Erythropoietin, Epoetin Alpha

Erythropoietin, Epoetin alpha (Epogen, Procrit)

JCODE: J3490

OFFICE / HOME HEALTH / OR SELF ADMINISTRATION

FDA approved indications (see Addendum 1 for additional information)

Anemia due to Chronic Renal Failure, including both dialysis and pre-dialysis patients

• (If a patient is on dialysis, the drug is usually provided by the dialysis center.) SCr > 2

Anemia due to Chemotherapy: For the treatment of anemia due to the effect of chemotherapy in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of two additional months. Studies to determine whether epoetin alfa increases mortality or decreases progression free/recurrence-free survival are ongoing:

• It is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy
• It 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 on progression-free and overall survival
• It 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
• Its use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being

HIV Treatment-Related Anemia

• Require a medication profile noting HIV regimen and initial Hct <30% or Hgb less than or equal to 10.
• Maintain: EPO level <500 milliunits/ml and Serum ferritin level>100 ng/ml or Transferrin saturation >20%

Reduction of allogeneic blood transfusion in surgery patients

• Anemic patients (Hgb>11 to <13 g/dl) scheduled for elective, non-cardiac, nonvascular surgery or patients at high risk for pre-operative transfusions with significant, anticipated blood loss

Non-FDA approved indications that require prior authorization:

Patient’s with Myelodysplastic Syndrome

• Patients having symptomatic anemia (Hgb <10 g/dL) AND endogenous epoetin levels < 500 milliunits/mL should receive 40,000-60,000 units epoetin alfa one-three times/week with appropriate iron repletion
• If the patient shows no response within an initial trial period of 6-8 weeks, treatment should be considered a failure and discontinued (rule out and treat deficient iron stores)
• If the patient responds to epoetin alfa therapy within the initial trial period of six-eight weeks, the dose should be decreased as tolerated

Anemia due to ribavirin therapy

• Patients on combination therapy (pegylated interferon and ribavirin) for treatment of hepatitis C may use epoetin alfa to treat anemia caused by ribavirin. The goal is to allow for treatment that allows the maintenance of the recommended ribavirin dose

Hematologic malignancies

The following criteria do not meet criteria for coverage:

Anemia due to:

• Cancer without Chemotherapy
• Congestive Heart Failure
• Porphyria
• Postpartum
• Prematurity
• Rheumatoid Arthritis
• Athletic Performance Management
• Beta-thalassemia
• Blood transfusion reduction
• Insulin resistance
• Sexual dysfunction
• Sickle-cell Anemia
• Transfusion iron overload

Contraindications to therapy include

• Hypersensitivity to hamster protein or albumin – Epoetin alfa is derived from Chinese hamster ovarian cells and is contraindicated in patients with a known hypersensitivity
• Pregnant patients or those with benzyl alcohol hypersensitivity – the multi-dose vial of epoetin alfa contains benzyl alcohol
• Patients with uncontrolled hypertension – although it appears the epoetin alfa does not have any direct pressor effects, blood pressure may increase during therapy. Do not administer in patients with uncontrolled hypertension
• Patients with serum epoetin greater than 500 milliunits/mL in chronic renal failure or HIV treatment

All of the following must be met as a condition(s) for coverage:

• Must have baseline Hgb < 10 g/dL
• For chemotherapy patients, an additional two months of planned chemotherapy
• For Hepatitis C patients, they must be on combination pegylated interferon and ribavirin therapy
• Must have documentation of adequate iron stores drawn within 60 days of the request for initiation of therapy and when epoetin alfa dose is increased
  • Percent transferrin saturation should be greater than or equal to 20%o
  • Ferritin should be greater than or equal to 100 ng/mL
• Documentation of ongoing iron supplementation

Dosing:

Anemia due to CRF

• Initially 50-100 units/kg, 3x/week, Do not initiate therapy at hemoglobin levels of greater than 10 g/dL
• If Hgb approaches or exceeds 11 g/dL for dialysis patients or 10 g/dL for patients not on dialysis, reduce or interrupt the dose. Use the lowest dose sufficient to reduce the need for RBC transfusions
• If the Hgb rises more than 1 g/dL in any 2-week period, reduce the dose by 25%
• If the Hgb has not increased 1 g/dL or more after 4 weeks of therapy, increase the dose by 25%
• For patients who do not respond adequately over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks
• Use the lowest dose sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia and discontinue therapy if responsiveness does not improve

Anemia in cancer patients on chemotherapy

Although no specific serum erythropoietin level has been established that predicts which patients would be unlikely to respond to epoetin alfa therapy, treatment of patients with grossly elevated serum erythropoietin levels (e.g. more than 200 milliunits/mL) is not recommended.

Hemoglobin should be monitored on a weekly basis in patients receiving epoetin alfa therapy until hemoglobin becomes stable. The dose of epoetin alfa should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion. Do not initiate therapy at hemoglobin levels of 10 g/dL or higher.

Epoetin Alfa Dosage Guidelines for Adult Cancer Patients on Chemotherapy

Starting dose:

• 150 units/kg subcutaneously three times per week or 40,000 units subcutaneously once weekly

Reduce dose by 25% when:

• Hemoglobin reaches a level needed to avoid transfusion or increases > 1g/dL in any two week period

Withhold dose if:

• Hemoglobin exceeds a level needed to avoid transfusion. Restart at 25% below the previous dose when hemoglobin approaches a level for which transfusions may be required

Increase dosage to 300 units/kg three times per week if:

• Response is not satisfactory (no reduction intransfusion requirements or rise in hemoglobin) after four weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion

Increase to 60,000 units subcutaneously weekly if:

• Response is not satisfactory (no increase in hemoglobin by > 1g/dL after four weeks of therapy, in the absence of an RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion

Discontinue:

• If after eight weeks of therapy, there is no response as measured by hemoglobin levels or if transfusions are still required

Anemia due to ribavirin therapy

• Epoetin 40,000 units once weekly, may increase to 60,000 units once weekly if Hgb level has not increased by at least 1 g/dL after four weeks of treatment

Anemia due to HIV Treatment

• Start with 100 units/kg 3x/week for eight weeks, increase every 4-8 weeks by 50-100 units/kg to a maximum of 300 units/kg 3x/week. Do not exceed Hgb of 12 g/dL

Surgery patients

• 300 units/kg/day 10 days before surgery, on the day of surgery, and for four days after surgery or 600 units/kg/week (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery

Myelodysplastic Syndrome

• Initial: 40,000-60,000 units epoetin alfa one-three times/week with appropriate iron repletion, for six-eight weeks
• No response to initial six-eight week trial: re-assess iron repletion and if appropriate discontinue therapy

Monitoring Requirements

• Hemoglobin at baseline, twice weekly for two-six weeks after initiation (or as required for dose adjustments discussed above) and following dosage changes and then monthly once hemoglobin level is stable
• TSAT and ferritin monthly if NOT on parenteral iron therapy
• TSAT and ferritin every three months if using parenteral iron therapy
• Blood pressure twice weekly, or more frequently in those with cardiovascular disease

>Discontinuation of therapy:

• Discontinue epoetin alfa if after eight weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required. Discontinue epoetin alfa following completion of a chemotherapy course

Approval:

• Initial Approval two months
• Ongoing review every two months
• If Hgb has not increased in six months, reassess therapy
• Aranesp (darbepoetin alpha) has no therapeutic advantage over epoetin alpha and must be prior approved for use based on intolerance to the preferred agents

Addendum 1. Additional Information:

Dosing – epoetin alfa and iron

• The therapeutic effects of erythropoietin are dose dependent, however, a greater biologic response is not observed at doses exceeding 300 units/kg 3x/week
• It takes several days for erythropoiesis. A clinically significant increase in Hct is usually not observed in less than two weeks and may require up to six weeks in some patients. Dose increases should generally not be made more frequently than every two weeks
• The national Kidney Foundation states: To achieve and maintain Hgb 11-12 g/dL and Hct 33%-36%, sufficient iron should be administered to maintain a TSAT of greater than 20%, and serum ferritin levels of greater than 100 ng/mL

>Patients with anemia on dialysis

• Consider initiating treatment only when Hgb is less than 10 g/dL and the rate of decline of Hgb indicates that the likelihood of requiring an RBC transfusion and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal

Patients with anemia on chemotherapy

• The American Society of Clinical Oncology & American Society of Hematology 2010 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin states: The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy associated anemia and an Hgb concentration that has decreased to less than 10 g/dL to decrease transfusions. An optimal target Hgb concentration cannot be definitively determined from the available literature. Modification to reduce the erythropoiesis stimulating agents (ESAs) dose is appropriate when Hgb reaches a level sufficient to avoid transfusion or the increase exceeds 1 g/dL in any two week period to avoid excessive ESA exposure
• National Comprehensive Cancer Network guidelines state that IV or oral iron products are recommended for iron repletion in cancer patients with absolute iron deficiency (ferritin < 30 ng/mL). Intravenous iron as superior efficacy and should be considered for supplementation. Oral iron has been used more commonly, but is less effective.

Clinical response in the treatment of myelodysplastic syndrome may include any of the following

• Hgb increase of at least 1 g/dL from baseline
• Maintenance of Hgb between 10-12 g/dL

Patients with anemia on dual therapy for Hepatitis C

• Based on HALT-C trial data there is a greater chance of achieving a sustained viral response (SVR) in patients with hepatitis C if the ribavirin dose can be maintained during the first 20 weeks of combination therapy

Definitions

• Transferrin saturation percent = (serum iron/total iron biding capacity)*100
• TIBC – total iron binding capacity
• TSAT – transferrin saturation

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