Epogen (Epoetin Alfa) - Indications and Dosage

INDICATIONS AND USAGE

Treatment of Anemia of Chronic Renal Failure Patients

EPOGEN^® is indicated for the treatment of anemia associated with CRF, including patients on dialysis and patients not on dialysis. EPOGEN^® is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients.

Non-dialysis patients with symptomatic anemia considered for therapy should have a hemoglobin less than 10 g/dL.

EPOGEN^® is not intended for patients who require immediate correction of severe anemia. EPOGEN^® may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion.

Prior to initiation of therapy, the patient’s iron stores should be evaluated. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Blood pressure should be adequately controlled prior to initiation of EPOGEN^® therapy, and must be closely monitored and controlled during therapy.

Treatment of Anemia in Zidovudine-treated HIV-infected Patients

EPOGEN^® is indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients. EPOGEN^® is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients. EPOGEN^® is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately. EPOGEN^® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

EPOGEN^®, at a dose of 100 Units/kg TIW, is effective in decreasing the transfusion requirement and increasing the red blood cell level of anemic, HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is ≤ 500 mUnits/mL and when patients are receiving a dose of zidovudine ≤ 4200 mg/week.

Treatment of Anemia in Cancer Patients on Chemotherapy

EPOGEN^® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether EPOGEN^® increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• EPOGEN^® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
• EPOGEN^® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of EPOGEN^® on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).
• EPOGEN^® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).
• EPOGEN^® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

DOSAGE AND ADMINISTRATION

IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events.

Chronic Renal Failure Patients

The recommended range for the starting dose of EPOGEN^® is 50 to 100 Units/kg TIW for adult patients. The recommended starting dose for pediatric CRF patients on dialysis is 50 Units/kg TIW. Individualize dosing to achieve and maintain hemoglobin levels between 10-12 g/dL. The dose of EPOGEN^® should be reduced as the hemoglobin approaches 12 g/dL or increases by more than 1 g/dL in any 2-week period. If hemoglobin excursions outside the recommended range occur, the EPOGEN^® dose should be adjusted as described below.

EPOGEN^® may be given either as an IV or SC injection. In patients on hemodialysis, the IV route is recommended (see WARNINGS: Pure Red Cell Aplasia). While the administration of EPOGEN^® is independent of the dialysis procedure, EPOGEN^® may be administered into the venous line at the end of the dialysis procedure to obviate the need for additional venous access. In adult patients with CRF not on dialysis, EPOGEN^® may be given either as an IV or SC injection.

Patients who have been judged competent by their physicians to self-administer EPOGEN^® without medical or other supervision may give themselves either an IV or SC injection. The table below provides general therapeutic guidelines for patients with CRF:

Individually titrate to achieve and maintain hemoglobin levels between 10 to 12 g/dL.

Starting Dose:
Adults	50 to 100 Units/kg TIW; IV or SC
Pediatric Patients	50 Units/kg TIW; IV or SC
Increase Dose by 25% If:	1. Hemoglobin is < 10 g/dL and has not increased by 1 g/dL after 4 weeks of therapy or 2. Hemoglobin decreases below 10 g/dL
Reduce Dose by 25% When:	1. Hemoglobin approaches 12 g/dL or, 2. Hemoglobin increases > 1 g/dL in any 2-week period

During therapy, hematological parameters should be monitored regularly. Doses must be individualized to ensure that hemoglobin is maintained at an appropriate level for each patient.

For patients whose hemoglobin does not attain a level within the range of 10 to 12 g/dL despite the use of appropriate EPOGEN^® dose titrations over a 12-week period:

• do not administer higher EPOGEN^® doses and use the lowest dose that will maintain a hemoglobin level sufficient to avoid the need for recurrent RBC transfusions,
• evaluate and treat for other causes of anemia (see PRECAUTIONS: Lack or Loss of Response), and
• thereafter, hemoglobin should continue to be monitored and if responsiveness improves, EPOGEN^® dose adjustments should be made as described above; discontinue EPOGEN^® if responsiveness does not improve and the patient needs recurrent RBC transfusions. 

Pretherapy Iron Evaluation: Prior to and during EPOGEN^® therapy, the patient’s iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels that will adequately support erythropoiesis stimulated by EPOGEN^®.

Dose Adjustment: The dose should be adjusted for each patient to achieve and maintain hemoglobin levels between 10 to 12 g/dL.

Increases in dose should not be made more frequently than once a month. If the hemoglobin is increasing and approaching 12 g/dL, the dose should be reduced by approximately 25%. If the hemoglobin continues to increase, dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25% below the previous dose. If the hemoglobin increases by more than 1 g/dL in a 2-week period, the dose should be decreased by approximately 25%.

If the increase in the hemoglobin is less than 1 g/dL over 4 weeks and iron stores are adequate (see PRECAUTIONS: Laboratory Monitoring), the dose of EPOGEN^® may be increased by approximately 25% of the previous dose. Further increases may be made at 4-week intervals until the specified hemoglobin is obtained.

Maintenance Dose: The maintenance dose must be individualized for each patient on dialysis. In the US phase 3 multicenter trial in patients on hemodialysis, the median maintenance dose was 75 Units/kg TIW, with a range from 12.5 to 525 Units/kg TIW. Almost 10% of the patients required a dose of 25 Units/kg, or less, and approximately 10% of the patients required more than 200 Units/kg TIW to maintain their hematocrit in the suggested target range. In pediatric hemodialysis and peritoneal dialysis patients, the median maintenance dose was 167 Units/kg/week (49 to 447 Units/kg per week) and 76 Units/kg per week (24 to 323 Units/kg/week) administered in divided doses (TIW or BIW), respectively to achieve the target range of 30% to 36%.

If the transferrin saturation is greater than 20%, the dose of EPOGEN^® may be increased. Such dose increases should not be made more frequently than once a month, unless clinically indicated, as the response time of the hemoglobin to a dose increase can be 2 to 6 weeks. Hemoglobin should be measured twice weekly for 2 to 6 weeks following dose increases. In adult patients with CRF not on dialysis, the dose should also be individualized to maintain hemoglobin levels between 10 to 12 g/dL. EPOGEN^® doses of 75 to 150 Units/kg/week have been shown to maintain hematocrits of 36% to 38% for up to 6 months.

Lack or Loss of Response: If a patient fails to respond or maintain a response, an evaluation for causative factors should be undertaken (see WARNINGS: Pure Red Cell Aplasia, PRECAUTIONS: Lack or Loss of Response, and PRECAUTIONS: Iron Evaluation). If the transferrin saturation is less than 20%, supplemental iron should be administered.

Zidovudine-treated HIV-infected Patients

Prior to beginning EPOGEN^®, it is recommended that the endogenous serum erythropoietin level be determined (prior to transfusion). Available evidence suggests that patients receiving zidovudine with endogenous serum erythropoietin levels > 500 mUnits/mL are unlikely to respond to therapy with EPOGEN^®.

In zidovudine-treated HIV-infected patients the dosage of EPOGEN^® should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not to exceed the upper safety limit of 12 g/dL.

Starting Dose: For adult patients with serum erythropoietin levels ≤ 500 mUnits/mL who are receiving a dose of zidovudine ≤ 4200 mg/week, the recommended starting dose of EPOGEN^® is 100 Units/kg as an IV or SC injection TIW for 8 weeks. For pediatric patients, see PRECAUTIONS: PEDIATRIC USE.

Increase Dose: During the dose adjustment phase of therapy, the hemoglobin should be monitored weekly. If the response is not satisfactory in terms of reducing transfusion requirements or increasing hemoglobin after 8 weeks of therapy, the dose of EPOGEN^® can be increased by 50 to 100 Units/kg TIW. Response should be evaluated every 4 to 8 weeks thereafter and the dose adjusted accordingly by 50 to 100 Units/kg increments TIW. If patients have not responded satisfactorily to an EPOGEN^® dose of 300 Units/kg TIW, it is unlikely that they will respond to higher doses of EPOGEN^®.

Maintenance Dose: After attainment of the desired response (ie, reduced transfusion requirements or increased hemoglobin), the dose of EPOGEN^® should be titrated to maintain the response based on factors such as variations in zidovudine dose and the presence of intercurrent infectious or inflammatory episodes. If the hemoglobin exceeds the upper safety limit of 12 g/dL, the dose should be discontinued until the hemoglobin drops below 11 g/dL. The dose should be reduced by 25% when treatment is resumed and then titrated to maintain the desired hemoglobin.

Cancer Patients on Chemotherapy

Although no specific serum erythropoietin level has been established which predicts which patients would be unlikely to respond to EPOGEN^® therapy, treatment of patients with grossly elevated serum erythropoietin levels (eg, > 200 mUnits/mL) is not recommended. Therapy should not be initiated at hemoglobin levels ≥ 10 g/dL. The hemoglobin should be monitored on a weekly basis in patients receiving EPOGEN^® therapy until hemoglobin becomes stable. The dose of EPOGEN^® should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion (see recommended Dose Modifications, below).

Recommended Dose: The initial recommended dose of EPOGEN^® in adults is 150 Units/kg SC TIW or 40,000 Units SC Weekly. The initial recommended dose of EPOGEN^® in pediatric patients is 600 Units/kg IV weekly. Discontinue EPOGEN^® following the completion of a chemotherapy course (see BOXED WARNINGS: Cancer ).

Dose Modification

TIW Dosing

Starting Dose:
Adults	150 Units/kg SC TIW
Reduce Dose by 25% when:	Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-week period.
Withhold Dose if:	Hemoglobin exceeds a level needed to avoid transfusion. Restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required.
Increase Dose to 300 Units/kg TIW if:	Response is not satisfactory (no reduction in transfusion requirements or rise in hemoglobin) after 4 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.
Discontinue:	If after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

Weekly Dosing

Starting Dose:
Adults	40,000 Units SC
Pediatrics	600 Units/kg IV (maximum 40,000 Units)
Reduce Dose by 25% when:	Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-weeks.
Withhold Dose if:	Hemoglobin exceeds a level needed to avoid transfusion and restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required.
Increase Dose if: For Adults: 60,000 Units SC Weekly For Pediatrics: 900 Units/kg IV (maximum 60,000 Units) if:	Response is not satisfactory (no increase in hemoglobin by ≥ 1g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.
Discontinue:	If after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

Surgery Patients

Prior to initiating treatment with EPOGEN^® a hemoglobin should be obtained to establish that it is > 10 to ≤ 13 g/dL.¹⁷ The recommended dose of EPOGEN^® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

An alternate dose schedule is 600 Units/kg EPOGEN^® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.¹⁸

All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with EPOGEN^® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS).

PREPARATION AND ADMINISTRATION OF EPOGEN ^®

• Do not shake. It is not necessary to shake EPOGEN^®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive.
• Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
• Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing EPOGEN^®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.
• Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions. 

  Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8° C after initial entry and between doses. Discard 21 days after initial entry.

• Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free EPOGEN^® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of EPOGEN^® containing benzyl alcohol.

HOW SUPPLIED

EPOGEN^®, containing Epoetin alfa, is available in the following packages:

1 mL Single-dose, Preservative-free Solution

      2000 Units/mL (NDC 55513-126-10)

      3000 Units/mL (NDC 55513-267-10)

      4000 Units/mL (NDC 55513-148-10)

      10,000 Units/mL (NDC 55513-144-10)

      40,000 Units/mL (NDC 55513-823-10)

Supplied in dispensing packs containing 10 single-dose vials.

2 mL Multidose, Preserved Solution

      10,000 Units/mL (NDC 55513-283-10)

1 mL Multidose, Preserved Solution

      20,000 Units/mL (NDC 55513-478-10)

Supplied in dispensing packs containing 10 multidose vials.

STORAGE

Store at 2° to 8° C (36° to 46° F). Do not freeze or shake. Protect from light.