Utilization Review Policy
Subject:
darbepoetin alfa injection (Aranesp®)
Date revised: 12/2/2009
Description
Darbepoetin alfa is an erythoid stimulating agent (ESA) that is approved by the Food and Drug
Administration (FDA) for the following indications.
Anemia with chronic renal failure (CRF).
Anemia with non-myeloid malignancies due to chemotherapy.
Darbepoetin alfa is given intravenously (IV) or subcutaneously (SC). Darbepoetin is available in
single-dose vials in two solutions, an albumin solution and a polysorbate solution. Darbepoetin
alfa is also available in single-dose prefilled syringes. The products are available in various
strengths.
Indications, Medically Necessary
1. Anemia in CRF: Indicated for the treatment of anemia associated with CRF in patients
(adults and children) who meet all of the following criteria.

Hb level is ≤ 10.0 g/dL for therapy initiation. Note: For patients currently receiving
darbepoetin alfa or epoetin alfa (Epogen, Procrit), hemoglobin (Hb) should be ≤ 12.0 g/dL.
Dosing in CRF: The starting dose for adults is 0.45 mcg/kg body weight SC or IV as a
single injection once weekly. Alternatively, in patients not receiving dialysis, in adults an
initial dose of 0.75 mcg/kg may be administered SC as a single injection once every 2 weeks.
The use of darbepoetin alfa in pediatric CRF patients as the initial treatment to correct
anemia has not been studied. However, for adult and pediatric patients receiving a weekly
epoetin alfa dose of ≥ 1,500 units/week, conversion doses from epoetin alfa to darbepoetin
alfa are available (refer to the package insert). The dose is individualized to achieve and
maintain Hb within the range of 10.0 to 12.0 g/dL. Refer to the package insert regarding
titration of darbepoetin alfa.1
Initial approval/extended approval in CRF: For patients initiating therapy, approval is for
3 months. Patients are evaluated for a response after 3 months. Approve for an additional
six months if a Hb response is achieved and Hb ≤ 12.0 g/dL. For patients not responding,
despite dose titrations during the first 3 months, discontinue darbepoetin alfa and evaluate
and treat for other causes of anemia. In some patients, Hb may not increase but stay the same
and not decrease further. This may be interpreted as a response. For patients on maintenance
therapy, approve for 6 months if the patient continues to respond and if Hb ≤ 12.0 g/dL.
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darbepoetin alfa injection (Aranesp)
Afterwards, continue to approve darbepoetin alfa at 6 month intervals if the patient is
responding and Hb ≤ 12.0 g/dL.
Duration of therapy in CRF: Use may be indefinite as long as patient has CRF.
Labs/Diagnostics required: Monitor Hb regularly. Iron status must be evaluated (for
example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin saturation
[TSAT], bone marrow biopsy) before initiating therapy and as needed during treatment.
Waste management: Single-dose vials and syringes are available in many different
strengths. The dose should be calculated and the number of vials/syringes needed assessed.
Refer
to
the
package
insert
for
more
information.
http://www.aranesp.com/professional/crf/full_prescribing_info/pi.jsp
Exclusions: CRF. Also see below.
 Use beyond 3 months in the absence of response in CRF patients.
2. Anemia due to cancer chemotherapy: Indicated for anemia in non-myeloid
malignancies due to chemotherapy in patients (adults and children) who meet all of the
following criteria.

Hb levels ≤ 10.0 g/dL for therapy initiation, and Note: For patients currently receiving
darbepoetin alfa or epoetin alfa (Procrit, Epogen), Hb should be ≤ 12.0 g/dL.

Patient is currently receiving myelosuppressive chemotherapy, and (Note: myelosuppressive
chemotherapy regimens associated with an increased risk of anemia are listed in the National
Comprehensive Cancer Network [NCCN] guidelines.2 These references may not be a
complete list, as new regimens are being developed).

Darbepoetin alfa is being prescribed by a hematologist or oncologist, and

Patient has a metastatic, non-myeloid malignancy and the anticipated outcome is not cure,
and

Absolute iron deficiency has been excluded (serum ferritin < 30 ng/dL and transferrin
saturation < 15%).
Dosing in anemia due to cancer chemotherapy: Various doses have been used. Initial and
some maximum doses are listed below for adults.
 darbepoetin alfa 2.25 mcg/kg weekly SC (increase darbepoetin alfa up to 4.5 mcg/kg
weekly SC).1
 darbepoetin alfa 500 mcg every 3 weeks by SC injection.1
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darbepoetin alfa injection (Aranesp)

darbepoetin alfa 100 mcg fixed dose every week by SC injection (increase
darbepoetin alfa up to 150-200 mcg fixed dose every week by SC injection).2
 darbepoetin alfa 200 mcg fixed dose every 2 weeks by SC injection (increase
darbepoetin alfa up to 300 mcg fixed dose every 2 weeks by SC injection).2
 darbepoetin alfa 300 mcg fixed dose every 3 weeks by SC injection (increase up to
500 mcg fixed dose every 3 weeks by SC injection).2
Note: Doses are not established in children. Darbepoetin alfa 2.25 mcg/kg SC (given at a
two week interval, followed by 2.25 mcg/kg SC once weekly) has been studied in a phase 1,
pharmacokinetic study involving pediatric patients with chemotherapy-induced anemia.3
The dose for all patients should be adjusted to maintain the lowest Hb level sufficient to
avoid red blood cell transfusions. Discontinue darbepoetin alfa if after 8-9 weeks of therapy
there is no response as measured by Hb levels or if transfusions are still required.
Initial approval/extended approval in anemia due to cancer chemotherapy: Approve for
an initial 2 months to monitor for Hb values and check the appropriate doses. Darbepoetin
alfa should be discontinued after 8 weeks of therapy if there is no response as measured by
Hb levels or if transfusions are still required; evaluate and treat for other causes of anemia. 1
In some patients, Hb may not increase but stay the same and not decrease further. This may
be interpreted as a response. If the patient has a response after 8 weeks (2 months), approve
at 4 month intervals if the patient is still receiving chemotherapy during this time frame (plus
within six weeks after chemotherapy discontinuation). At each 4-month interval, assure that
Hb values are ≤ 12.0 g/dL at all times, otherwise therapy should be discontinued or withheld.
Discontinue darbepoetin alfa when chemotherapy treatment is complete and anemia has
resolved, usually within 6 weeks.2
Labs/Diagnostics required: After dose adjustment, the Hb should be assessed weekly for at
least 4 weeks until it has been determined that the Hb has stabilized in response to the dose
change. The Hb should be monitored at regular intervals. Iron status should be evaluated
(for example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin
saturation [TSAT], bone marrow biopsy) before initiating therapy and as needed during
treatment. Hb should always be ≤ 12.0 g/dL for continuation of therapy.
Waste management: Single-dose vials and syringes are available in many different
strengths. The dose should be calculated and the number of vials/syringes needed assessed.
Refer
to
the
package
insert
for
more
information.
http://www.aranesp.com/professional/crf/full_prescribing_info/pi.jsp
Exclusions: anemia due to cancer chemotherapy. See also below.
 Use beyond 8-9 weeks in the absence of response or in those receiving transfusions.
 Continued use when chemotherapy treatment is complete and anemia has resolved
(usually within 6 weeks of the last dose of chemotherapy).
 Absolute iron deficiency (serum ferritin < 30 ng/dL and transferrin saturation < 15%).
 Use is not indicated for patients when the anticipated outcome is cure.
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darbepoetin alfa injection (Aranesp)
3. Anemia in myelodysplastic syndromes (MDS): Indicated for the treatment of anemia
associated with MDS in adults who meet all of the following criteria. [NOT FDAAPPROVED INDICATION]

Hb levels ≤ 12.0 g/dL for therapy initiation, and

Serum erythropoietin levels ≤ 500 mU/mL, and

Darbepoetin alfa is prescribed by a hematologist or an oncologist.
Dosing in MDS: The dose of darbepoetin alfa is 150-300 mcg SC once per week.4
Initial approval/extended approval in MDS: For patients initiating therapy, approval is for
4 months. Patients are evaluated for an erythroid response after 4 months. Approve for an
additional six months if an erythroid response is achieved (increase in Hb or a decrease in
transfusions) and Hb ≤ 12.0 g/dL. For patients not responding, despite dose titrations and/or
concomitant use of granulocyte colony stimulating factor (G-CSF) during the first 4 months,
discontinue darbepoetin alfa and evaluate and treat for other causes of anemia. For patients
on maintenance therapy, approve for 4 months if the patient continues to have an erythroid
response and if Hb ≤ 12.0 g/dL. Afterwards, continue to approve darbepoetin alfa at 4-month
intervals if the patient has had an erythroid response and Hb ≤ 12.0 g/dL.
Duration of therapy in MDS: may be indefinite as long as the patient has MDS.
Labs/Diagnostics required in MDS: Evaluate for erythroid response (Hb increase and/or a
decrease in transfusions) regularly. Iron status should be evaluated (for example, serum iron,
total iron binding capacity, serum ferritin, per cent transferrin saturation [TSAT], bone
marrow biopsy) before initiating therapy and as needed during treatment.
Waste management: Single-dose vials and syringes are available in many different
strengths. The dose should be calculated and the number of vials/syringes needed assessed.
Refer to the package insert for more information.
http://www.aranesp.com/professional/crf/full_prescribing_info/pi.jsp
Exclusions: MDS. See also below.
 Serum erythropoietin levels > 500 mU/mL.
 Use beyond 4 months in the absence of an erythroid response in MDS patients.
 Use in children (aged < 18 years).
4. Treatment of anemia associated with chronic hepatitis C treatment (e.g.,
peginterferon/interferon [PEG-Intron, Pegasys] plus ribavirin therapy): Indicated for
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darbepoetin alfa injection (Aranesp)
the treatment of anemia associated with chronic hepatitis C treatment in adults who meet all
of the following criteria. [NOT FDA-APPROVED INDICATION]

Hb levels ≤ 10.0 g/dL for therapy initiation, and Note: For patients currently receiving
darbepoetin alfa or epoetin alfa (Procrit, Epogen), Hb should be ≤ 12.0 g/dL.

Patient is receiving therapy for the treatment of chronic hepatitis C (e.g., peginterferon
alfa/interferon alfa therapy plus ribavirin), and

Darbepoetin alfa is prescribed by a hepatologist, gastroenterologist, or infectious disease
physician who specializes in the management of hepatitis C.
Dosing in anemia due to chronic hepatitis C treatment: The initial dose is darbepoetin
alfa 3 mcg/kg once every other week or 0.45 mcg/kg/week, titrating to Hb response (and Hb
≤ 12.0 g/dL).5-6
Initial approval/extended approval in anemia due to chronic hepatitis C treatment: For
patients initiating therapy, approval is for 6 months if the duration of the treatment for
hepatitis C (peginterferon alfa/interferon alfa plus ribavirin) also is this long (if not, only
approve for the duration of the hepatitis C therapy). Patients are evaluated for a Hb response
after 6 months. Approve for an additional six months if an increase in Hb is achieved and Hb
≤ 12.0 g/dL. For patients not responding, despite dose titrations, discontinue darbepoetin
alfa; evaluate and treat for other causes of anemia. For patients on maintenance therapy,
approve for 6 months if the patient continues to have a Hb response and if Hb ≤ 12.0 g/dL.
For all patients, therapy with darbepoetin alfa should stop when the treatment with ribavirin
for hepatitis C is discontinued (generally one year total).
Duration of therapy in anemia due to chronic hepatitis C treatment: patients can receive
darbepoetin alfa therapy only if the patient is also receiving therapy with ribavirin for
hepatitis C, which is usually approximately one year for most patients.
Labs/Diagnostics required: Monitor Hb regularly and evaluate for response. Iron status
has been evaluated (for example, serum iron, total iron binding capacity, serum ferritin, per
cent transferrin saturation [TSAT], bone marrow biopsy) before initiating therapy and as
needed during treatment.
Waste management: Single-dose vials and syringes are available in many different
strengths. The dose should be calculated and the number of vials/syringes needed assessed.
Refer
to
the
package
insert
for
more
information.
http://www.aranesp.com/professional/crf/full_prescribing_info/pi.jsp
Exclusions: anemia due to chronic hepatitis C treatment. See also below.
 Anemia in a patient with hepatitis C who is not receiving ribavirin.
 Use beyond 6 months in the absence of a Hb response.
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darbepoetin alfa injection (Aranesp)

Use in children (aged < 18 years).
Exclusions for all:
 Continued use when Hb exceeds 12.0 g/dL.
 Treatment of cancer-related anemia in those not receiving myelosuppressive chemotherapy.
 Darbepoetin alfa is not indicated for use in patients receiving hormonal agents, therapeutic
biologic products, or radiotherapy unless receiving concomitant myelosuppressive
chemotherapy.
 Treatment of anemia in patients with acute myelogenous leukemia or chronic myelogenous
leukemias (examples of myeloid cancers).
 Use in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell
anemia, thalassemia, porphyria).
 For reduction in allogeneic red blood cell transfusions in patients scheduled for surgical
procedures.
 To treat anemia in patients with other risk factors such as iron deficiency, folate deficiency or
B12 deficiency, hemolysis, gastrointestinal bleeding, active or occult bleeding.
 Patients with uncontrolled hypertension.
 Anemia in patients due to acute blood loss.
ABBREVIATIONS
CRF = chronic renal failure
FDA = Food and Drug Administration
ESA = erythroid stimulating agent
G-CSF = granulocyte colony-stimulating factor
Hb = hemoglobin
IV = intravenous
MDS = myelodysplastic syndrome
mL = milliliter
NCCN = National Comprehensive Cancer Network
SC = subcutaneous
TSAT = percent transferrin saturation
< less than
≤ less than or equal to
> greater than
≥ greater than or equal to
REFERENCES
1.
2.
Aranesp® for injection [package insert]. Thousand Oaks, CA: Amgen; April 2009.
NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Cancer- and chemotherapyinduced anemia. V.2.2010. Printed 10/27/2009.
12/2/2009
6
darbepoetin alfa injection (Aranesp)
3.
Blumer J, Berg S, Adamson PC, et al. Pharmacokinetic evaluation of darbepoetin alfa for the treatment of pediatric patients
with chemotherapy-induced anemia. Pediatr Blood Cancer. 2007;49:687-693.
4. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Myelodysplastic syndromes.
V.2.2010. Printed 10/27/2009.
5. Younossi ZM, Nader FM, Bai C, et al. A phase II dose finding study of darbepoetin alpha and filgrastim for the
management of anaemia and neutropenia in chronic hepatitis C treatment. J Viral Hepatitis. 2008;15(5):370-378.
6. Kamar N, Guitard J, Ribes D, et al. A monocentric observational study of darbepoetin alfa in anemic hepatitis-C-virus
transplant patients treated with ribavirin. Exp Clin Transplant. 2008;6(4):271-275.
Chronic kidney disease

Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with
cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584-590.

KDOQI; National Kidney Foundation. Clinical practice guidelines and clinical practice recommendations for anemia in
chronic kidney disease in adults. Am J Kidney Dis. 2006;47(5 Suppl 3):S16-S85.

KDOQI; National Kidney Foundation. KDOQI clinical practice guideline and clinical practice recommendations for anemia
in chronic kidney disease. 2007 update of the hemoglobin target. Am J Kidney Dis. 2007;50(3):476-530.

KDOQI; National Kidney Foundation. III. Clinical practice recommendations for anemia in chronic kidney disease in
children. Am J Kidney Dis. 2006;47(5 Suppl 3):S86-S108.

Pfeffer MA, Burdmann EA, Chen CY, et al, for the TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and
chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032.

Pfeffer MA, Burdmann EA, Chen CY, et al, on behalf of the TREAT Investigators. Baseline characteristics in the trial to
reduce cardiovascular events with Aranesp Therapy (TREAT). Am J Kidney Dis. 2009;54:59-69.

Singh AK, Szczech L, Tang KL, et al, for the CHOIR investigators. Correction of anemia with epoetin alfa in chronic
kidney disease. N Engl J Med. 2006;355:2085-2098.
Cancer patients receiving chemotherapy

Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients
with cancer: a meta-analysis of randomized trials. Lancet. 2009;373:1532-1542.

Bohlius J, Wilson J, Seidenfled J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of
57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708-714.

Henke M, Laszig R, Rube C, et al. Erythropoetin to treat head and neck cancer patients with anemia undergoing
radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet. 2003;362:1255-1260.

Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly
nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol.
2005;23:5960-5972.

Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American
Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol.
2008;26(1):132-149.

Smith RE, Aapro MS, Ludwig H, et al. Darbepoetin alfa for the treatment of anemia in patients with active cancer not
receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled
study. J Clin Oncol. 2008;26:1040-1050.

Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0
g/dL with erythropoietin vs. above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and
cisplatin for cervical cancer. Gynecol Oncol. 2008;108(2):317-325.

Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to
cancer: a meta-analysis. CMAJ. 2009;180(11):E62-E71.

Wright MR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-smallcell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-1032.
Myelodysplastic syndromes [NOT FDA-APPROVED]

Gabrilove J, Paquette R, Lyons RM, et al. Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for
correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol. 2008;142(3):379-393.

Giraldo P, Nomdedeu B, Loscertales J, et al. Darbepoetin α for the treatment of anemia in patients with myelodysplastic
syndromes. Cancer. 2006;107:2807-2816.

Gotlib J, Lavori P, Quesada S, et al. A phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or
without granulocyte-colony stimulating factor in myelodysplastic syndromes. Am J Hematol. 2009;84(1):15-20.

Mannone L, Gardin C, Quarre MC, et al, for the Groupe Francais des Myelodysplasies (GFM). High-dose darbepoetin
alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol.
2006;133:513-519.

Moyo V, Lefebvre P, Duh MS, et al. Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic
syndromes: a meta-analysis. Ann Hematol. 2008;87(7):527-536.
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darbepoetin alfa injection (Aranesp)

Musto P, Lanza F, Balleari E, et al. Darbepoetin alfa for the treatment of anemia in low-intermediate risk myelodysplastic
syndromes. Br J Haematol. 2004;128:204-209.

Stasi R, Abruzzese E, Lanzetta G, et al. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1
risk myelodysplastic syndromes. Ann Oncol. 2005;16:1921-1927.
Anemia in hepatitis C [NOT FDA-APPROVED]

Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: an update.
Hepatology. 2009;49(4):2335-1374.

McHutchison JG, Lawitz EJ, Schiffman ML, et al, for the IDEAL study team. Peginterferon alfa-2b or alfa-2a with
ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
Anemia in chronic heart failure [NOT FDA-APPROVED]

Anand IS. Anemia in chronic heart failure. Implications and treatment options. J Am Coll Cardiol. 2008;52(7):501-511.

Ghali JK, Anand IS, Abraham WT, et al, on behalf of the Study of Anemia in Heart Failure Trial (STAMINA-HeFT) group.
Randomized, double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation.
2008;117:526-535.

Jessup, M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management
of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task
Force on Practice guidelines: developed in collaboration with the international society of heart and lung transplantation.
Circulation. 2009;119:1977-2016.

McMurray JJ, Anand IS, Diaz R, et al, RED-HF Committees and Investigators. Design and the reduction of events with
darbepoetin alfa in heart failure (RED-HF): a phase III, anaemia correction, morbidity-mortality trial. Eur J Heart Fail.
2009;11(8):795-801.

Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with
symptomatic chronic heart failure. A randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol.
2007;49(7):753-762.

Van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo-controlled study to evaluate the
effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J.
2007;28(18):2208-2216.
Anemia in inflammatory bowel disease [NOT FDA-APPROVED]

Koutroubakis IE, Karmiris K, Makreas S, et al. Effectiveness of darbepoetin-alfa in combination with intravenous iron
sucrose in patients with inflammatory bowel disease and refractory anemia: a pilot study. Eur J Gastroenterol. Hepatol.
2006;18:421-425.
Aplastic anemia [NOT FDA-APPROVED]

Marsh JCW, Ball SE, Cavenagh J, et al, for the British Committee for Standards in Haematology. Guidelines for the
diagnosis and management of aplastic anemia. Br J Haematol. 2009;147:43-70.
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