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Indications/Uses
Epoetin alfa (Eprex) is indicated for the treatment of anemia associated with chronic renal failure in pediatric and adult patients on hemodialysis and peritoneal dialysis.
Epoetin alfa (Eprex) is indicated for the treatment of severe anemia of renal origin accompanied by clinical symptoms in adult patients with renal insufficiency not yet undergoing dialysis.
Epoetin alfa (Eprex) is indicated for the treatment of anemia and reduction of transfusion requirements in adult cancer patients with non-myeloid malignancies receiving chemotherapy.
Epoetin alfa (Eprex) is indicated for the treatment of anemia in adult HIV-infected patients being treated with zidovudine having endogenous erythropoietin levels ≤500 mU/mL.
Epoetin alfa (Eprex) is indicated in adults to facilitate autologous blood collection within a predeposit program and decrease the risk of receiving allogeneic blood transfusions in patients with moderate anemia (hematocrits of 33-39%, hemoglobin of 10-13 g/dL, [6.2-8.1 mmol/L], no iron deficiency), who are scheduled for major elective surgery and are
expected to require more blood than that which can be obtained through autologous blood collection techniques in the absence of Epoetin alfa (Eprex). Treatment should only be given to patients if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).
Epoetin alfa (Eprex) is indicated to augment erythropoiesis in the perisurgical period in order to reduce allogeneic blood transfusions and correct postoperative anemia in adult non-iron deficient patients undergoing major elective orthopedic surgery. Use should be restricted to patients with moderate anemia (e.g Hb 10-13 g/dL) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
Epoetin alfa (Eprex) is indicated for the treatment of anemia (hemoglobin concentration of ≤10 g/dL) in adults with low- or intermediate-1-risk myelodysplastic syndromes (MDS) who have low serum erythropoietin (<200 mU/mL).
Epoetin alfa (Eprex) is indicated for the treatment of severe anemia of renal origin accompanied by clinical symptoms in adult patients with renal insufficiency not yet undergoing dialysis.
Epoetin alfa (Eprex) is indicated for the treatment of anemia and reduction of transfusion requirements in adult cancer patients with non-myeloid malignancies receiving chemotherapy.
Epoetin alfa (Eprex) is indicated for the treatment of anemia in adult HIV-infected patients being treated with zidovudine having endogenous erythropoietin levels ≤500 mU/mL.
Epoetin alfa (Eprex) is indicated in adults to facilitate autologous blood collection within a predeposit program and decrease the risk of receiving allogeneic blood transfusions in patients with moderate anemia (hematocrits of 33-39%, hemoglobin of 10-13 g/dL, [6.2-8.1 mmol/L], no iron deficiency), who are scheduled for major elective surgery and are
expected to require more blood than that which can be obtained through autologous blood collection techniques in the absence of Epoetin alfa (Eprex). Treatment should only be given to patients if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).
Epoetin alfa (Eprex) is indicated to augment erythropoiesis in the perisurgical period in order to reduce allogeneic blood transfusions and correct postoperative anemia in adult non-iron deficient patients undergoing major elective orthopedic surgery. Use should be restricted to patients with moderate anemia (e.g Hb 10-13 g/dL) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
Epoetin alfa (Eprex) is indicated for the treatment of anemia (hemoglobin concentration of ≤10 g/dL) in adults with low- or intermediate-1-risk myelodysplastic syndromes (MDS) who have low serum erythropoietin (<200 mU/mL).
Dosage/Direction for Use
Method of Administration: Epoetin alfa (Eprex) may be administered by intravenous or subcutaneous injection. As for any parenterally administered drug, the injection solution should be inspected for particles and discoloration prior to administration. Do not shake, shaking may denature the glycoprotein, rendering it inactive. Epoetin alfa (Eprex) in single use syringes contains no preservatives. Do not re-use syringe. Discard unused portion.
Intravenous Injection: Epoetin alfa should be administered over at least one to five minutes, depending on the total dose.
A slower injection may be preferable in patients who react to the treatment with flu-like symptoms.
In hemodialysis patients, a bolus injection may be given during dialysis via a suitable venous port in the dialysis line. Alternatively, at the completion of a hemodialysis session, the injection can be given via the fistula needle tubing, followed by 10 mL of isotonic saline to rinse the tubing and to ensure satisfactory injection of the product into the circulation.
Epoetin alfa should not be administered by intravenous infusion or mixed with other drugs.
Subcutaneous Injection: The maximum volume per injection site should be 1 mL. In case of larger volumes, more than one injection site should be used.
The injections should be given in the limbs or the anterior abdominal wall.
Chronic Renal Failure Patients: In patients with chronic renal failure where intravenous access is routinely available (hemodialysis patients), administration by the intravenous route is preferable. Where intravenous access is not readily available (patients not yet undergoing dialysis and peritoneal dialysis patients), Epoetin alfa may be administered subcutaneously.
The hemoglobin concentration aimed for should be between 10 to 12 g/dL (6.2-7.5 mmol/L) in adults and 9.5 to 11 g/dL (5.9-6.8 mmol/L) in children.
In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range (see Renal Failure Patients under Precautions).
When changing the route of administration, the same dose should be used initially and then titrated to keep hemoglobin in the hemoglobin concentration range. In the correction phase, the dose of Epoetin alfa should be increased if the hemoglobin does not increase at least 1 g/dL (0.62 mmol/L) per month.
A clinically significant increase in hemoglobin is usually not observed in less than 2 weeks and may require up to 6-10 weeks in some patients.
When the hemoglobin concentration is within range, the dose should be decreased by 25 IU/kg/dose in order to avoid exceeding the hemoglobin concentration range. Dose should be reduced when hemoglobin approaches 12 g/dL.
Dose reductions may be made by omitting one of the weekly doses or by decreasing the amount of each dose.
Adult Hemodialysis Patients: In patients on hemodialysis, where intravenous access is readily available, administration by the intravenous route is preferable.
The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: Adjust dosage in order to maintain hemoglobin values at the desired level: Hb between 10 and 12 g/dL (6.2-7.5 mmol/L).
The maintenance dose should be individualised for each chronic renal failure patient. The recommended total weekly dose is between 75 and 300 IU/kg.
Available data suggests that patients with a baseline hemoglobin (<6 g/dL or <3.7 mmol/L) may require higher maintenance doses than patients with a baseline hemoglobin (>8 g/dL or >5 mmol/L).
Pediatric Hemodialysis Patients: The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week by the intravenous route.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (9.5-11 g/dL [5.9-6.8 mmol/L]) is achieved.
Maintenance phase: Appropriate adjustment of the dose should be made in order to maintain the hemoglobin concentration within the desired range between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L).
Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment. (See Table 6.)
Available data suggest that patients whose initial hemoglobin is very low (hemoglobin <6.8 g/dL [4.2 mmol/L]) may require higher maintenance doses than patients whose initial hemoglobin is higher (hemoglobin >6.8 g/dL [4.2 mmol/L]).
Adult Peritoneal Dialysis Patients: In peritoneal dialysis patients, where intravenous access is not readily available, Epoetin alfa may be administered subcutaneously.
The treatment is divided into two stages: Correction phase: 50 IU/kg twice per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg twice per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: The usual dose to maintain the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is between 25 and 50 IU/kg twice per week in two equal injections.
Pediatric Peritoneal Dialysis Patients: The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week by the intravenous or subcutaneous route. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (9.5-11 g/dL [5.90-6.83 mmol/L]) is achieved.
Maintenance phase: Generally, children <30 kg require higher maintenance doses than children >30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment. (See Table 7.)
Available data suggest that patients with an initial hemoglobin <6.8 g/dL [4.2 mmol/L]) may require higher maintenance doses than patients with an initial hemoglobin >6.8 g/dL [4.2 mmol/L].
Adult Predialysis Patients [Adult Patients With End Stage Renal Insufficiency]: In patients with renal insufficiency not yet undergoing dialysis, where intravenous access is not readily available, Epoetin alfa may be administered subcutaneously. The treatment is divided into two stages:Correction phase: 50 IU/kg three times per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: The usual dose to maintain the hemoglobin concentration range is between 17 and 33 IU/kg three times per week. The maximum dosage should not exceed 200 IU/kg 3 times per week. During the maintenance phase, Epoetin alfa (Eprex) can be administered either 3 times per week, and in the case of subcutaneous administration, once weekly or once every 2 weeks.
Appropriate adjustment of dose and dose intervals should be made in order to maintain hemoglobin values at the desired level: Hb between 10 and 12 g/dL (6.2-7.5 mmol/L). Extending dose intervals may require an increase in dose.
The maximum dosage should not exceed 150 IU/kg 3 times per week, 240 IU/kg (up to a maximum of 20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU) once every 2 weeks.
Cancer Patients: Adult Cancer Patients: The subcutaneous route of administration should be used.
The hemoglobin concentration range should be 10 to 12 g/dL (7.5 mmol/L) in men and women and it should not be exceeded.
Epoetin alfa therapy should continue until one month after the end of chemotherapy. However, the need to continue Epoetin alfa therapy should be re-evaluated periodically.
The initial dose for the treatment of anemia should be 150 IU/kg 3 times per week.
Alternatively, Epoetin alfa can be administered at an initial dose of 40,000 IU subcutaneously once weekly.
If after 4 weeks of treatment at the initial dose, the hemoglobin has increased by at least 1 g/dL (0.6 mmol/L) or the reticulocyte count has increased ≥40,000 cells/μL above baseline the dose should remain unchanged.
If after 4 weeks of treatment at the initial dose, the hemoglobin has not increased by ≥1 g/dL (0.6 mmol/L) and the reticulocyte count has not increased by ≥40,000 cells/μL above baseline, in the absence of red blood cell transfusion, the dose should be increased to 300 IU/kg 3 times per week or 60,000 IU weekly.
If after 4 weeks of additional therapy with 300 IU/kg 3 times per week or 60,000 IU weekly, the hemoglobin has increased ≥1 g/dL (≥ 0.6 mmol/L), or the reticulocyte count has increased ≥40,000 cells/μL the dose should remain unchanged.
If after 4 weeks of additional therapy with 300 IU/kg three times per week or 60,000 IU per week, the hemoglobin has increased <1 g/dL (0.6 mmol/L) and the reticulocyte count has increased <40,000 cells/μL above baseline, response is unlikely and treatment should be discontinued.
The recommended dosing regimen is described in the following diagram: See diagram.
A rate of rise in hemoglobin of greater than 1 g/dL (0.6 mmol/L) per 2 week or 2 g/dL (1.25 mmol/L) per month or hemoglobin levels of >12 g/dL (>8.1 mmol/L) should be avoided. If the hemoglobin is rising by more than 1 g/dL (0.6 mmol/L) per two week or 2 g/dL (1.25 mmol/L) per month or hemoglobin is approaching 12 g/dL (7.5 mmol/L), reduce the Epoetin alfa dose by about 25-50% depending upon the rate of rise of hemoglobin. If the hemoglobin exceeds 12 g/dL (7.5 mmol/L), withhold therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinitiate Epoetin alfa therapy at a dose 25% below the previous dose.
Pediatric Cancer Patients: Published literature has reported the use in pediatric cancer patients between the ages 6 months to 18 years who were treated with 25 to 300 IU/kg of Epoetin alfa by subcutaneous or intravenous injection, three to seven times per week that resulted in an increase in hemoglobin and a decrease in transfusion requirements.
Epoetin alfa 600 IU/kg once weekly has been evaluated in studies in pediatric cancer patients.
Zidovudine Treated HIV-Infected Patients: Adult Zidovudine Treated HIV-Infected Patients: Prior to beginning Epoetin alfa, it is recommended that the endogenous serum erythropoietin level be determined prior to transfusion. Available data suggests that patients with endogenous serum erythropoietin levels >500 mU/mL are unlikely to respond to therapy with Epoetin alfa.
The treatment is divided into two stages: Correction phase: 100 IU/kg three times per week by the subcutaneous or intravenous route for 8 weeks.
If the response is not satisfactory (i.e., reduced transfusion requirements or increased hemoglobin) after 8 weeks of therapy, the dose of Epoetin alfa can be increased. Dose increases should be made in increments of 50 to 100 IU/kg three times per week at intervals of at least 4 weeks. If patients have not responded satisfactorily to an Epoetin alfa dose of 300 IU/kg three times per week, it is unlikely that they will respond to higher doses.
Maintenance phase: After the desired response is attained, the dose should be titrated to maintain the hematocrit between 30-35%, based on factors such as variations in zidovudine dose and the presence of intercurrent infections or inflammatory episodes. If the hematocrit exceeds 40%, the dose should be discontinued until the hematocrit decreases to 36%. When treatment is resumed, the dose should be reduced by 25% and then titrated to maintain the desired hematocrit.
In zidovudine-treated HIV-infected patients the hemoglobin concentration should not exceed 12 g/dL (7.5mmol/L).
Adult Surgery Patients in an Autologous Pre-Donation Programme: The intravenous route of administration should be used. Epoetin alfa should be administered after the completion of each blood donation procedure.
Mildly anemic patients (hematocrit of 33 to 39% and/or hemoglobin 10 to 13 g/dL [6.2-8.1 mmol/L]) requiring predeposit of ≥4 units of blood should be treated with Epoetin alfa at 600 IU/kg 2 times weekly for 3 weeks prior to surgery.
For those patients who require a lesser degree of erythropoietic stimulation, a dose regimen of 150-300 IU/kg administered twice weekly has been shown to augment autologous pre-donation and to decrease the subsequent decline in hematocrit.
Adult Perisurgery Patients (Without Autologous Blood Donation): The subcutaneous route of administration should be used.
The recommended dose regimen is 600 IU/kg of Epoetin alfa given weekly for three weeks (days -21, -14 and -7) prior to surgery and on the day of surgery.
In cases where there is a medical need to reduce the time before surgery to less than three weeks, the recommended dose regimen is 300 IU/kg for 10 consecutive days before surgery, on the day of surgery and up to 4 days after surgery. 300 IU/kg/day is recommended for hemoglobin levels ≤13 g/dL (8.1 mmol/L). If the hemoglobin level reaches 15 g/dL, or higher, administration of Epoetin alfa should be stopped and further dose should not be given.
Adult Patients with low- or intermediate-1-risk MDS: The recommended starting dose is Epoetin alfa (Eprex) 450 IU/kg (maximum total dose is 40000 IU) administered subcutaneously once every week. It is recommended that response be assessed at week 8. If no erythroid response is achieved after 8 weeks according to IWG 2006 criteria, and the hemoglobin concentration is below 11 g/dL (6.8 mmol/L), the dose should be increased from 450 IU/kg once every week to 1050 IU/kg once every week (maximum dose is 80000 IU per week).
Intravenous Injection: Epoetin alfa should be administered over at least one to five minutes, depending on the total dose.
A slower injection may be preferable in patients who react to the treatment with flu-like symptoms.
In hemodialysis patients, a bolus injection may be given during dialysis via a suitable venous port in the dialysis line. Alternatively, at the completion of a hemodialysis session, the injection can be given via the fistula needle tubing, followed by 10 mL of isotonic saline to rinse the tubing and to ensure satisfactory injection of the product into the circulation.
Epoetin alfa should not be administered by intravenous infusion or mixed with other drugs.
Subcutaneous Injection: The maximum volume per injection site should be 1 mL. In case of larger volumes, more than one injection site should be used.
The injections should be given in the limbs or the anterior abdominal wall.
Chronic Renal Failure Patients: In patients with chronic renal failure where intravenous access is routinely available (hemodialysis patients), administration by the intravenous route is preferable. Where intravenous access is not readily available (patients not yet undergoing dialysis and peritoneal dialysis patients), Epoetin alfa may be administered subcutaneously.
The hemoglobin concentration aimed for should be between 10 to 12 g/dL (6.2-7.5 mmol/L) in adults and 9.5 to 11 g/dL (5.9-6.8 mmol/L) in children.
In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range (see Renal Failure Patients under Precautions).
When changing the route of administration, the same dose should be used initially and then titrated to keep hemoglobin in the hemoglobin concentration range. In the correction phase, the dose of Epoetin alfa should be increased if the hemoglobin does not increase at least 1 g/dL (0.62 mmol/L) per month.
A clinically significant increase in hemoglobin is usually not observed in less than 2 weeks and may require up to 6-10 weeks in some patients.
When the hemoglobin concentration is within range, the dose should be decreased by 25 IU/kg/dose in order to avoid exceeding the hemoglobin concentration range. Dose should be reduced when hemoglobin approaches 12 g/dL.
Dose reductions may be made by omitting one of the weekly doses or by decreasing the amount of each dose.
Adult Hemodialysis Patients: In patients on hemodialysis, where intravenous access is readily available, administration by the intravenous route is preferable.
The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: Adjust dosage in order to maintain hemoglobin values at the desired level: Hb between 10 and 12 g/dL (6.2-7.5 mmol/L).
The maintenance dose should be individualised for each chronic renal failure patient. The recommended total weekly dose is between 75 and 300 IU/kg.
Available data suggests that patients with a baseline hemoglobin (<6 g/dL or <3.7 mmol/L) may require higher maintenance doses than patients with a baseline hemoglobin (>8 g/dL or >5 mmol/L).
Pediatric Hemodialysis Patients: The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week by the intravenous route.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (9.5-11 g/dL [5.9-6.8 mmol/L]) is achieved.
Maintenance phase: Appropriate adjustment of the dose should be made in order to maintain the hemoglobin concentration within the desired range between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L).
Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment. (See Table 6.)
Available data suggest that patients whose initial hemoglobin is very low (hemoglobin <6.8 g/dL [4.2 mmol/L]) may require higher maintenance doses than patients whose initial hemoglobin is higher (hemoglobin >6.8 g/dL [4.2 mmol/L]).
Adult Peritoneal Dialysis Patients: In peritoneal dialysis patients, where intravenous access is not readily available, Epoetin alfa may be administered subcutaneously.
The treatment is divided into two stages: Correction phase: 50 IU/kg twice per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg twice per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: The usual dose to maintain the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is between 25 and 50 IU/kg twice per week in two equal injections.
Pediatric Peritoneal Dialysis Patients: The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week by the intravenous or subcutaneous route. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (9.5-11 g/dL [5.90-6.83 mmol/L]) is achieved.
Maintenance phase: Generally, children <30 kg require higher maintenance doses than children >30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment. (See Table 7.)
Available data suggest that patients with an initial hemoglobin <6.8 g/dL [4.2 mmol/L]) may require higher maintenance doses than patients with an initial hemoglobin >6.8 g/dL [4.2 mmol/L].
Adult Predialysis Patients [Adult Patients With End Stage Renal Insufficiency]: In patients with renal insufficiency not yet undergoing dialysis, where intravenous access is not readily available, Epoetin alfa may be administered subcutaneously. The treatment is divided into two stages:Correction phase: 50 IU/kg three times per week.
When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the hemoglobin concentration range (10-12 g/dL [6.2-7.5 mmol/L]) is achieved.
Maintenance phase: The usual dose to maintain the hemoglobin concentration range is between 17 and 33 IU/kg three times per week. The maximum dosage should not exceed 200 IU/kg 3 times per week. During the maintenance phase, Epoetin alfa (Eprex) can be administered either 3 times per week, and in the case of subcutaneous administration, once weekly or once every 2 weeks.
Appropriate adjustment of dose and dose intervals should be made in order to maintain hemoglobin values at the desired level: Hb between 10 and 12 g/dL (6.2-7.5 mmol/L). Extending dose intervals may require an increase in dose.
The maximum dosage should not exceed 150 IU/kg 3 times per week, 240 IU/kg (up to a maximum of 20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU) once every 2 weeks.
Cancer Patients: Adult Cancer Patients: The subcutaneous route of administration should be used.
The hemoglobin concentration range should be 10 to 12 g/dL (7.5 mmol/L) in men and women and it should not be exceeded.
Epoetin alfa therapy should continue until one month after the end of chemotherapy. However, the need to continue Epoetin alfa therapy should be re-evaluated periodically.
The initial dose for the treatment of anemia should be 150 IU/kg 3 times per week.
Alternatively, Epoetin alfa can be administered at an initial dose of 40,000 IU subcutaneously once weekly.
If after 4 weeks of treatment at the initial dose, the hemoglobin has increased by at least 1 g/dL (0.6 mmol/L) or the reticulocyte count has increased ≥40,000 cells/μL above baseline the dose should remain unchanged.
If after 4 weeks of treatment at the initial dose, the hemoglobin has not increased by ≥1 g/dL (0.6 mmol/L) and the reticulocyte count has not increased by ≥40,000 cells/μL above baseline, in the absence of red blood cell transfusion, the dose should be increased to 300 IU/kg 3 times per week or 60,000 IU weekly.
If after 4 weeks of additional therapy with 300 IU/kg 3 times per week or 60,000 IU weekly, the hemoglobin has increased ≥1 g/dL (≥ 0.6 mmol/L), or the reticulocyte count has increased ≥40,000 cells/μL the dose should remain unchanged.
If after 4 weeks of additional therapy with 300 IU/kg three times per week or 60,000 IU per week, the hemoglobin has increased <1 g/dL (0.6 mmol/L) and the reticulocyte count has increased <40,000 cells/μL above baseline, response is unlikely and treatment should be discontinued.
The recommended dosing regimen is described in the following diagram: See diagram.
A rate of rise in hemoglobin of greater than 1 g/dL (0.6 mmol/L) per 2 week or 2 g/dL (1.25 mmol/L) per month or hemoglobin levels of >12 g/dL (>8.1 mmol/L) should be avoided. If the hemoglobin is rising by more than 1 g/dL (0.6 mmol/L) per two week or 2 g/dL (1.25 mmol/L) per month or hemoglobin is approaching 12 g/dL (7.5 mmol/L), reduce the Epoetin alfa dose by about 25-50% depending upon the rate of rise of hemoglobin. If the hemoglobin exceeds 12 g/dL (7.5 mmol/L), withhold therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinitiate Epoetin alfa therapy at a dose 25% below the previous dose.
Pediatric Cancer Patients: Published literature has reported the use in pediatric cancer patients between the ages 6 months to 18 years who were treated with 25 to 300 IU/kg of Epoetin alfa by subcutaneous or intravenous injection, three to seven times per week that resulted in an increase in hemoglobin and a decrease in transfusion requirements.
Epoetin alfa 600 IU/kg once weekly has been evaluated in studies in pediatric cancer patients.
Zidovudine Treated HIV-Infected Patients: Adult Zidovudine Treated HIV-Infected Patients: Prior to beginning Epoetin alfa, it is recommended that the endogenous serum erythropoietin level be determined prior to transfusion. Available data suggests that patients with endogenous serum erythropoietin levels >500 mU/mL are unlikely to respond to therapy with Epoetin alfa.
The treatment is divided into two stages: Correction phase: 100 IU/kg three times per week by the subcutaneous or intravenous route for 8 weeks.
If the response is not satisfactory (i.e., reduced transfusion requirements or increased hemoglobin) after 8 weeks of therapy, the dose of Epoetin alfa can be increased. Dose increases should be made in increments of 50 to 100 IU/kg three times per week at intervals of at least 4 weeks. If patients have not responded satisfactorily to an Epoetin alfa dose of 300 IU/kg three times per week, it is unlikely that they will respond to higher doses.
Maintenance phase: After the desired response is attained, the dose should be titrated to maintain the hematocrit between 30-35%, based on factors such as variations in zidovudine dose and the presence of intercurrent infections or inflammatory episodes. If the hematocrit exceeds 40%, the dose should be discontinued until the hematocrit decreases to 36%. When treatment is resumed, the dose should be reduced by 25% and then titrated to maintain the desired hematocrit.
In zidovudine-treated HIV-infected patients the hemoglobin concentration should not exceed 12 g/dL (7.5mmol/L).
Adult Surgery Patients in an Autologous Pre-Donation Programme: The intravenous route of administration should be used. Epoetin alfa should be administered after the completion of each blood donation procedure.
Mildly anemic patients (hematocrit of 33 to 39% and/or hemoglobin 10 to 13 g/dL [6.2-8.1 mmol/L]) requiring predeposit of ≥4 units of blood should be treated with Epoetin alfa at 600 IU/kg 2 times weekly for 3 weeks prior to surgery.
For those patients who require a lesser degree of erythropoietic stimulation, a dose regimen of 150-300 IU/kg administered twice weekly has been shown to augment autologous pre-donation and to decrease the subsequent decline in hematocrit.
Adult Perisurgery Patients (Without Autologous Blood Donation): The subcutaneous route of administration should be used.
The recommended dose regimen is 600 IU/kg of Epoetin alfa given weekly for three weeks (days -21, -14 and -7) prior to surgery and on the day of surgery.
In cases where there is a medical need to reduce the time before surgery to less than three weeks, the recommended dose regimen is 300 IU/kg for 10 consecutive days before surgery, on the day of surgery and up to 4 days after surgery. 300 IU/kg/day is recommended for hemoglobin levels ≤13 g/dL (8.1 mmol/L). If the hemoglobin level reaches 15 g/dL, or higher, administration of Epoetin alfa should be stopped and further dose should not be given.
Adult Patients with low- or intermediate-1-risk MDS: The recommended starting dose is Epoetin alfa (Eprex) 450 IU/kg (maximum total dose is 40000 IU) administered subcutaneously once every week. It is recommended that response be assessed at week 8. If no erythroid response is achieved after 8 weeks according to IWG 2006 criteria, and the hemoglobin concentration is below 11 g/dL (6.8 mmol/L), the dose should be increased from 450 IU/kg once every week to 1050 IU/kg once every week (maximum dose is 80000 IU per week).
Overdosage
The therapeutic margin of Epoetin alfa is very wide. Overdosage of Epoetin alfa may produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high hemoglobin levels occur. Additional supportive care should be provided as necessary.
Contraindications
Patients who develop antibody-mediated Pure Red Cell Aplasia (PRCA) following treatment with any erythropoietin should not receive Epoetin alfa or any other erythropoietin (see Pure Red Cell Aplasia under Precautions); Uncontrolled hypertension; Hypersensitivity to the active substance or to any of the excipients.
All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with Epoetin alfa.
The use of Epoetin alfa in patients scheduled for major elective orthopaedic surgery and not participating in an autologous blood predonation programme is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.
All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with Epoetin alfa.
The use of Epoetin alfa in patients scheduled for major elective orthopaedic surgery and not participating in an autologous blood predonation programme is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.
Special Precautions
General: In all patients receiving Epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension.
It may be necessary to initiate or increase anti-hypertensive treatment during Epoetin alfa therapy. If blood pressure cannot be controlled, Epoetin alfa treatment should be discontinued.
Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases.
Epoetin alfa should be used with caution in patients with chronic liver failure. The safety of Epoetin alfa has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with Epoetin alfa.
An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see Adverse Reactions). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral hemorrhage and transient ischemic attacks) have been reported.
The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with preexisting risk factors. In all patients, hemoglobin concentration should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at hemoglobin concentrations above the range for the indication of use.
The safety and efficacy of Epoetin alfa therapy have not been established in patients with underlying hematologic diseases (e.g. hemolytic anaemia, sickle cell anaemia, thalassemia).
There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with Epoetin alfa. This regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count should be regularly monitored during the first 8 weeks of therapy.
Other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with Epoetin alfa, and when deciding to increase the dose. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to Epoetin alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary: For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for adults and 100-200 mg/day orally for pediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferring saturation is below 20%.
For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting Epoetin alfa therapy, and throughout the course of Epoetin alfa therapy.
For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Epoetin alfa therapy. If possible, iron supplementation should be initiated prior to starting Epoetin alfa therapy to achieve adequate iron stores.
Very rarely, the initial presentation or exacerbation of porphyria has been observed in Epoetin alfa-treated patients. Epoetin alfa should be used with caution in patients with porphyria.
Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be emphasised that patients should only be switched from one ESA (such as Epoetin alfa (Eprex)) to another ESA with the authorisation of the treating physician.
Pure Red Cell Aplasia: Antibody-mediated pure red cell aplasia (PRCA) has been very rarely reported after months to years of subcutaneous Epoetin treatment in chronic renal failure patients.
Cases also have been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are not approved in the management of anemia associated with hepatitis C.
In chronic renal failure patients developing sudden lack of efficacy, defined by a decrease in hemoglobin (1 to 2 g/dL per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g., iron folate or Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be investigated. If the reticulocyte count corrected for anemia (i.e., the reticulocyte "index") is low (<20,000/mm3 or <20,000/uL or <0.5%) platelet and white blood cell counts are normal, and if no other cause of loss of effect has been found, anti-erythropoietin antibodies should be determined and a bone marrow examination should be considered for diagnosis of PRCA.
If anti-erythropoietin, antibody-mediated PRCA is suspected, therapy with Epoetin alfa should be discontinued immediately. No other ESA therapy should be commenced because of the risk of cross-reaction. Appropriate therapy, such as blood transfusions, may be given to patients when indicated.
Renal Failure Patients: Treatment of symptomatic anemia in adult and pediatric chronic renal failure patients: Chronic renal failure patients being treated with Epoetin alfa should have hemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.
In chronic renal failure patients the rate of increase in hemoglobin should be approximately 1 g/dL (0.62 mmol/L)/per month and should not exceed 2 g/dL (1.2 mmol/L)/per month to minimise risks of an increase in hypertension. Dose should be reduced when hemoglobin approaches 12 g/dL.
In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range as recommended under Dosage & Administration. Hemoglobin levels targeted to 13 g/dL or higher may be associated with a higher risk of cardiovascular events, including death.
Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not maintain adequate hemoglobin levels (see Pharmacology: Pharmacodynamics under Actions) and may require an increase in epoetin alfa dose. Hemoglobin levels should be monitored regularly.
Patients with chronic renal failure and insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients.
Based on information available to date, the use of Epoetin alfa in predialysis end stage renal insufficiency patients does not accelerate the rate of progression of renal insufficiency.
Shunt thromboses have occurred in hemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g., stenoses, aneurisms, etc.) Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.
Hyperkalemia has been observed in isolated cases, though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to the appropriate treatment of the hyperkalemia, consideration should be given to ceasing Epoetin alfa administration until the serum potassium level has been corrected.
As a result of an increase in packed cell volume, hemodialysis patients receiving Epoetin alfa frequently require an increase in heparin dose during dialysis. If heparinisation is not optimal, occlusion of the dialysis system is possible. In some female chronic renal failure patients, menses have resumed following Epoetin alfa therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
Cancer Patients: Cancer patients on Epoetin alfa should have hemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter.
ESAs are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of tumours.
In controlled clinical studies, use of Epoetin alfa and other ESAs have shown: decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to a hemoglobin target of greater than 14 g/dL (8.7 mmol/L); shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to a hemoglobin target of 12-14 g/dL (7.5-8.7 mmol/L); another ESA (darbepoietin alfa) increased risk of death when administered to target a hemoglobin of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.
The decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors to consider in this assessment include: the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see Pharmacology: Pharmacodynamics under Actions).
In cancer patients receiving chemotherapy, the 2-3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be considered when assessing whether or not Epoetin alfa therapy is appropriate (in particular for patients at risk of transfusion).
HIV-Infected Patients: If HIV-infected patients fail to respond or maintain a response to Epoetin alfa, other etiologies including iron deficiency anaemia should be considered and evaluated.
Adult Surgery Patients in an Autologous Pre-Donation Programme: All special warnings and special precautions associated with autologous blood donation programmes, especially routine volume replacement, should be respected in patients being supplemented with Epoetin alfa.
Adult Perisurgery Patients (Without Autologous Blood Donation): Good blood management practices should always be used in the perisurgical setting.
Patients scheduled for major elective orthopedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline hemoglobin of >13 g/dL (8.1 mmol/L), the possibility that Epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline hemoglobin >13 g/dL (8.1 mmol/L).
The use of Epoetin alfa is not recommended in perisurgery patients with a baseline hemoglobin of >13 g/dL (8.1 mmol/L).
Effects on Ability to Drive and Use Machines: No studies on the effects of Epoetin alfa on the ability to drive and use machines have been performed.
Geriatric Use: Among 1051 patients enrolled in the 5 clinical studies of Epoetin alfa for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received Epoetin alfa and 306 received placebo. Of the 745 patients who received Epoetin alfa, 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epoetin alfa in geriatric and younger patients within the 4 studies using the three times per week schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.
Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received Epoetin alfa and 125 received placebo. Of the 757 patients who received Epoetin alfa, 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the hemoglobin concentration range (see Dosage & Administration).
Insufficient numbers of patients age 65 or older were enrolled in clinical studies for the treatment of anaemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.
It may be necessary to initiate or increase anti-hypertensive treatment during Epoetin alfa therapy. If blood pressure cannot be controlled, Epoetin alfa treatment should be discontinued.
Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases.
Epoetin alfa should be used with caution in patients with chronic liver failure. The safety of Epoetin alfa has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with Epoetin alfa.
An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see Adverse Reactions). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral hemorrhage and transient ischemic attacks) have been reported.
The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with preexisting risk factors. In all patients, hemoglobin concentration should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at hemoglobin concentrations above the range for the indication of use.
The safety and efficacy of Epoetin alfa therapy have not been established in patients with underlying hematologic diseases (e.g. hemolytic anaemia, sickle cell anaemia, thalassemia).
There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with Epoetin alfa. This regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count should be regularly monitored during the first 8 weeks of therapy.
Other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with Epoetin alfa, and when deciding to increase the dose. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to Epoetin alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary: For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for adults and 100-200 mg/day orally for pediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferring saturation is below 20%.
For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting Epoetin alfa therapy, and throughout the course of Epoetin alfa therapy.
For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Epoetin alfa therapy. If possible, iron supplementation should be initiated prior to starting Epoetin alfa therapy to achieve adequate iron stores.
Very rarely, the initial presentation or exacerbation of porphyria has been observed in Epoetin alfa-treated patients. Epoetin alfa should be used with caution in patients with porphyria.
Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be emphasised that patients should only be switched from one ESA (such as Epoetin alfa (Eprex)) to another ESA with the authorisation of the treating physician.
Pure Red Cell Aplasia: Antibody-mediated pure red cell aplasia (PRCA) has been very rarely reported after months to years of subcutaneous Epoetin treatment in chronic renal failure patients.
Cases also have been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are not approved in the management of anemia associated with hepatitis C.
In chronic renal failure patients developing sudden lack of efficacy, defined by a decrease in hemoglobin (1 to 2 g/dL per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g., iron folate or Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be investigated. If the reticulocyte count corrected for anemia (i.e., the reticulocyte "index") is low (<20,000/mm3 or <20,000/uL or <0.5%) platelet and white blood cell counts are normal, and if no other cause of loss of effect has been found, anti-erythropoietin antibodies should be determined and a bone marrow examination should be considered for diagnosis of PRCA.
If anti-erythropoietin, antibody-mediated PRCA is suspected, therapy with Epoetin alfa should be discontinued immediately. No other ESA therapy should be commenced because of the risk of cross-reaction. Appropriate therapy, such as blood transfusions, may be given to patients when indicated.
Renal Failure Patients: Treatment of symptomatic anemia in adult and pediatric chronic renal failure patients: Chronic renal failure patients being treated with Epoetin alfa should have hemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.
In chronic renal failure patients the rate of increase in hemoglobin should be approximately 1 g/dL (0.62 mmol/L)/per month and should not exceed 2 g/dL (1.2 mmol/L)/per month to minimise risks of an increase in hypertension. Dose should be reduced when hemoglobin approaches 12 g/dL.
In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range as recommended under Dosage & Administration. Hemoglobin levels targeted to 13 g/dL or higher may be associated with a higher risk of cardiovascular events, including death.
Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not maintain adequate hemoglobin levels (see Pharmacology: Pharmacodynamics under Actions) and may require an increase in epoetin alfa dose. Hemoglobin levels should be monitored regularly.
Patients with chronic renal failure and insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients.
Based on information available to date, the use of Epoetin alfa in predialysis end stage renal insufficiency patients does not accelerate the rate of progression of renal insufficiency.
Shunt thromboses have occurred in hemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g., stenoses, aneurisms, etc.) Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.
Hyperkalemia has been observed in isolated cases, though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to the appropriate treatment of the hyperkalemia, consideration should be given to ceasing Epoetin alfa administration until the serum potassium level has been corrected.
As a result of an increase in packed cell volume, hemodialysis patients receiving Epoetin alfa frequently require an increase in heparin dose during dialysis. If heparinisation is not optimal, occlusion of the dialysis system is possible. In some female chronic renal failure patients, menses have resumed following Epoetin alfa therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
Cancer Patients: Cancer patients on Epoetin alfa should have hemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter.
ESAs are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of tumours.
In controlled clinical studies, use of Epoetin alfa and other ESAs have shown: decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to a hemoglobin target of greater than 14 g/dL (8.7 mmol/L); shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to a hemoglobin target of 12-14 g/dL (7.5-8.7 mmol/L); another ESA (darbepoietin alfa) increased risk of death when administered to target a hemoglobin of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.
The decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors to consider in this assessment include: the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see Pharmacology: Pharmacodynamics under Actions).
In cancer patients receiving chemotherapy, the 2-3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be considered when assessing whether or not Epoetin alfa therapy is appropriate (in particular for patients at risk of transfusion).
HIV-Infected Patients: If HIV-infected patients fail to respond or maintain a response to Epoetin alfa, other etiologies including iron deficiency anaemia should be considered and evaluated.
Adult Surgery Patients in an Autologous Pre-Donation Programme: All special warnings and special precautions associated with autologous blood donation programmes, especially routine volume replacement, should be respected in patients being supplemented with Epoetin alfa.
Adult Perisurgery Patients (Without Autologous Blood Donation): Good blood management practices should always be used in the perisurgical setting.
Patients scheduled for major elective orthopedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline hemoglobin of >13 g/dL (8.1 mmol/L), the possibility that Epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline hemoglobin >13 g/dL (8.1 mmol/L).
The use of Epoetin alfa is not recommended in perisurgery patients with a baseline hemoglobin of >13 g/dL (8.1 mmol/L).
Effects on Ability to Drive and Use Machines: No studies on the effects of Epoetin alfa on the ability to drive and use machines have been performed.
Geriatric Use: Among 1051 patients enrolled in the 5 clinical studies of Epoetin alfa for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received Epoetin alfa and 306 received placebo. Of the 745 patients who received Epoetin alfa, 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epoetin alfa in geriatric and younger patients within the 4 studies using the three times per week schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.
Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received Epoetin alfa and 125 received placebo. Of the 757 patients who received Epoetin alfa, 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the hemoglobin concentration range (see Dosage & Administration).
Insufficient numbers of patients age 65 or older were enrolled in clinical studies for the treatment of anaemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.
Use In Pregnancy & Lactation
Use During Pregnancy: In animal studies, Epoetin alfa has been shown to decrease fetal body weight, delay ossification and increase fetal mortality when given in weekly doses of approximately 20 times the recommended human weekly dose. These changes are interpreted as being secondary to decreased maternal body weight gain.
There are no adequate and well-controlled studies in pregnant women.
Epoetin alfa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Pharmacology: Toxicology: Reproduction Toxicology under Actions).
Use During Lactation: Erythropoietin is present in human milk. However, it is not known whether Epoetin alfa is distributed into human milk. Epoetin alfa should be used with caution in nursing women.
In pregnant or lactating surgical patients participating in an autologous blood predonation programme, the use of Epoetin alfa (Eprex) is not recommended.
There are no adequate and well-controlled studies in pregnant women.
Epoetin alfa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Pharmacology: Toxicology: Reproduction Toxicology under Actions).
Use During Lactation: Erythropoietin is present in human milk. However, it is not known whether Epoetin alfa is distributed into human milk. Epoetin alfa should be used with caution in nursing women.
In pregnant or lactating surgical patients participating in an autologous blood predonation programme, the use of Epoetin alfa (Eprex) is not recommended.
Adverse Reactions
Summary of the Safety Profile: The most frequent adverse drug reaction during treatment with Epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be performed, particularly at the start of therapy. The most frequently occurring adverse drug reactions observed in clinical trials of Epoetin alfa are diarrhea, nausea, vomiting, pyrexia, and headache.
Post-marketing Experience: Adverse drug reactions identified during the post-marketing experience with Epoetin alfa are included in Table 8. In Table 8, the frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000, <1/1,000; Very rare <1/10,000, including isolated reports.
Antibody-mediated pure red cell aplasia has been very rarely reported (<1/10,000 cases per patient-year) after months to years of treatment with Epoetin alfa (Eprex). (See Table 8.)
Influenza-like illness may occur especially at the start of treatment.
Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal insufficiency not yet undergoing dialysis.
An increased incidence of thrombotic vascular events (TVEs), has been observed in patients receiving ESAs (see Precautions).
Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reaction, and angioedema have been reported.
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during Epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal.
Clinical Trial Experience: Of a total 3559 subjects in 27 randomized, double-blinded, placebo or standard of care controlled studies, the overall safety profile of Epoetin alfa was evaluated in 2136 anemic subjects. Included were 228 Epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in predialysis [N=131 exposed CRF subjects not yet on dialysis] and 2 in dialysis [N=97 exposed CRF subjects on dialysis]; 1,404 exposed cancer subjects in 16 studies of anemia due to chemotherapy; 144 exposed subjects in 4 HIV-infection studies; 147 exposed subjects in 2 studies for autologous blood donation; and 213 exposed subjects in 1 study in the perisurgical setting. Adverse drug reactions reported by ≥1% of subjects treated with Epoetin alfa in these trials are shown in Table 9: See Table 9.
Post-marketing Experience: Adverse drug reactions identified during the post-marketing experience with Epoetin alfa are included in Table 8. In Table 8, the frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000, <1/1,000; Very rare <1/10,000, including isolated reports.
Antibody-mediated pure red cell aplasia has been very rarely reported (<1/10,000 cases per patient-year) after months to years of treatment with Epoetin alfa (Eprex). (See Table 8.)
Influenza-like illness may occur especially at the start of treatment.
Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal insufficiency not yet undergoing dialysis.
An increased incidence of thrombotic vascular events (TVEs), has been observed in patients receiving ESAs (see Precautions).
Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reaction, and angioedema have been reported.
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during Epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal.
Clinical Trial Experience: Of a total 3559 subjects in 27 randomized, double-blinded, placebo or standard of care controlled studies, the overall safety profile of Epoetin alfa was evaluated in 2136 anemic subjects. Included were 228 Epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in predialysis [N=131 exposed CRF subjects not yet on dialysis] and 2 in dialysis [N=97 exposed CRF subjects on dialysis]; 1,404 exposed cancer subjects in 16 studies of anemia due to chemotherapy; 144 exposed subjects in 4 HIV-infection studies; 147 exposed subjects in 2 studies for autologous blood donation; and 213 exposed subjects in 1 study in the perisurgical setting. Adverse drug reactions reported by ≥1% of subjects treated with Epoetin alfa in these trials are shown in Table 9: See Table 9.
Drug Interactions
No evidence exists that indicates that treatment with Epoetin alfa alters the metabolism of other drugs. Drugs that decrease erythropoiesis may decrease the response to Epoetin alfa.
Since cyclosporin is bound by red blood cells there is potential for a drug interaction. If Epoetin alfa is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the hematocrit rises.
No evidence exists that indicates an interaction between Epoetin alfa and G-CSF or GM-CSF with regard to hematological differentiation or proliferation of tumour cells from biopsy specimens in vitro.
The effect of Epoetin alfa may be potentiated by the simultaneous therapeutic administration of a hematinic agent, such as ferrous sulphate, when a deficiency state exists.
In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL Epoetin alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.
Since cyclosporin is bound by red blood cells there is potential for a drug interaction. If Epoetin alfa is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the hematocrit rises.
No evidence exists that indicates an interaction between Epoetin alfa and G-CSF or GM-CSF with regard to hematological differentiation or proliferation of tumour cells from biopsy specimens in vitro.
The effect of Epoetin alfa may be potentiated by the simultaneous therapeutic administration of a hematinic agent, such as ferrous sulphate, when a deficiency state exists.
In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL Epoetin alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.
Caution For Usage
Instructions for Use and Handling: The product is for single use only.
The product should not be used, and should be discarded if: the seal is broken; the liquid is colored or particles are in it; it may have been frozen, or; there has been a refrigeration failure.
Any waste material should be disposed of in accordance with local requirements.
Patient Instructions for Use and Handling and Disposal: Injecting Epoetin alfa (Eprex) under the skin: At the start of the therapy, Epoetin alfa (Eprex) may be injected by medical or nursing staff. However, the doctor may decide that it is right for a patient to learn how to inject Epoetin alfa (Eprex) under the skin (subcutaneously). A patient will receive appropriate training to do this. Under no circumstances should patient attempt to inject himself/herself unless he/she has been trained to do so.
If Epoetin alfa (Eprex) is injected under the skin (subcutaneously), the amount injected is not normally more than one milliliter (1 mL) in a single injection.
Epoetin alfa (Eprex) is given alone and not mixed with other liquids for injection.
Do not shake Epoetin alfa (Eprex) syringes or vials. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, don't use it.
How to inject using a prefilled syringe: The pre-filled syringes are fitted with the PROTECS needle guard device to help prevent needle stick injuries after use. This is indicated on the packaging.
Take a syringe out of the refrigerator. The liquid needs to come to room temperature. This usually takes between 15 to 30 minutes. Do not remove the syringe's needle cover while allowing it to reach room temperature.
Check the syringe, to make sure it is the right dose, has not passed its expiry date, is not damaged, and the liquid is clear and not frozen.
Choose an injection site. Good sites are the top of the thigh and around the tummy (abdomen) but away from the navel. Vary the site from day to day.
Wash the hands. Use an antiseptic swab on the injection site, to disinfect it.
Hold the pre-filled syringe by the body of the syringe with the covered needle pointing upward.
Do not hold by the plunger head, plunger, needle guard wings, or needle cover.
Do not pull back on the plunger at any time.
Do not remove the needle cover from the pre-filled syringe until the patient is ready to inject the Epoetin alfa (Eprex).
Take the cover off the syringe by holding the barrel and pulling the cover off carefully without twisting it. Don't push the plunger, touch the needle or shake the syringe.
Do not touch the needle activation clips to prevent prematurely covering the needle with the needle guard.
Pinch a fold of skin between thumb and index finger. Don't squeeze it.
Push the needle in fully. A doctor or nurse may have shown how to do this.
Push the plunger with thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skinfold pinched. The PROTECS needle guard will not activate unless the entire dose is given. A patient may hear a click when the PROTECS needle guard has been activated.
When the plunger is pushed as far as it will go, take out the needle and let go of the skin.
Slowly take the thumb off the plunger. Allow the syringe to move up until the entire needle is covered by the needle guard.
When the needle is pulled out of the skin, there may be a little bleeding at the injection site. This is normal. The patient can press an antiseptic swab over the injection site for a few seconds after the injection.
Dispose the used syringe in a safe container.
Only take one dose of Epoetin alfa (Eprex) from each syringe. If any liquid remains in the syringe after an injection, the syringe should be properly disposed of, not reused. See How to dispose of Epoetin alfa (Eprex) as follows.
What to do if a patient uses too much Epoetin alfa (Eprex): Tell the doctor or nurse immediately if a patient thinks too much Epoetin alfa (Eprex) has been injected.
What to do if a patient forgets to use Epoetin alfa (Eprex): Make the next injection as soon as he/she remembers. If a patient is within a day of his/her next injection, forget the missed one and carry on with the normal schedule. Do not double up the injections.
Other important points: Epoetin alfa (Eprex) should not be used: After the expiry date on the label; if the seal is broken; if the liquid is colored or particles are floating in it; if it may have been accidentally frozen; if there has been a refrigerator failure.
How to dispose of Epoetin alfa (Eprex): Medicines should not be disposed of via waste water or in household waste. Ask a pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
Incompatibilities: Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in conjunction with other drug solutions.
The product should not be used, and should be discarded if: the seal is broken; the liquid is colored or particles are in it; it may have been frozen, or; there has been a refrigeration failure.
Any waste material should be disposed of in accordance with local requirements.
Patient Instructions for Use and Handling and Disposal: Injecting Epoetin alfa (Eprex) under the skin: At the start of the therapy, Epoetin alfa (Eprex) may be injected by medical or nursing staff. However, the doctor may decide that it is right for a patient to learn how to inject Epoetin alfa (Eprex) under the skin (subcutaneously). A patient will receive appropriate training to do this. Under no circumstances should patient attempt to inject himself/herself unless he/she has been trained to do so.
If Epoetin alfa (Eprex) is injected under the skin (subcutaneously), the amount injected is not normally more than one milliliter (1 mL) in a single injection.
Epoetin alfa (Eprex) is given alone and not mixed with other liquids for injection.
Do not shake Epoetin alfa (Eprex) syringes or vials. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, don't use it.
How to inject using a prefilled syringe: The pre-filled syringes are fitted with the PROTECS needle guard device to help prevent needle stick injuries after use. This is indicated on the packaging.
Take a syringe out of the refrigerator. The liquid needs to come to room temperature. This usually takes between 15 to 30 minutes. Do not remove the syringe's needle cover while allowing it to reach room temperature.
Check the syringe, to make sure it is the right dose, has not passed its expiry date, is not damaged, and the liquid is clear and not frozen.
Choose an injection site. Good sites are the top of the thigh and around the tummy (abdomen) but away from the navel. Vary the site from day to day.
Wash the hands. Use an antiseptic swab on the injection site, to disinfect it.
Hold the pre-filled syringe by the body of the syringe with the covered needle pointing upward.
Do not hold by the plunger head, plunger, needle guard wings, or needle cover.
Do not pull back on the plunger at any time.
Do not remove the needle cover from the pre-filled syringe until the patient is ready to inject the Epoetin alfa (Eprex).
Take the cover off the syringe by holding the barrel and pulling the cover off carefully without twisting it. Don't push the plunger, touch the needle or shake the syringe.
Do not touch the needle activation clips to prevent prematurely covering the needle with the needle guard.
Pinch a fold of skin between thumb and index finger. Don't squeeze it.
Push the needle in fully. A doctor or nurse may have shown how to do this.
Push the plunger with thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skinfold pinched. The PROTECS needle guard will not activate unless the entire dose is given. A patient may hear a click when the PROTECS needle guard has been activated.
When the plunger is pushed as far as it will go, take out the needle and let go of the skin.
Slowly take the thumb off the plunger. Allow the syringe to move up until the entire needle is covered by the needle guard.
When the needle is pulled out of the skin, there may be a little bleeding at the injection site. This is normal. The patient can press an antiseptic swab over the injection site for a few seconds after the injection.
Dispose the used syringe in a safe container.
Only take one dose of Epoetin alfa (Eprex) from each syringe. If any liquid remains in the syringe after an injection, the syringe should be properly disposed of, not reused. See How to dispose of Epoetin alfa (Eprex) as follows.
What to do if a patient uses too much Epoetin alfa (Eprex): Tell the doctor or nurse immediately if a patient thinks too much Epoetin alfa (Eprex) has been injected.
What to do if a patient forgets to use Epoetin alfa (Eprex): Make the next injection as soon as he/she remembers. If a patient is within a day of his/her next injection, forget the missed one and carry on with the normal schedule. Do not double up the injections.
Other important points: Epoetin alfa (Eprex) should not be used: After the expiry date on the label; if the seal is broken; if the liquid is colored or particles are floating in it; if it may have been accidentally frozen; if there has been a refrigerator failure.
How to dispose of Epoetin alfa (Eprex): Medicines should not be disposed of via waste water or in household waste. Ask a pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
Incompatibilities: Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in conjunction with other drug solutions.
Storage
In hospital, vials and pre-filled syringes are stored unopened in a refrigerator between 2 and 8 degrees centigrade. If a patient is using Epoetin alfa (Eprex) at home, it is important that the vial or pre-filled syringe is stored in a refrigerator although not in the freezer compartment. Epoetin alfa (Eprex) should not be frozen. Allow the vial or pre-filled syringe to reach room temperature prior to using it. This usually takes between 15 and 30 minutes. Epoetin alfa (Eprex) vials or pre-filled syringes that are being used or about to be used can be kept at room temperature (not above 25°C) for a maximum single period of 7 days.
Vials and pre-filled syringes should be protected from light.
Vials and pre-filled syringes should be protected from light.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the key regulator of red blood cell (RBC) production. EPO is involved in all phases of erythroid development, and has its principal effect at the level of erythroid precursors. After EPO binds to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosis and stimulates erythroid cell proliferation. Recombinant human EPO (Epoetin alfa), expressed in Chinese hamster ovary cells, has a 165 amino acid sequence identical to that of human urinary EPO; the 2 are indistinguishable on the basis of functional assays. The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton.
Pharmacodynamic responses to HSA-free Epoetin alfa, change in percent reticulocytes, hemoglobin, and total red blood cell counts as well as the area under the curve (AUCs) of these pharmacodynamic parameters, were similar between two dosing regimens (150 IU/kg SC three times per week to 40,000 IU/mL SC once weekly).
ESAs are growth factors that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.
Clinical efficacy and safety: Chronic renal failure: Epoetin alfa has been studied in clinical trials in adult anemic CRF patients, including patients on dialysis and patients not yet on dialysis, to treat anaemia and maintain hematocrit within a concentration range of 30-36%.
In clinical trials at starting doses of 50-150 IU/kg three times per week, approximately 95% of all patients responded with a clinically significant increase in hematocrit. After approximately two months of therapy, virtually all patients were transfusion-independent. Once the hematocrit concentration range was achieved, the maintenance dose was individualised for each patient.
In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dose necessary to maintain the hematocrit between 30-36% was approximately 75 IU/kg given three times per week.
In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients on hemodialysis, clinically and statistically significant improvement was shown in the patients treated with Epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients from the group treated with Epoetin alfa were also enrolled in an open-label extension study which demonstrated improvements in their quality of life were maintained for an additional 12 months.
Adult patients with renal insufficiency not yet undergoing dialysis: In clinical trials conducted in patients with CRF not on dialysis treated with Epoetin alfa, the average duration of therapy was nearly five months. These patients responded to Epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when Epoetin alfa was administered by either an intravenous or subcutaneous route. Similar rates of rise of hematocrit were noted when Epoetin alfa was administered by either route. Moreover, Epoetin alfa doses of 75-150 IU/kg per week have been shown to maintain hematocrits of 36-38% for up to six months.
In a study with extended interval maintenance dosing of Epoetin alfa (Eprex), (once weekly, once every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain adequate hemoglobin levels and reached protocol-defined hemoglobin withdrawal criteria (0% in once weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4 weeks groups).
A randomized prospective trial (CHOIR) evaluated 1432 anemic chronic renal failure patients who were not undergoing dialysis. Patients were assigned to Epoetin alfa treatment targeting a maintenance hemoglobin level of 13.5 g/dL (higher than the recommended target hemoglobin level) or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p=0.03).
Treatment of patients with chemotherapy-induced anaemia: Epoetin alfa has been studied in clinical trials in adult anemic cancer patients with lymphoid and solid tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these trials, Epoetin alfa administered three times a week (tiw) and once weekly has been shown to increase hemoglobin and decrease transfusion requirements after the first month of therapy in anemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received Epoetin alfa and a maintenance of effect was observed.
Available evidence suggests the hematopoietic response to Epoetin alfa therapy is similar between patients with non-myeloid hematologic and solid tumors and in patients with or without tumor bone marrow infiltration. Comparable intensity of chemotherapy in the Epoetin alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area under the neutrophil time curve in patients treated with Epoetin alfa and placebo-treated patients, as well as by a similar proportion of patients in groups treated with Epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1000 and 500 cells/μL.
In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anemic patients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of anemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy-Anaemia (FACT-An) general scale, FACT-An fatigue scale, and Cancer Linear Analogue Scale (CLAS).
The totality of evidence, including results of meta-analyses and clinical experience from controlled studies of ESAs in patients with cancer, continues to support a favorable benefit-risk balance for the use of ESAs in patients with chemotherapy-induced anemia, when used according to the prescribing information. In meta-analyses of studies in which patients were receiving chemotherapy there were no statistically significant increases in either mortality or tumour progression. Signals in individual studies conducted outside of the recommendations in the product labeling (hemoglobin targets above 12 g/dL and/or no chemotherapy treatment) have raised concerns (see Cancer Patients under Precautions).
Pharmacokinetics: Intravenous Administration: Measurement of Epoetin alfa following multiple dose intravenous (IV) administration of 50 to 100 IU/kg revealed a half-life of approximately 4 hours in healthy subjects and a longer half-life in renal failure patients of approximately 5 hours after doses of 50, 100 and 150 IU/kg. A half-life of approximately 6 hours has been reported in children. With at least 4 days of PK blood sampling, half-life estimates ranging from 20.1 to 33.0 hours were observed in cancer subjects receiving 667 and 1500 IU/kg IV doses of Epoetin alfa.
Subcutaneous Administration: Serum concentrations following subcutaneous injection are lower than those following intravenous injection. Serum levels increase slowly and reach a peak 12 to 18 hours after subcutaneous dosing. The peak serum concentration is below the peak observed using the intravenous route (approximately 1/20th of the value).
There is no accumulation: serum levels remain the same, whether data are collected 24 hours after the first injection or 24 hours after the last injection. Concentration-time profiles of erythropoietin on Week 1 and Week 4 were similar during multiple dosing of 600 IU/kg/once weekly in healthy subjects.
The pharmacokinetic data indicate no apparent difference in half-life among adult patients above or below 65 years of age.
A study of 7 preterm very low birth weight neonates and 10 healthy adults given IV erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
The half-life for the subcutaneous route of administration is approximately 24 hours. Mean half-life values in healthy subjects were 19.4±8.1 and 15.0±6.1 with multiple dosing of 150 IU/kg three times per week and 40,000 IU/mL once weekly, respectively.
In a study comparing 40,000 IU SC once weekly to 150 IU/kg SC three times per week dosing regimens of HSA-containing Epoetin alfa in healthy subjects, the following parameters were estimated using data corrected for predose endogenous erythropoietin concentration during Week 4: See Table 2.
Based on AUC comparison, relative bioavailability of Epoetin alfa 40,000 IU once weekly versus 150 IU/kg three times per week was 176%.
In a study comparing 40,000 IU SC once weekly versus 150 IU/kg SC three times per week dosing of HSA-free Epoetin alfa in healthy subjects, the following parameters were estimated using data corrected for predose endogenous erythropoietin concentration during Week 4: See Table 3.
Based on AUC comparison, relative bioavailability of Epoetin alfa 40,000 IU/mL once weekly versus 150 IU/kg three times per week was 239%.
The bioavailability of subcutaneous Epoetin alfa after a dose of 120 IU/kg is much lower than that of the intravenous drug: approximately 20%.
Pharmacokinetic parameters were estimated in healthy subjects and anemic cancer subjects receiving cyclic chemotherapy and either 150 IU/kg three times per week or 40,000 IU/mL once weekly of HSA-containing Epoetin alfa. The pharmacokinetic parameters of anemic cancer subjects were different from those observed in healthy subjects during Week 1 (when the anemic cancer subjects were receiving chemotherapy) but were similar during Week 3 (when the anemic cancer subjects were not receiving chemotherapy). (See Table 4.)
Pharmacokinetics of HSA-free Epoetin alfa were studied in anemic cancer subjects receiving cyclic chemotherapy after the 150 IU/kg three times per week and 40,000 IU/mL once weekly dosing regimens. In general, there was a high degree of variability associated with the pharmacokinetic parameters in anemic cancer subjects. In general, the first pharmacokinetic profile of Epoetin alfa during Week 1 (when the anemic cancer subjects were receiving chemotherapy) demonstrated higher Cmax, increased half-life, and lower clearance than the second pharmacokinetic profile during Week 3 or 4 (when the anemic cancer subjects were not receiving chemotherapy). (See Table 5.)
Toxicology: Preclinical Safety Data: Chronic Toxicity: In some pre-clinical toxicological studies in dogs and rats, but not in monkeys, Epoetin alfa therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of chronic renal failure in humans; it may be related to secondary hyperparathyroidism or unknown factors. In one study, there was no difference in the incidence of bone marrow fibrosis in hemodialysis patients treated with Epoetin alfa for 3 years and hemodialysis patients not treated with Epoetin alfa.
Carcinogenicity: Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the literature regarding ESAs as tumour proliferators. The clinical significance of these reports, based on in vitro findings from human tumour samples, are unknown.
Mutagenicity: Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.
Reproduction Toxicology: Preclinical studies have shown no evidence of teratogenicity in rats or rabbits at dosages up to 500 IU/kg/day administered intravenously. However, intravenous administration of Epoetin alfa causes a slight but not statistically significant decrease in fertility at 500 IU/kg, increased pre- and post-implantation loss and decreased fetal body weight at 100 and 500 IU/kg/day and delayed ossification at 20, 100, and 500 IU/kg/day. The latter finding was associated with reduced maternal body weight. Intravenous administration to lactating rats resulted in decreases in body weight gain, delays in appearance of abdominal hair and eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 IU/kg/day group. There were no Epoetin alfa-related effects on the F2 generation fetuses.
Pharmacodynamic responses to HSA-free Epoetin alfa, change in percent reticulocytes, hemoglobin, and total red blood cell counts as well as the area under the curve (AUCs) of these pharmacodynamic parameters, were similar between two dosing regimens (150 IU/kg SC three times per week to 40,000 IU/mL SC once weekly).
ESAs are growth factors that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.
Clinical efficacy and safety: Chronic renal failure: Epoetin alfa has been studied in clinical trials in adult anemic CRF patients, including patients on dialysis and patients not yet on dialysis, to treat anaemia and maintain hematocrit within a concentration range of 30-36%.
In clinical trials at starting doses of 50-150 IU/kg three times per week, approximately 95% of all patients responded with a clinically significant increase in hematocrit. After approximately two months of therapy, virtually all patients were transfusion-independent. Once the hematocrit concentration range was achieved, the maintenance dose was individualised for each patient.
In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dose necessary to maintain the hematocrit between 30-36% was approximately 75 IU/kg given three times per week.
In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients on hemodialysis, clinically and statistically significant improvement was shown in the patients treated with Epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients from the group treated with Epoetin alfa were also enrolled in an open-label extension study which demonstrated improvements in their quality of life were maintained for an additional 12 months.
Adult patients with renal insufficiency not yet undergoing dialysis: In clinical trials conducted in patients with CRF not on dialysis treated with Epoetin alfa, the average duration of therapy was nearly five months. These patients responded to Epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when Epoetin alfa was administered by either an intravenous or subcutaneous route. Similar rates of rise of hematocrit were noted when Epoetin alfa was administered by either route. Moreover, Epoetin alfa doses of 75-150 IU/kg per week have been shown to maintain hematocrits of 36-38% for up to six months.
In a study with extended interval maintenance dosing of Epoetin alfa (Eprex), (once weekly, once every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain adequate hemoglobin levels and reached protocol-defined hemoglobin withdrawal criteria (0% in once weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4 weeks groups).
A randomized prospective trial (CHOIR) evaluated 1432 anemic chronic renal failure patients who were not undergoing dialysis. Patients were assigned to Epoetin alfa treatment targeting a maintenance hemoglobin level of 13.5 g/dL (higher than the recommended target hemoglobin level) or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p=0.03).
Treatment of patients with chemotherapy-induced anaemia: Epoetin alfa has been studied in clinical trials in adult anemic cancer patients with lymphoid and solid tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these trials, Epoetin alfa administered three times a week (tiw) and once weekly has been shown to increase hemoglobin and decrease transfusion requirements after the first month of therapy in anemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received Epoetin alfa and a maintenance of effect was observed.
Available evidence suggests the hematopoietic response to Epoetin alfa therapy is similar between patients with non-myeloid hematologic and solid tumors and in patients with or without tumor bone marrow infiltration. Comparable intensity of chemotherapy in the Epoetin alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area under the neutrophil time curve in patients treated with Epoetin alfa and placebo-treated patients, as well as by a similar proportion of patients in groups treated with Epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1000 and 500 cells/μL.
In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anemic patients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of anemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy-Anaemia (FACT-An) general scale, FACT-An fatigue scale, and Cancer Linear Analogue Scale (CLAS).
The totality of evidence, including results of meta-analyses and clinical experience from controlled studies of ESAs in patients with cancer, continues to support a favorable benefit-risk balance for the use of ESAs in patients with chemotherapy-induced anemia, when used according to the prescribing information. In meta-analyses of studies in which patients were receiving chemotherapy there were no statistically significant increases in either mortality or tumour progression. Signals in individual studies conducted outside of the recommendations in the product labeling (hemoglobin targets above 12 g/dL and/or no chemotherapy treatment) have raised concerns (see Cancer Patients under Precautions).
Pharmacokinetics: Intravenous Administration: Measurement of Epoetin alfa following multiple dose intravenous (IV) administration of 50 to 100 IU/kg revealed a half-life of approximately 4 hours in healthy subjects and a longer half-life in renal failure patients of approximately 5 hours after doses of 50, 100 and 150 IU/kg. A half-life of approximately 6 hours has been reported in children. With at least 4 days of PK blood sampling, half-life estimates ranging from 20.1 to 33.0 hours were observed in cancer subjects receiving 667 and 1500 IU/kg IV doses of Epoetin alfa.
Subcutaneous Administration: Serum concentrations following subcutaneous injection are lower than those following intravenous injection. Serum levels increase slowly and reach a peak 12 to 18 hours after subcutaneous dosing. The peak serum concentration is below the peak observed using the intravenous route (approximately 1/20th of the value).
There is no accumulation: serum levels remain the same, whether data are collected 24 hours after the first injection or 24 hours after the last injection. Concentration-time profiles of erythropoietin on Week 1 and Week 4 were similar during multiple dosing of 600 IU/kg/once weekly in healthy subjects.
The pharmacokinetic data indicate no apparent difference in half-life among adult patients above or below 65 years of age.
A study of 7 preterm very low birth weight neonates and 10 healthy adults given IV erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
The half-life for the subcutaneous route of administration is approximately 24 hours. Mean half-life values in healthy subjects were 19.4±8.1 and 15.0±6.1 with multiple dosing of 150 IU/kg three times per week and 40,000 IU/mL once weekly, respectively.
In a study comparing 40,000 IU SC once weekly to 150 IU/kg SC three times per week dosing regimens of HSA-containing Epoetin alfa in healthy subjects, the following parameters were estimated using data corrected for predose endogenous erythropoietin concentration during Week 4: See Table 2.
Based on AUC comparison, relative bioavailability of Epoetin alfa 40,000 IU once weekly versus 150 IU/kg three times per week was 176%.
In a study comparing 40,000 IU SC once weekly versus 150 IU/kg SC three times per week dosing of HSA-free Epoetin alfa in healthy subjects, the following parameters were estimated using data corrected for predose endogenous erythropoietin concentration during Week 4: See Table 3.
Based on AUC comparison, relative bioavailability of Epoetin alfa 40,000 IU/mL once weekly versus 150 IU/kg three times per week was 239%.
The bioavailability of subcutaneous Epoetin alfa after a dose of 120 IU/kg is much lower than that of the intravenous drug: approximately 20%.
Pharmacokinetic parameters were estimated in healthy subjects and anemic cancer subjects receiving cyclic chemotherapy and either 150 IU/kg three times per week or 40,000 IU/mL once weekly of HSA-containing Epoetin alfa. The pharmacokinetic parameters of anemic cancer subjects were different from those observed in healthy subjects during Week 1 (when the anemic cancer subjects were receiving chemotherapy) but were similar during Week 3 (when the anemic cancer subjects were not receiving chemotherapy). (See Table 4.)
Pharmacokinetics of HSA-free Epoetin alfa were studied in anemic cancer subjects receiving cyclic chemotherapy after the 150 IU/kg three times per week and 40,000 IU/mL once weekly dosing regimens. In general, there was a high degree of variability associated with the pharmacokinetic parameters in anemic cancer subjects. In general, the first pharmacokinetic profile of Epoetin alfa during Week 1 (when the anemic cancer subjects were receiving chemotherapy) demonstrated higher Cmax, increased half-life, and lower clearance than the second pharmacokinetic profile during Week 3 or 4 (when the anemic cancer subjects were not receiving chemotherapy). (See Table 5.)
Toxicology: Preclinical Safety Data: Chronic Toxicity: In some pre-clinical toxicological studies in dogs and rats, but not in monkeys, Epoetin alfa therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of chronic renal failure in humans; it may be related to secondary hyperparathyroidism or unknown factors. In one study, there was no difference in the incidence of bone marrow fibrosis in hemodialysis patients treated with Epoetin alfa for 3 years and hemodialysis patients not treated with Epoetin alfa.
Carcinogenicity: Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the literature regarding ESAs as tumour proliferators. The clinical significance of these reports, based on in vitro findings from human tumour samples, are unknown.
Mutagenicity: Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.
Reproduction Toxicology: Preclinical studies have shown no evidence of teratogenicity in rats or rabbits at dosages up to 500 IU/kg/day administered intravenously. However, intravenous administration of Epoetin alfa causes a slight but not statistically significant decrease in fertility at 500 IU/kg, increased pre- and post-implantation loss and decreased fetal body weight at 100 and 500 IU/kg/day and delayed ossification at 20, 100, and 500 IU/kg/day. The latter finding was associated with reduced maternal body weight. Intravenous administration to lactating rats resulted in decreases in body weight gain, delays in appearance of abdominal hair and eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 IU/kg/day group. There were no Epoetin alfa-related effects on the F2 generation fetuses.
MedsGo Class
Haematopoietic Agents
Features
Brand
Eprex
Full Details
Dosage Strength
4000 IU / 0.4 mL
Drug Ingredients
- Epoetin Alfa
Drug Packaging
Solution for Injection 2ml x 1's
Generic Name
Epoetin alfa
Dosage Form
Solution for Injection
Registration Number
DRP-701
Drug Classification
Prescription Drug (RX)