Recombinant human erythropoietin α.
Each 1 mL of solution contains: Epoetin alpha 4000 units, Albumin human 2.5 mg, Sodium citrate 5.88 mg, Citric acid 0.06 mg, Sodium chloride 5.84 mg, Water for Injection 1 mL.
Pharmacology: Pharmacodynamics: Chronic Renal Failure Patients: The level of tissue oxygenation normally regulates endogenous production of erythropoietin. Hypoxia and anemia generally increase the production of erythropoietin which in turn stimulates erythropoiesis. In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 units/mL and increase up to 100 to 1000 fold during hypoxia or anemia. In contrast, in patients with chronic renal failure (CRF), production of erythropoietin is impaired, and this erythropoiet in is the primary cause of their anemia.
The clinical situation where there is a progressive and usually irreversible decline in kidney function is chronic renal failure (CRF). Renal dysfunction, including anemia, with or without regular dialysis can be manifested in some patients. Those patients with CRF who require regular dialysis or dialysis or kidney transplantation for survival are patients with end-stage renal disease (ESRD). Epoetin alpha stimulates erythropoiesis in anemic patients with CRF for both patients requiring dialysis or Epoetin alpha not.
An increase in the reticulocyte count within 10 days, followed by increases in the red cell count hemoglobin, and hematocrit is the first evidence of a response to Epoetin alpha treatment of three times weekly administration of the drug. Because of the length of time required for erythropoiesis which is several days for erythroid progenitors to mature and be released into the circulation, it will take at least 2-6 weeks for a clinically significant increase in hematiocrit level. Upon reaching the suggested target range (30%-36%) for hematocrit increase. Epoetin alpha can sustain that level in the absence of iron deficiency and concurrent illnesses.
that level in the absence of iron deficiency and concurrent illnesses.
Hematocrit increase varies between patients and is dependent upon the dose of Epoetin alpha with the given therapeutic range of approximately 50 to 300 units/kg three times weekly. If the dose exceeds 300 units/kg three times weekly, a greater biologic response is not observed. The baseline hematocrit, availability of iron stores and the presence of concurrent medical problems are other factors that can affect the rate and extent of response.
Zidovudine-treated HIV infected patients: Epoetin alpha response in HIV-infected patients is dependent upon the endogenous serum erythropoietin level prior to treatment. Patients with endogenous serum erythropoietin level ≤0.5 units/mL and who are receiving a dose of zidovudine ≤ 420 mg/week, may respond to Epoetin alpha therapy. Patients with endogenous serum erythropoietin levels > 0.5 units/mL do not appear to respond to Epoetin alpha therapy. In a series of four clinical trials involving 255 patients, 60% to 80% of HIV-infected patients treated with zidovudine had endogenous serum erythropoietin levels ≤ 0.5 units/mL. Reduced transfusion requirements and increased hematocrit are manifestations of a response to Epoetin alpha in Zidovudine-treated HIV-patients.
Cancer patients on Chemotherapy: Concomitant use of chemotherapeutic drug can cause anemia in cancer patients. Epoetin alpha has been shown to increase hematocrit and decrease transfusion requirements after the first month of therapy (months 2 and 3), in anemic cancer patients undergoing chemotherapy.
A series of clinical trials involved 131 anemic cancer patients who were receiving cisplatin or non-cisplatin containing chemotherapy. Endogenous baseline serum erythropoietin levels varied among patients in these trials with approximately 75% (n = 83/110) having endogenous serum erythropoietin levels > 0.5 units/mL. In general, patients with lower baseline serum erythropoietin levels responded more vigorously to Epoetin alpha than patients with higher baseline erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would unlikely to respond to Epoetin alpha therapy. Treatment of patients with grossly elevated serum erythropoietin levels (e.g. >0.2 units/mL) is not recommended.
Pharmacokinetics: Epoetin alpha administered intravenously is eliminated at a rate consistent with first order kinetics. Half-life of Epoetin alpha in patients with chronic renal failure ranges from 4 to 13 hours. Generally after 24 hours of administration of Epoetin alpha, plasma levels return to their baseline levels. After subcutaneous administration of Epoetin alpha, peak serum levels are achieved within 5 to 24 hours after administration, and decline more slowly thereafter.
In healthy volunteers, half-life after intravenous administration is 20% shorter than the one observed for chronic renal failure patients. Recombinant human erythropoietin is available only for injection. The onset of response has been reported to occur as early as 7 days. However, some patients may require as long as 6 weeks of treatment to achieve optimal effect. Peak serum levels occur within 5 to 24 hour after subcutaneous administration and decrease slowly.
Measurable plasma levels of Epoetin alpha are sustained for at least 24 hours. Recombinant human erythropoietin is extracted from plasma by erythroid precursors. It is eliminated via first-order kinetics with circulating half-life of 4 to 13 hours after intravenous administration in patients with CRF. The half-life in healthy adults is 20% shorter than in CRF patients.
Subcutaneous administration results in a prolonged half-life between patients with CRF not on dialysis and those maintained on dialysis. The pharmacokinetics of Epoetin alpha in children and adolescents appear similar to those of adults. Phamacokinetics data in neonates is limited. In children on continuous ambulatory peritoneal dialysis (CAPD), Epoetin alpha is sometimes administered by the intraperitoneal route in order to avoid the psychological distress associated with subcutaneous administration.
A study by Kausz colleagues evaluated the efficacy and Pharmacokinetics of intraperitoneal Epoetin alpha in eight children. A single dose of 100 units/kg in 50 mL of dialysate was administered into a dry peritoneal cavity after nightime dialysis. Relative bioavailability was similar to subcutaneous dosing. Patients maintained a normal hematocrit level with an intraperitoneal Epoetin dose that was similar to their previous subcutaneous dose.
Epoetin alpha (Renogen) is indicated in the following: Treatment of anemia associated with CRF: Epoetin alpha indicated in patients with anemia on dialysis (ESRD) and patients not on dialysis. Epoetin alpha can elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and decrease the need for transfusions in these patients. Patients who do not undergo dialysis but with symptomatic anemia considered for therapy should have a hematocrit less than 30%. Epoetin alpha is not intended for patients who require immediate correction of severe anemia.
Epoetin alpha may prevent the need for maintenance transfusions but is not a substitute for emergency transfusion.
Patient's iron stores should be evaluated prior to initiation of therapy.
Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL.
Blood pressure should be adequately controlled prior to initiation of Epoetin alpha therapy, and must be closely monitored and controlled during therapy. Epoetin alpha should be administered under the guidance of a qualified physician.
Treatment of Anemia in Zidovudine treated HIV-infected patients: Epoetin alpha is indicated for the anemia related to therapy with zidovudine in HIV-infected patients.
Epoetin alpha is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding, which should be managed appropriately.
Epoetin alpha at a dose of 100 units/kg three times weekly is effective in decreasing the transfusion requirement and increasing the red blood cell level of anemic, HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is ≤ 500 units/mL and when patients are receiving a dose of zidovudine ≤ 4200 mg/week.
Treatment of Anemia in Cancer Patients on Chemotherapy: Epoetin alpha is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. Epoetin alpha is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months. Epoetin alpha is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding, which should be managed appropriately.
see Table 1.
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Maintenance dose: Dose should be individualized for each patient upon reaching the target hematocrit range.
Mode of Administration:
Intravenous and Subcutaneous administration.
Information to Patients:
The dose Renogen should be reduced as the hematocrit level approaches 36% or has increased by more than 4 points in any 2-week period.
Renogen should be given through intravenous and subcutaneous administration only.
Do not shake. Vigorous shaking of Renogen may denature any glycoprotein, rendering it biologically inactive. Do not use if there is any particulate matter or discoloration.
Using aseptic techniques, attach a sterile needle to a sterile syringe.
Remove the flip top from the vial containing Renogen and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.
Renogen does not contain any preservatives: discard unused portions.
Do not dilute or administer with other drug solutions.
Maximum dose for Epoetin alpha that can be safely administer either in bolus or infusion has not been defined yet. Doses up to 1500 units/kg three times weekly have been used without any direct toxic effects. Epoetin alpha treatment can produce polycythemia and patients may refer symptoms such as headache, dizziness, etc. If they occur, phlebotomy may be indicated to decrease hematocrit.
Hypersensitivity to mammalian cell-derived products.
Hypersensitivity to albumin (human).
Pure Red Blood Cell Aplasia (PRCA): According to the increased incidence of antibody-mediated pure red blood cell aplasia (PRCA) in chronic renal failure patients who were administered Epoetin subcutaneously for long term treatment, as well as Hepatitis C patients who were treated Erythropoiesis-stimulating agents (ESAs) with interferon and ribavirin as combination therapy.
For those patients who poorly responsive to ESA therapy and require transfusion, a reticulocyte count testing should be investigated, in case of reticulocyte index less than 20,000/microliters or less than 0.5% with normal platelets and white blood cells, the anti-erythropoietin antibodies and bone marrow testing should be performed to investigate the PRCA.
Unless the test results are clear, the patient should be warned to discontinue the treatment with Epoetin including ESA therapy due to cross-reaction.
Erythropoiesis-stimulating agents (ESAs) might be associated with serious adverse events, for example, hypertension, lack of effect/efficacy(LOE), and pure red blood cell aplasia (PRCA).
According to the incidence of thrombotic vascular events (TVEs)might increase in patients who were administered ESAs, therefore the benefit-risk assessment is recommended should be observed from the treatment in patients with an increased risk of thrombotic vascular events, for example, obesity, patients with a prior history of TVEs (e.g. deep venous thrombosis or pulmonary embolism) and patients with cancer.
Patients who develop antibody-mediated Pure Red Cell Aplasia (PRCA)following treatment with Renogen, must be immediately discontinued and testing for erythropoietin antibodies should be considered.
Patients with conditions associated with thrombotic/vascular events should be closely monitored.
Epoetin alpha should be administered under the guidance of a physician experienced in the use of such therapy.
Hematocrit should be determined at least once a week in HIV-infected patients with zidovudine-induced anemia or cancer patients with chemotherapy-induced anemia and at least once or twice weekly in patients with anemia of chronic renal failure until it has stabilized within the desired target range; subsequence the monitoring of hematocrit should be performed at regular intervals.
If the increase in hematocrit exceeds 4% in any 2-week period, the dosage of Epoetin alpha should be reduced to minimize the possibility of adverse effects, including exacerbation of hypertension in chronic renal patients. Blood pressure monitoring is particularly important in patients with an underlying history of hypertension or cardiovascular disease.
The safety and efficacy of Epoetin alpha has not been established in patients with a preexisting seizure order, and the drug should be used with caution in such patients.
Epoetin alpha treatment should be discontinued if anaphylactoid reactions should occur. Mild and transient rash and urticaria have been reported rarely.
Patients with iron overload prior to starting therapy with the drug may not require such supplementation initially as the shift of excess iron tissues and/or the reticuloendothelial system occurs, however profound iron deficiency may develop subsequently, so monitoring serum and tissue iron stores is essential during Epoetin alpha therapy.
Compliance with concurrent drug therapy, dietary restrictions and dialysis schedules should be encouraged in chronic renal failure patients receiving Epoetin alpha therapy.
Conditions that may diminish or block the effects of Epoetin alpha include states of acute or chronic inflammation, infection, neoplastic disease or malignancy, underlying myelodysplastic disorders, marrow suppression from uremia, aluminium overload (possibly by interfering iron availability), hyperparathyroidism/osteitis fibrosa cystica, hypersplenism, acute or chronic blood loss, erythrocyte enzyme abnormalities (e.g. pyruvate kinase deficiency), and/or folic acid or Vitamin B12 deficiency.
Pure Red Cell Aplasia: In most of these PRCA patients antibodies to erythropoietins have been reported. If no cause is identified, a bone marrow examination should be considered.
If pure red cell aplasia (PRCA) is diagnosed, Epoetin must be immediately discontinued and testing for erythropoietin antibodies should be considered. If antibodies to erythropoietin are detected patients should not be switched to another ESA (Erythropoiesis-stimulating agents) product as anti-erythropoietin antibodies cross-react with other ESAs. Other causes of pure red cell aplasia should be excluded, and appropriate therapy instituted.
Use in Children: Efficacy and safety of Epoetin alpha has not been established. But the drug has been used for the treatment of anemia (e.g. anemia of chronic renal failure, anemia of prematurity) in a limited number of children younger than 12 years of age.
Use in Elderly: While safety and efficacy of Epoetin alpha have not been established specifically in geriatric patients, a large proportion of patients treated with the drug for anemia associated with chronic renal failure have been 65 years or older. Based on the clinical studies with Epoetin alpha therapy for the treatment of anemia in this age group, special precautions generally do not appear necessary for use of the drug in geriatric patients. However, because of an increased risk of renal and/ or cardiovascular complications in geriatric patient, careful monitoring of blood chemistry and blood pressure may be necessary.
Caution in use of Epoetin alpha in pregnant women/nursing women.
Epoetin alpha is generally well tolerated. The following are the reported adverse reactions in Epoetin alpha therapy: Hypertension:
The most frequent adverse effect observed in patients receiving Epoetin alpha for anemia of chronic renal failure is development or exacerbation of hypertension. The risk of hypertensive episodes is greatest in patients with chronic renal failure who have preexisting hypertension or a history of hypertensive disease, however up to 80% of patients with chronic renal failure have a history of hypertension.
Patients with extremely low baseline hematocrits (e.g. less than 22%) also may be at risk for the development of hypertension.
Hypertension, associated with a clinically important increase in hematocrit, has been reported rarely during Epoetin alpha therapy in cancer patients with chemotherapy-induced anemia.
An increased incidence of partial or complete clotting at the site of vascular access has been observed in renal dialysis patients receiving Epoetin alpha.
Nervous system effects:
Seizures have been reported occasionally in patients receiving Epoetin alpha.
Renal and electrolyte effects:
Predialysis increases in serum concentrations of potassium, blood urea nitrogen (BUN), creatinine, uric acid and phosphate have been reported with Epoetin alpha therapy, especially in patients with chronic electrolyte abnormalities.
Other reported adverse reactions:
see Table 2.
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There are no known clinically significant drug interactions but the effect of Epoetin may be potentiated by the simultaneous therapeutic administration of a haematinic agent such as ferrous sulphate when a deficiency state exists.
Since cyclosporine is bound by red blood cells there is potential for a drug interaction. If Epoetin is given concomitantly with cyclosporine, blood levels of cyclosporine should be monitored and the dose of cyclosporine adjusted as the haematocrit rises.
In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL epoetin alfa with transtuzumab (6mg/kg) had no effect on the pharmacokinetics of trastuzumab.
Store between 2 and 8°C. Do not shake or freeze. Single use only.
Discard unused portion
B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.