormal response would not occur, by injecting little amount of erythropoietin into vein.
During therapy, hemoglobin and hematocrit should be regularly monitored (about once a week in the early phase of administration, once per every other week in the maintenance phase) with sufficient care to avoid exceeding target range of hematopoiesis (≥12g/dl as hemoglobin or ≥36% as hematocrit). If it is recognized hematopoiesis required is exceeded, appropriate treatments including discontinuance of administration should be made.
Since rise in blood pressure and hypertensive encephalopathy may occur, blood pressure and hematocrit should be increased slowly. Also, hematocrit may increase even after administration is discontinued, and sufficient monitoring should be made. Therefore, blood pressure in patients treated with erythropoietin, particularly patients with cardiovascular disease or patients with chance of hypertension should be carefully monitored. As in case of patients with rapid increase in hematocrit (increases by more than 4% in a 2-week period), excessive rise in hematocrit may exacerbate hypertension, dose should be adjusted.
Among patients with chronic renal failure (CRF) involved in clinical trials of erythropoietin, seizures have been observed. Higher rate of seizures (about 2.5% of patients) appeared in patients on dialysis during the first 90 days of therapy than later time period. In double-blind, placebo-controlled trials involving cancer patients on chemotherapy, seizures were reported in 3.2% (N = 2/63) of patients treated with erythropoietin and 2.9% (N = 2/68) of patients treated with placebo. However, both patients treated with erythropoietin had underlying CNS disease which might have been related to seizures. Therefore, blood pressure and previously known neurologic symptoms should be closely monitored in patients treated with erythropoietin.
Since the thrombotic events such as myocardial infarction, pulmonary embolism, cerebrovascular accident, or transient ischemic attack were observed during erythropoietin therapy, the patients with vascular disease should be carefully monitored.
Since hyperkalemia may be caused by erythropoietin administration, proper dietary management should be carried out.
Since iron is important to erythropoietin therapy, in case of iron deficiency, iron should be supplemented.
Erythropoietin is primarily a growth factor of erythropoiesis. However, the possibility that erythropoietin may act as a growth factor of tumor type, particularly such as myeloid malignancies cannot be excluded.
Incidence of pure red cell anemia (PRCA) has been rarely reported among CRF patients with administration of erythropoietin preparation from months to years. Since most cases of PRCA were found after administration of erythropoietin preparation via s.c. injection, The i.v. route is recommended for the injection of this product. Anti-erythropoietin antibody was found in most cases of PRCA patients. In cases of unexpected diminish of effect, the patients should be checked for the typical causes of non-response to this preparation such as iron, folic acid, or vitamin B12 deficiency, aluminum storage disease, infection or inflammation, exsanguinations, and hematolysis. For the case of PRCA with unknown causes, inspection of marrow should be considered. Diagnosis of PRCA should be followed by checking the presence of anti-erythropoietin antibody and discontinue of administration of this preparation. Since antibodies against erythropoietin preparation show cross-reactivity to other erythropoietin preparations, any erythropoietin preparations should not be used. Other causes of PRCA should be checked for adequate treatments.
Use In Pregnancy & Lactation
Since the safety of Epotiv Prefilled lnj. in pregnant patients has not been established, it is desirable not to administer Epotiv Prefilled lnj. to women who are pregnant or have possibility to be pregnant. However, Epotiv Prefilled lnj. may be administered only if benefit for the treatment exceeds potential risk.
Information of use in children have not been established.
Adverse Reactions
Epotiv Prefilled lnj. is generally well tolerated. The adverse effects reported are frequent sequelae of CRF and may not necessarily attributable to erythropoietin therapy.
Shock: Because shock may occur in rare case, sufficient monitoring should be made and if abnormality is recognized, the administration should be discontinued and proper treatments should be made.
Circulatory system: Rise in blood pressure, thrombosis of blood vessel contact region and so on, and sometimes tachycardia may occur.
Hypertensive Encephalopathy: Since hypertensive encephalopathy showing headache, consciousness disorder, seizure etc caused by sudden rise in the blood pressure is observed and cerebral hemorrhage may occur, administer with sufficient care monitoring the trend of blood pressure, hematocrit and so on.
Encephalopathy: As encephalopathy may occur, observe sufficiently and administration should be discontinued and appropriate treatment should be made in case abnormality is recognized.
Skin: Itch, rash, acne and so on may sometimes occur.
Liver: Hepatosis including AST, ALT, LDH, ALP, Total bilirubin, etc may sometimes occur.
Digestive system: Nausea, vomiting, anorexia and diarrhea may sometimes occur. Abdominal pain can also occur.
Blood: Increase in leukocyte and eosinophil may sometimes occur. Decrease in granulocyte may sometimes occur. Serum potassium, BUN, creatinine and uric acid may sometimes increase. Rickets may sometimes occur. Incidence of pure red cell anemia (PRCA) has been rarely reported among CRF patients with administration of erythropoietin preparation from months to years.
Others: Eye ground hemorrhage, splenomegaly, nasal hemorrhage, sometimes headache, dizziness, pyrexia, slight fever, feeling of flush, malaise, arthralgia, myalgia, bitter taste of mouth, convulsion and blepharedma may occur.
Drug Interactions
Erythropoietin should not be injected in conjunction with other drugs.
Store in hermetic container below 2-8°C in the refrigerator.
Shelf-life: 24 Months.
ATC Classification
B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Soln for inj [colorless or bright light yellow solution (pre-filled syringe)] 4,000 IU/0.4 mL x 1's. 10,000 IU/mL x 1's.
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