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RxAmerica Clinical Coverage
Position Statement
Trade Name:
Generic Name:
Manufacturer:
Epogen®; Procrit®
Epoetin alfa
Amgen; Ortho Biotech
Drug Description
Epoetin alfa (Epogen®; Procrit®) is a recombinant form of erythropoietin that is used to stimulate the
production, maturation, and release of red blood cells and is used for the treatment of anemia.
FDA Indications
INDICATION
Treatment of anemia of chronic
kidney disease – X
Treatment of anemia in cancer
(non-myeloid malignancies) patients
on chemotherapy – X
Treatment of anemia in zidovudinetreated HIV-infected patients – X
Reduction of allogeneic blood
transfusion in surgery patients – X
ICD-9
Codes
Q0136
(for nonend stage
renal
disease
use)
Dose
80-300 units/kg/week IV or
subcutaneous in 2-3 divided doses
per week
OR
10,000 units subcutaneous once
weekly
Q4055
(for end
stage renal
disease on
dialysis)
Q0136
Children ≥3 months (≥1 month if on
dialysis): 50-250 units/kg IV or
subcutaneous 1-3 times per week
Q0136
Q0136
150 units/kg subcutaneous three
times weekly
OR
40,000 units subcutaneous once
weekly
Children ≥6 months:
25-300 units/kg IV or subcutaneous 37 times per week
100 units/kg IV or subcutaneous three
times weekly for 8 weeks
OR
40,000 units subcutaneous once
weekly for 8 weeks
Children ≥8 months:
50-400 units/kg IV or subcutaneous 23 times per week
300 units/kg/day subcutaneous for 10
days prior to surgery, on day of
surgery, and for 4 days after surgery
OR
600 units/kg subcutaneous once
weekly x4 doses on days 21, 14, and
7 days prior to surgery and on day of
surgery
Treatment of anemia associated with
malignancy but not receiving
chemotherapy – O
Q0136
Treatment of anemia associated with
myelodysplastic syndromes – O
Q0136
Prevention of anemia associated with
frequent blood donations – O
Q0136
Treatment of ribavirin-induced anemia in
patients with hepatitis C – O
Treatment of anemia associated with
rheumatoid arthritis and rheumatic
disease – O
Q0136
Q0136
100 units/kg subcutaneous three
times weekly
OR
150-300 units/kg subcutaneous three
times weekly
150 units/kg/day subcutaneous
OR
40,000 units subcutaneous once or
twice weekly
600 units/kg IV twice weekly for 3
weeks starting 25-35 days prior to
surgery
40,000 units subcutaneous once
weekly
80-720 units/kg/week IV or
subcutaneous divided in 2-3 doses
per week
X – FDA-approved indication
O – Not an FDA-approved indication, but shown to be effective in clinical trials
Black Box Warnings: NONE
WARNINGS / Special Alerts
Cardiovascular Events: Cardiovascular events may be increased in patients receiving epoetin alfa.
Higher hemoglobin concentrations and higher rates of rise of hemoglobin may precipitate these events.
In a clinical trial involving epoetin alfa, adverse effects, including death, occurred more frequently at
hemoglobin concentrations of 14 g/dL compared to concentrations of 10 g/dL. Therefore, target
hemoglobin concentrations should be ≤12 g/dL. An increase in adverse effects was also associated with
an increase in hemoglobin of >1 g/dL during a 2-week period in the darbepoetin alfa trials. Epoetin alfa
dosage reduction is recommended if this rate is exceeded. Other cardiac adverse events included
cardiac arrest, seizures, strokes, hypertension, congestive heart failure, vascular access
thrombosis/ischemia/infarction, myocardial infarction, and fluid overload.
Hypertension: Increases in blood pressure have occurred with epoetin alfa therapy. Epoetin alfa is
contraindicated in patients with uncontrolled hypertension. Epoetin alfa dosage reductions are
recommended if difficulty in blood pressure control occurs despite pharmacologic or dietary measures.
Epoetin alfa is not associated with exacerbations of hypertension in zidovudine-treated patients infected
with HIV.
Seizures: Seizures have occurred with epoetin alfa therapy. Monitor blood pressure and neurologic
status closely, and decrease the dose of epoetin alfa if the hemoglobin rise exceeds 1 g/dL in a 2-week
period. The risk of seizures is greatest during the first few months of therapy. Epoetin alfa is not
associated with exacerbations of seizures in zidovudine-treated patients infected with HIV.
Thrombotic Events and Increased Mortality: Thrombotic events (pulmonary embolism,
thrombophlebitis, thrombosis) are increased in patients receiving epoetin alfa. Therefore, target
hemoglobin concentrations should be ≤12 g/dL. Epoetin alfa is not associated with exacerbations of
thrombotic events in zidovudine-treated patients infected with HIV.
Pure Red Cell Aplasia: Pure red cell aplasia (PRCA) with neutralizing antibodies to native erythropoietin
has occurred with epoetin alfa therapy. Patients with PRCA are resistant to epoetin alfa therapy and rely
on blood transfusions to maintain acceptable hemoglobin concentrations. PRCA has not been reported
when darbepoetin alfa has been the sole agent or when epoetin alfa has been given solely by intravenous
administration. Route of administration may play a role in the development of PRCA (intravenous versus
subcutaneous). Discontinue therapy in patients with suspected PRCA and do not administer any
erythropoietic agents to patients with PRCA secondary to erythropoietin neutralizing antibodies due to
cross-reactivity between agents. It is not known if epoetin alfa therapy may be resumed after recovery
from erythropoietin-induced PRCA. One case report describes a patient who responded to darbepoetin
alfa despite persistent erythropoietin antibodies and PRCA after epoetin alfa therapy. Another case
report describes a chronic renal failure patient who developed PRCA from subcutaneous epoetin alfa,
was treated with rituximab with CD20 depletion, and then was able to tolerate intravenous epoetin alfa
upon rechallenge with a satisfactory correction of anemia. Additional courses of rituximab may be
required due to β-cell regeneration.
Albumin (Human): Epoetin alfa contains human albumin and therefore carries the risk of transmitting
viral diseases and Creutzfeldt-Jakob disease (CJD). The risk of transmission is considered extremely
remote due to effective donor screening and the product manufacturing process. Transmission of viral
diseases or CJD has not been identified with albumin.
Position: 1-24
Epoetin alfa therapy is recommended for all patients with anemia associated with chronic kidney disease,
non-myeloid malignancies in patients being treated with chemotherapy, zidovudine-treated HIV-infected
patients, and for the reduction of allogeneic blood transfusions in surgery patients. Epoetin alfa therapy
may also be considered in patients with anemia associated with non-myeloid malignancies not being
treated with chemotherapy, myelodysplastic syndromes, rheumatoid arthritis and rheumatic disease,
ribavirin therapy in patients with hepatitis C, and for the prevention of anemia associated with frequent
blood donations.
Disease Definition:
Anemia in patients with chronic kidney disease is primarily due to insufficient quantities of
endogenous erythropoietin. The anemia is usually normocytic and normochromic. Therapy is
typically initiated when hemoglobin concentrations are <11 g/dL and all other causes of anemia
have been excluded. Chronic kidney disease is defined as either kidney damage or creatinine
clearance less than 60 mL/min for at least 3 months. It may include patients on dialysis and
patients not on dialysis.
Anemia in patients with cancer may be related to the cancer chemotherapy, infiltration of the
bone marrow by cancer cells, or nonspecific processes like iron deficiency, low endogenous
erythropoietin levels, or the inhibitory effect of tumor necrosis factor. Therapy is typically initiated
when hemoglobin concentrations are <10 g/dL and all other causes of anemia have been
excluded. Therapy may be recommended for hemoglobin concentrations <12 g/dL but >10 g/dL
depending on clinical circumstances. Anemia may be defined as mild (hemoglobin 10-11 g/dL),
moderate (hemoglobin 8-10 g/dL), or severe (hemoglobin <8 g/dL).
Non-myeloid malignancies are defined as cancers that do not involve blood cells.
Basis for Position: 1-4, 6-24
Epoetin alfa may be considered medically necessary in patients meeting all of the following criteria:
1. Chart notes support a diagnosis of chronic kidney disease (creatinine clearance less than 60
mL/min for at least 3 months) AND
2. Hemoglobin is less than 11 g/dL AND
3. Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
4. The prescribing physician is a nephrologist.
OR
5. Chart notes support a diagnosis of chemotherapy-induced anemia in patients with non-myeloid
malignancies AND
6. Hemoglobin is less than 10 g/dL OR
7.
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35.
Hemoglobin is less than 12 g/dL but greater than 10 g/dL and patient has symptoms of anemia
affecting functional capacity or quality of life (extreme fatigue or malaise, cold intolerance,
tachycardia, congestive heart failure, shortness of breath, severe angina, severe hypotension,
severe pulmonary distress) AND
Patient has received chemotherapy for at least 2 months OR
Patient has documented post-chemotherapy anemia after treatment within the past year AND
Erythropoietin concentration ≤200 mUnits/mL AND
Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
The prescribing physician is an oncologist.
OR
Chart notes support a diagnosis of anemia associated with zidovudine therapy in patients with
HIV AND
Hemoglobin is less than 13 g/dL in men or <12 g/dL in women AND
Erythropoietin concentration ≤500 mUnits/mL AND
Zidovudine doses <4200 mg/week AND
Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
Patient has symptoms of anemia (extreme fatigue or malaise, cold intolerance, tachycardia,
congestive heart failure, shortness of breath, severe angina, severe hypotension, severe pulmonary
distress) AND
The prescribing physician is an infectious disease specialist.
OR
Chart notes support the preoperative use of epoetin alfa for the reduction of allogeneic blood
transfusions AND
Hemoglobin is between 10-13 g/dL AND
Patient is scheduled for major, elective, noncardiac, nonvascular surgery and is expected to require
>2 units of blood AND
Patient is unable or unwilling to participate in an autologous blood donation program AND
Patient has anemia of chronic disease AND
The prescribing physician is a surgeon.
OR
Chart notes support a diagnosis of anemia in patients with non-myeloid malignancies who are
not receiving chemotherapy AND
Hemoglobin is less than 11 g/dL AND
Erythropoietin concentration ≤200 mUnits/mL AND
Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
Patient has symptoms of anemia (extreme fatigue or malaise, cold intolerance, tachycardia,
congestive heart failure, shortness of breath, severe angina, severe hypotension, severe pulmonary
distress) AND
The prescribing physician is an oncologist.
OR
Chart notes support the diagnosis of myelodysplastic syndrome AND
Hemoglobin is ≤10 g/dL AND
Erythropoietin concentration <500 mUnits/mL AND
Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
Patient has symptoms of anemia (extreme fatigue or malaise, cold intolerance, tachycardia,
congestive heart failure, shortness of breath, severe angina, severe hypotension, severe pulmonary
distress) AND
The prescribing physician is an oncologist.
OR
36. Chart notes support the preoperative use of epoetin alfa for the prevention of anemia associated
with frequent blood donations AND
37. Patient is scheduled for elective surgery and is expected to donate ≥4 units of blood AND
38. The prescribing physician is a surgeon.
OR
39. Chart notes support the diagnosis of ribavirin-induced anemia in patients with hepatitis C AND
40. Hemoglobin is ≤12 g/dL AND
41. Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
42. Patient has symptoms of anemia (extreme fatigue or malaise, cold intolerance, tachycardia,
congestive heart failure, shortness of breath, severe angina, severe hypotension, severe pulmonary
distress) AND
43. The prescribing physician is an internist.
OR
44. Chart notes support the diagnosis of rheumatoid arthritis or rheumatic disease AND
45. Hemoglobin is ≤11 g/dL AND
46. Other causes of anemia (iron deficiency, folic acid and vitamin B12 deficiencies, occult blood loss,
infectious/malignant/inflammatory processes, hematologic disease, aluminum intoxication,
hemolysis, osteitis fibrosa cystica) have been excluded or appropriately treated AND
47. Patient has symptoms of anemia (extreme fatigue or malaise, cold intolerance, tachycardia,
congestive heart failure, shortness of breath, severe angina, severe hypotension, severe pulmonary
distress) AND
48. The prescribing physician is a rheumatologist.
Limitations of Coverage:
In clinical trials, epoetin alfa administered three times weekly was not superior to every week
administration. Subcutaneous dosing of epoetin alfa is the preferred route of administration.
CMS National Coverage Policy:
Epogen®: Medicare Part B
Procrit®: Medicare Part B; Medicare Part D
Alternative Medications
Generic Name
Darbepoetin alfa
Trade Name
Aranesp®
Route of Administration
IV or Subcutaneous
Monitoring Parameters: 1-4, 6-24
Laboratory Values:
1. Hemoglobin/Hematocrit: Baseline, twice weekly until dose stabilization, for at least 2-6 weeks
after any dosage adjustment until hemoglobin stabilizes, and then every 2-4 weeks thereafter
unless additional monitoring is warranted.
2. Serum iron, Total iron binding capacity, Ferritin, Transferrin saturation: Baseline, monthly
during initiation and with any dosage adjustments in patients not receiving iron and at least
every 3 months in patients who are receiving iron until the target hemoglobin concentration is
reached. Monitoring may be extended to every 3 months once the hemoglobin goals are
met. Maintain transferrin saturation ≥20% and ferritin ≥100 ng/mL.
Dosing:
1. Do not adjust dose more often than once per month.
2. Increase dose:
a. by 25% of previous dose if increase in hemoglobin is <1 g/dL over 4 weeks with adequate
iron stores in chronic kidney disease patients, anemia associated with malignancy but
not receiving chemotherapy, myelodysplastic syndromes, and rheumatoid arthritis.
b. to 300 units/kg three times weekly or 60,000 units once weekly if rise in hemoglobin is <1
g/dL after 4 weeks with adequate iron stores in patients with chemotherapy-induced
anemia.
c. by 50-100 units/kg three times weekly or to 60,000 units once weekly if rise in hemoglobin
is <1 g/dL after 8 weeks with adequate iron stores in patients with anemia associated with
zidovudine therapy in patients infected with HIV; evaluate response every 4-8 weeks
and adjust dose by 50-100 unit/kg increments three times weekly as necessary.
3. Decrease dose:
a. by 25% of previous dose for hemoglobin concentrations approaching 12 g/dL.
b. by 25% of previous dose for hemoglobin concentrations rising >1 g/dL in any 2 week
period.
4. Discontinue therapy:
a. if unable to achieve or maintain target hemoglobin doses of 450 units/kg/week IV or 300
units/kg/week subcutaneous within 4-6 months in chronic kidney disease patients with
adequate iron stores.
b. if rise in hemoglobin is <1-2 g/dL or if no reduction in transfusion requirements at doses of
300 units/kg three times weekly after 6-8 weeks of therapy or 60,000 units once weekly
after 4 weeks of therapy in patients with chemotherapy-induced anemia; discontinue
therapy after completion of chemotherapy if hemoglobin is stable and no transfusions are
required.
c. if unable to achieve or maintain target hemoglobin at doses of 300 units/kg three times
weekly in anemia associated with zidovudine therapy in patients infected with HIV.
d. if erythropoietin concentrations are >100 units/L or ferritin concentrations are >400 ng/mL
after 2 weeks of therapy in patients with anemia associated with malignancy but not
receiving chemotherapy.
e. if rise in hemoglobin is <1 g/dL after 12 weeks with adequate iron stores in patients with
anemia of chronic disease (malignancies not treated with chemotherapy,
myelodysplastic syndromes, rheumatoid arthritis).
Adverse Effects: Monthly
1. Blood pressure (monitor more frequently if clinically necessary)
2. Monitor for serious adverse effects including arrhythmias, congestive heart failure, sepsis,
vascular access thrombosis; dehydration, dyspnea, and pneumonia.
3. Monitor for common adverse effects including diarrhea, headache, hypertension,
hypotension, infection, myalgia; fatigue, fever, edema, nausea, and vomiting.
Effectiveness: Monthly
1. A lack of response may occur with deficiencies of iron, folic acid, or vitamin B 12 and with
concurrent infections, inflammatory or malignant processes, hemolysis, blood loss,
osteofibrosis cystica, bone marrow fibrosis, and aluminum toxicity.
2. Target hemoglobin concentration is 12 g/dL.
Compliance: Monthly
Patient Support:
Epogen®
Amgen Safety Net® Program
http://www.reimbursementconnection.com
1-800-272-9376
Procrit®
Procrit® (epoetin alfa) Patient Assistance Program
http://www.procritline.com
1-800-553-3851
References:
1.
2.
Amgen I. Epogen (Epoetin alfa) package insert. Thousand Oaks, CA.: Amgen Inc; November
2004.
Biotech. O. Procrit (epoetin alfa) package insert. Raritan, NJ.: Ortho Biotech; January 2005.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Revised European Best Practice Guidelines for the Management of Anemia in Patients with
Chronic Renal Failure. Nephrol Dial Transplant. 2004;19(Suppl 2):ii6-ii47.
National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney
Disease, 2000. Am J Kidney Dis. 2001;37(suppl 1):S182-S238.
Network. NCC. Clinical Practice Guidelines in Oncology: Cancer and treatment-related anemia.
Available at: www.nccn.org/professionals/physician_gls/pdf/anemia.pdf; 2004.
Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer: evidence-based
clinical practice guidelines of the American Society of Clinical Oncology and the American Society
of Hematology. J Clin Oncol. Oct 1 2002;20(19):4083-4107.
Smith RD, Tchekmedyian, S., Chan, D., Meza, L. Open-label, phase I/II dose escalation study of
NESP in patients with chronic anemia of cancer.[abstract]. European J Cancer. October 2001
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Anon. Epoetin, systemic. USP DI Volume 1. Drug Information for the Health Care Professional.
25th ed. Greenwood Village, CO: Thomson Micromedex; 2005:1288-1293.
McEvoy GK, Snow EK, Kester L, Miller J, Welsh OH, Litvak K. Epoetin alfa. AHFS 2005 Drug
Information. Bethesda, MD: American Society of Health-System Pharmacists; 2005:1486-1498.
Volberding PA, Levine AM, Dieterich D, Mildvan D, Mitsuyasu R, Saag M. Anemia in HIV
infection: clinical impact and evidence-based management strategies. Clin Infect Dis. May 15
2004;38(10):1454-1463.
A randomized double-blind placebo-controlled study with subcutaneous recombinant human
erythropoietin in patients with low-risk myelodysplastic syndromes. Italian Cooperative Study
Group for rHuEpo in Myelodysplastic Syndromes. Br J Haematol. Dec 1998;103(4):1070-1074.
Musto P, Falcone A, Sanpaolo G, et al. Efficacy of a single, weekly dose of recombinant
erythropoietin in myelodysplastic syndromes. Br J Haematol. Jul 2003;122(2):269-271.
Spiriti MA, Latagliata R, Niscola P, et al. Impact of a new dosing regimen of epoetin alfa on
quality of life and anemia in patients with low-risk myelodysplastic syndrome. Ann Hematol. Mar
2005;84(3):167-176.
Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and
chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. Semin
Oncol. Apr 1994;21(2 Suppl 3):21-28.
Quirt I, Robeson C, Lau CY, et al. Epoetin alfa therapy increases hemoglobin levels and improves
quality of life in patients with cancer-related anemia who are not receiving chemotherapy and
patients with anemia who are receiving chemotherapy. J Clin Oncol. Nov 1 2001;19(21):41264134.
Fantini F, Gattinara M, Gerloni V, Bergomi P, Cirla E. Severe anemia associated with active
systemic-onset juvenile rheumatoid arthritis successfully treated with recombinant human
erythropoietin: a pilot study. Arthritis Rheum. Jun 1992;35(6):724-726.
Gudbjornsson B, Hallgren R, Wide L, Birgegard G. Response of anaemia in rheumatoid arthritis
to treatment with subcutaneous recombinant human erythropoietin. Ann Rheum Dis. Jun
1992;51(6):747-752.
Kaltwasser JP, Kessler U, Gottschalk R, Stucki G, Moller B. Effect of recombinant human
erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis. J
Rheumatol. Nov 2001;28(11):2430-2436.
Murphy EA, Bell AL, Wojtulewski J, Brzeski M, Madhok R, Capell HA. Study of erythropoietin in
treatment of anaemia in patients with rheumatoid arthritis. Bmj. Nov 19 1994;309(6965):13371338.
Peeters HR, Jongen-Lavrencic M, Vreugdenhil G, Swaak AJ. Effect of recombinant human
erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia
of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial. Ann
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Pettersson T, Rosenlof K, Friman C, Mickos A, Teppo AM, Fyhrquist F. Successful treatment of
the anemia of rheumatoid arthritis with subcutaneously administered recombinant human
erythropoietin. Slower response in patients with more severe inflammation. Scand J Rheumatol.
1993;22(4):188-193.
Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in
correction of anemia in rheumatoid arthritis. Am J Med. Aug 1990;89(2):161-168.
23.
24.
Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected
patients: a prospective, double-blind, randomized controlled study. Gastroenterology. May
2004;126(5):1302-1311.
Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and
facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin
plus interferon alfa. Am J Gastroenterol. Nov 2003;98(11):2491-2499.
Disclaimer:
These Position Statements for prior authorization are for reference only. They do not replace the
professional judgement of the prescribing physician and do not necessarily apply to all patient-specific
situations. Position Statements are the property of RxAmerica LLC and may not be reproduced, changed
or distributed without written permission.
REVISION HISTORY AND EXPLANATION
Created: August 2005
Proposed revision date: August 2006
© 2005 University of Utah, Drug Information Service, Salt Lake City, UT. Adapted by RxAmerica with
permission.