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Use of Darbepotein and Epoetin in Non-Nephrology Patients – Adult/Pediatric – Inpatient/Ambulatory

Use of Darbepotein and Epoetin in Non-Nephrology Patients – Adult/Pediatric – Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


Use of Darbepoetin and Epoetin in
Non-Nephrology Patients –
Adult/Pediatric –
Inpatient/Ambulatory
Clinical Practice Guideline
Table of Contents
Executive Summary ......................................................................................... 3
Scope ............................................................................................................. 7
Methodology ................................................................................................... 7
Definitions (optional): ...................................................................................... 8
Introduction.................................................................................................... 8
Recommendations........................................................................................... 9
UW Health Implementation............................................................................ 19
References ................................................................................................... 19
CPG Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS, Manager, DPP
Phone Number: 608-263-1328
Email address: PTrapskin@uwhealth.org
CPG Contact for Content:
Name: Jason Bergsbaken, PharmD
Phone Number: 608-265-0341
Email address: JBergsbaken@uwhealth.org
Note: Active Table of Contents
Click to follow link
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

Guideline Authors:
Jason Bergsbaken, PharmD
Coordinating Team Members:
Monica Bogenschulz, PharmD
Cindy Gaston, PharmD, BCPS
Jennifer Nguyen, PharmD
Meghann Voegeli, PharmD, MS
Review Individuals/Bodies:
Sharon Bartosh, MD
Kenneth DeSantes, MD
Scott Hagen, MD
Mark Juckett, MD
Walter Longo, MD
Michael Lucey, MD
Dan Mulkerin, MD
Allison Redpath Mahon, MD
Aaron Wightman, MD
Eliot Williams, MD
Committee Approvals/Dates:
UW Health Pharmacy & Therapeutics Committee: January 2005, January 2011,
July 2015
Release Date: July 2015
Next review date: July 2018
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

Executive Summary
Guideline Overview
Recommendations for the appropriate indications, dosage, administration and
monitoring parameters for the use of darbepoetin alfa and epoetin alfa in adult
and pediatric non-nephrology patients in the ambulatory and inpatient setting
Key Practice Recommendations
General Recommendations
1. Darbepoetin is the least costly, generally best-reimbursed, and most cost-
effective agent for anemia management (compared to conventional
epoetin) and the preferred agent
2. Epoetin is significantly more costly and is generally not as well reimbursed
as darbepoetin, and therefore should be restricted to use under the
following circumstances listed in this guideline
Adult Use
1. Darbepoetin Indications and Dosing
a. Anemia due to chemotherapy in patients with non-myeloid
malignancies (see Appendix A)
i. Goal is to maintain a stable hemoglobin (Hgb) concentration;
lowest dose necessary should be used to avoid
transfusions1,2 (Class I, Level of Evidence A)
ii. Targeted Hgb concentrations greater than 10 g/dL in
oncology patients are not recommended1,2 (Class III, Level
of Evidence A)
iii. Recommended starting dose and schedule1 (Class I, Level
of Evidence A):
1. Darbepoetin 2.25 mcg/kg subcutaneously every week
until completion of chemotherapy course OR
2. Darbepoetin 500 mcg subcutaneously every three
weeks until completion of chemotherapy course
iv. Recommended dose adjustments are listed in Table 11
(Class I, Level of Evidence A)
v. Supplemental IV or oral iron supplementation should be
administered when serum ferritin is <30 ng/mL and
transferrin saturation is < 20%; supplemental IV or oral iron
supplementation should be considered when serum ferritin is
30-800 ng/mL and transferrin saturation is 20-50% 2 (Class I,
Level of Evidence A)
vi. For patients receiving chemotherapy, darbepoetin should be
discontinued following completion of a chemotherapy
course1-3 (Class I, Level of Evidence A)
b. Myelodysplastic syndrome (MDS) (see Appendix B)
i. Use of darbepoetin should be considered in patients who
meet requirements for initiation3-12 (Class I, Level of
Evidence A)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

1. Documented diagnosis of both low grade MDS and
anemia
2. Low risk myelodysplasia with less than 5% blasts
3. Pretreatment erythropoietin levels ≤500 mU/mL
4. Hgb concentration < 10 g/dL
ii. The starting dose of 150 to 300 mcg subcutaneously weekly
is recommended3 (Class I, Level of Evidence A)
iii. Two months after initiating erythropoiesis-stimulating agent
(ESA) therapy, a therapeutic response defined as an
increase in clinically significant Hgb levels or a decrease in
transfusion requirements must be documented to continue
ESA treatment
c. Severe autoimmune hemolytic anemia due to cold agglutinins
i. Darbepoetin may be considered as some patients benefit
from modest doses to support an increased rate of bone
marrow RBC production13 (Class IIb, Level of Evidence C)
d. Ribavirin-induced anemia
i. Darbepoetin may be considered to avoid ribavirin dose
adjustments that compromise antiviral activity, however no
evidence exists ESAs improve sustained viral response14-16
(Class IIb, Class of Evidence C)
2. Epoetin Indications and Dosing
a. Anemia due to chemotherapy in patients with non-myeloid
malignancies
i. Darbepoetin therapy is preferred due to cost17 (see General
Recommendations) (Class I, Level of Evidence A)
b. Myelodysplastic syndrome (MDS)3-12,18
i. Darbepoetin therapy is preferred due to cost19 (see General
Recommendations) (Class I, Level of Evidence A)
c. Anemia due to zidovudine in HIV-infected patients
i. Therapy should be considered if measured endogenous
serum erythropoietin levels ≤ 500 mUnits/mL and receiving
zidovudine doses of 4,200 mg or less per week2,3,19 (Class I,
Level of Evidence A)
ii. The starting dose of 100 units/kg subcutaneously three times
weekly is recommended19(Class I, Level of Evidence A)
d. Religious beliefs prohibiting blood transfusions25 (Class IIb, Level of
Evidence C)
i. Time to start of treatment, dosages, route of administration
and treatment duration varied widely among case reports;
thus if clinically indicated a standardized dosing regimen
may be considered25 (Class IIb, Level of Evidence C)25
3. Monitoring Parameters
a. Iron Status
i. Evaluate iron status in all patients before and during
treatment and maintain iron repletion1,2,19 (Class I, Level of
Evidence A)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

ii. Goals of therapy for ESAs should include serum ferritin ≥
100 ng/mL and transferrin saturation is ≥ 20% saturation1
(Class I, Level of Evidence A)
b. Blood Pressure
i. Blood pressure should be controlled prior to initiating ESA
therapy and monitor periodically during therapy1,19 (Class I,
Level of Evidence A)
c. Hemoglobin
i. Hgb should be monitored weekly until it has stabilized and
maintenance dose has been established1,19 (Class I, Level of
Evidence A)
ii. After an adjustment in dose, Hgb should be monitored
weekly for at least four weeks until stabilized; following
stabilization Hgb may be monitored monthly1,19 (Class I,
Level of Evidence A)
4. Warnings/Cautions
a. ESAs increase the risk for death, myocardial infarction, stroke,
venous thromboembolism, thrombosis of vascular access and
tumor progression or recurrence, particularly when administered to
target a Hgb of >12 g/dL; it is recommended to use the lowest dose
of ESA to increase the Hgb concentration to the lowest level
sufficient to avoid the need for RBC transfusion1,19,26-28 (Class I,
Level of Evidence A)
5. Eligibility Period
a. For patients receiving chemotherapy, ESAs should be discontinued
following completion of a chemotherapy course1-3,19 (Class I, Level
of Evidence A)
6. Special Considerations for Oncology Indication1,19
a. Prescribing of ESAs for patients with chemotherapy-induced
anemia is restricted to UW Heath prescribers who have completed
training and are currently enrolled in the ESA APPRISE Oncology
Program1,19,29 (Class I, Level of Evidence A)
b. Approved prescribers must counsel each patient regarding risks of
ESA therapy prior to new course1,19,29 (Class I, Level of Evidence
A)
c. Prescriber and patient must sign approved ESA APPRISE
acknowledgement form (available from website) prior to initiation
and administration of ESAs; a copy of the signed acknowledgement
form must be made available in patient’s medical record and given
to patient1,19,29 (Class I, Level of Evidence A)
d. Prior to each administration of an ESA, a medication guide should
be distributed to the patient per product labeling1,19,29 (Class I, Level
of Evidence A)
Pediatric Use
1. Darbepoetin Indications and Dosing
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

a. Use of darbepoetin in pediatric patients is not indicated as safety
and effectiveness have not been established19 (Class III, Level of
Evidence A)
2. Epoetin Indications and Dosing
a. Treatment of anemia in patients 5 to 18 years old due to
concomitant myelosuppressive chemotherapy19 (Class I, Level of
Evidence A)
i. The starting dose of epoetin 600 units/kg intravenously
weekly until completion of a chemotherapy course is
recommended19 (Class I, Level of Evidence A)
b. Anemia due to zidovudine in HIV-infected pediatric patients19
(Class I, Level of Evidence A)
i. The starting dose of epoetin 50 to 400 units/kg
subcutaneously or intravenously 2 to 3 times per week is
recommended19 (Class I, Level of Evidence A)
c. Reduction of blood transfusions in pediatric patients with acute
kidney injury30-32 (Class IIb, Level of Evidence C)
i. Use may be considered but effectiveness is not well
established30-32 (Class IIb, Level of Evidence C)
ii. Initiation of therapy may be considered if Hgb is less than 10
g/dL30-32 (Class IIb, Level of Evidence C)
iii. No specific pediatric dosing recommendations are present
with acute kidney injury; initial dosing strategies and dose
adjustments may be based on anemia in chronic kidney
disease17,30-32 (Class IIb, Level of Evidence C)
3. See adult section for monitoring parameters, warnings/cautions and
documentation requirements
Companion Documents
Anemia Management in Chronic Kidney Disease – Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

Scope
Disease/Condition(s): Adult or pediatric non-nephrology patients requiring
darbepoetin alfa or epoetin alfa
Clinical Specialty: Hematology, Oncology, Hepatology, HIV, Pediatrics
Intended Users: Physicians, Physician Assistants, Advanced Practice
Nurses, Pharmacists
CPG objective(s): To standardize and provide recommendations for the
appropriate indications, use and monitoring for darbepoetin alfa and epoetin alfa
for adult and pediatric patients across UW Health
Target Population: Adult or pediatric inpatient or ambulatory patients with
indication for darbepoetin alfa or epoetin alfa therapy
Interventions and Practices Considered:
This guideline provides management recommendations for non-nephrology adult
and pediatric patients requiring darbepoetin alfa or epoetin alfa in order to help
standardize care in the inpatient and ambulatory setting
Methodology
Methods Used to Collect/Select the Evidence:
Searches of electronic databases (e.g., national and international guidelines for
darbepoetin and epoetin use and cancer and chemotherapy induced anemia)
Methods Used to Assess the Quality and Strength of the
Evidence:
Weighting according to rating scheme (scheme given below)
Rating Scheme for the Strength of the Evidence:
A rating scheme must be used to indicate the strength of the evidence.
Recommended rating systems include the GRADE system or the United States
Preventive Services Task Force (USPSTF) grading system.
Rating Scheme for the Strength of the Recommendations:
A modified Grading of Recommendations Assessment, Development and
Evaluation (GRADE) developed by the American Heart Association and
American College of Cardiology (Figure 1) have been used to assess the Quality
and Strength of the Evidence in this Clinical Practice Guideline1
Figure 1: Quality of Evidence and Strength of Recommendation Grading Matrix*
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

*Modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) developed by the American
Heart Association and American College of Cardiology
Methods Used to Analyze the Evidence:
National Guideline Reviews, Systemic Reviews, Expert Opinion
Methods Used to Formulate the Recommendations:
See the “Rating Scheme for the Strength of Evidence.”
Definitions (optional):
1. Erythropoiesis-stimulating agent (ESA): Medications used to stimulate the
production of red blood cells such as epoetin alfa (epoetin) and
darbepoetin alfa (darbepoetin)
Introduction
Darbepoetin alfa (also referred to as darbepoetin) and erythropoietin alfa (also
referred to as epoetin alfa or epoetin) are both synthetic, recombinant forms of
the glycoprotein hormone erythropoietin and are hematopoietic agents that
principally affect erythropoiesis (erythropoiesis-stimulating agents or ESAs).2
Unlike transfusion which immediately boosts the hemoglobin level, ESAs can
take weeks to elicit a response, but they are effective in maintaining a target
hemoglobin level with repeated administration.2 Darbepoetin differs structurally
from the endogenous hormone and epoetin by the addition of two carbohydrate
chains. This structural modification results in a longer terminal half-life allowing
darbepoetin to be less frequently administered. Possible benefits of ESAs include
avoidance of blood transfusion; however risks in some disease states include
thromboembolism, hypertension/seizures and possible increased mortality.2
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

This guideline is intended to define the appropriate indications for use of ESAs at
UWHC for non-nephrology patients, taking into consideration available clinical
data on efficacy, cost to UWHC and reimbursement by third-party payers. A
separate guideline is available that addresses the use of these two products in
nephrology patients.
Recommendations
General Recommendations
1. Darbepoetin is the least costly, generally best-reimbursed, and most cost-
effective agent for anemia management (compared to conventional
epoetin) and the preferred agent
2. Epoetin is significantly more costly and is generally not as well reimbursed
as darbepoetin, and therefore should be restricted to use under the
following circumstances listed in this guideline
Adult Use
1. Darbepoetin Indications
a. Anemia due to chemotherapy in patients with non-myeloid
malignancies1,2 (see Appendix A)
i. The goal of ESA therapy for anemic cancer patients
receiving concurrent chemotherapy is to reduce transfusion
requirements and benefit should be weighed with the risk
profile, including an increased incidence of thromboembolic
reactions33,34 (Class IIa, Level of Evidence A)
ii. Treatment goal is to maintain a stable Hgb concentration;
lowest dose necessary should be used to avoid transfusions;
a minimum of two additional months of planned
chemotherapy is required1,2 (Class I, Level of Evidence A)
iii. ESA therapy should not be prescribed for an improvement in
quality of life (QOL) or improved cancer outcomes as
available evidence does not support this1 (Class III, Level of
Evidence A)
iv. ESAs should not be used when anticipated outcome is cure
as ESAs may promote tumor growth in an off-target manner2
(Class III, Level of Evidence A)
v. Cancer patients not receiving active chemotherapy or
undergoing radiation treatment should not receive ESAs as
administration of ESAs in this patient population has offered
no benefit and shortened time to death2 (Class III, Level of
Evidence A)
vi. Supplemental IV or oral iron supplementation should be
administered when serum ferritin is <30 ng/mL and
transferrin saturation is < 20%; supplemental IV or oral iron
supplementation should be considered when serum ferritin is
30-800 ng/mL and transferrin saturation is 20-50%2 (Class I,
Level of Evidence A)
b. Myelodysplastic syndrome (MDS)4-12 (see Appendix B)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

i. ESAs may be considered for symptomatic patients with
symptomatic anemia, as studies suggest ESAs may provide
clinical benefit to patients with low-risk myelodysplastic
syndrome3 (Class IIb, Level of Evidence A)
1. Coexisting causes of anemia should be treated first,
including replacement of iron, folate, vitamin B12 if
needed; current standard of care for symptomatic
patients is red blood cell (RBC) transfusion support3
(Class I, Level of Evidence A)
ii. Use of darbepoetin should be considered in patients who
meet requirements for initiation3 (Class I, Level of Evidence
A) (see Appendix B):
1. Documented diagnosis of both low grade MDS and
anemia
2. Low risk myelodysplasia with less than 5% blasts
3. Pretreatment erythropoietin levels ≤500 mU/mL
4. Hgb concentration < 10 g/dL
c. Severe autoimmune hemolytic anemia due to cold agglutinins
i. Darbepoetin may be considered as some patients benefit
from modest doses to support an increased rate of bone
marrow RBC production13 (Class IIb, Level of Evidence C)
d. Ribavirin-induced anemia
i. Darbepoetin may be considered to avoid ribavirin dose
adjustments that compromise antiviral activity, however no
evidence exists ESAs improve sustained viral response14-16
(Class IIb, Class of Evidence C)
e. Limitations of use
i. Darbepoetin is not indicated for use:1 (Class III, Level of
Evidence A)
1. In patients with cancer receiving hormonal agents,
biological products, or radiotherapy; unless receiving
concomitant myelosuppressive chemotherapy
2. In patients receiving myelosuppressive chemotherapy
when the anticipated outcome is cure
3. As a substitute for RBC transfusions in patients who
require immediate correction of anemia
4. For reduction of RBC transfusion in patients
scheduled for surgical procedures
2. Darbepoetin Dosing and Administration
a. Anemia due to chemotherapy in patients with non-myeloid
malignancies
i. Targeted Hgb concentrations greater than 10 g/dL in
oncology patients are not recommended1,2 (Class III, Level
of Evidence A)
ii. The lowest dose necessary should be used to avoid
transfusions1 (Class I, Level of Evidence A)
iii. Recommended starting dose and schedule1 (Class I, Level
of Evidence A):
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

1. Darbepoetin 2.25 mcg/kg subcutaneously every week
until completion of chemotherapy course OR
2. Darbepoetin 500 mcg subcutaneously every three
weeks until completion of chemotherapy course
iv. Recommended dose adjustments are listed in Table 11
(Class I, Level of Evidence A)
Table 1: Darbepoetin Dose Adjustments for chemotherapy-associated anemia
Dose Adjustment Weekly Schedule Every 3 Week Schedule
ξ If Hgb increases
greater than 1 g/dL in
any 2-week period
OR
ξ If Hgb reaches a level
needed to avoid RBC
transfusion
Reduce dose by 40% Reduce dose by 40%
If Hgb exceeds a level
needed to avoid
RBC transfusion
ξ Withhold dose until
Hgb approaches a
level where RBC
transfusions may be
required
ξ Reinitiate at a dose
40% below the
previous dose
ξ Withhold dose until
Hgb approaches a
level where RBC
transfusions may be
required
ξ Reinitiate at a dose
40% below the
previous dose
If Hgb increases by less
than 1 g/dL and
remains below 10 g/dL
after 6 weeks of therapy
Increase dose to 4.5
mcg/kg/week No dose adjustment
ξ If there is no response
as measured by Hgb
levels or if RBC
transfusions are still
required after 8 weeks
of therapy
ξ Following completion
of a chemotherapy
course
Discontinue darbepoetin Discontinue darbepoetin
b. Myelodysplastic syndrome
i. The starting dose of 150 to 300 mcg subcutaneously weekly
is recommended3 (Class I, Level of Evidence A)
ii. Two months after initiating ESA therapy, a therapeutic
response defined as an increase in clinically significant Hgb
levels or a decrease in transfusion requirements must be
documented to continue ESA treatment
c. Ribavirin-induced anemia
i. Darbepoetin may be considered to avoid ribavirin dose
adjustments that compromise antiviral activity, however no
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

evidence exists ESAs improve sustained viral response14-16
(Class IIb, Class of Evidence C)
1. During the first two weeks of ribavirin treatment,
darbepoetin may be used for hemoglobin declines of
> 2 g/dL or for hemoglobin < 10 g/dL, before ribavirin
dose adjustment is attempted
2. Between weeks 2 and 12 of ribavirin treatment,
darbepoetin may be used for hemoglobin < 10 g/dL
before ribavirin dose adjustment is attempted
3. After 12 weeks of ribavirin therapy, ribavirin dose
adjustment should be attempted as an initial response
to hemoglobin value < 10 g/dL; if hemoglobin values
do not respond to a ribavirin dose adjustment and
hemoglobin remains < 10 g/dL, darbepoetin should be
initiated
4. Cardiac patients may require earlier darbepoetin
initiation or more aggressive darbepoetin dosing
3. Epoetin Indications
a. Anemia due to chemotherapy in patients with non-myeloid
malignancies
i. Epoetin is indicated in patients with non-myeloid
malignancies where anemia is due to the effect of
concomitant myelosuppressive chemotherapy, however
darbepoetin therapy is preferred due to cost17 (see General
Recommendations) (Class I, Level of Evidence A)
b. Myelodysplastic syndrome3-12,18
i. Epoetin is indicated in patients with low risk MDS, however
darbepoetin therapy is preferred due to cost17 (see General
Recommendations) (Class I, Level of Evidence A)
c. Anemia due to zidovudine in HIV-infected patients
i. Epoetin therapy is only recommended for HIV-infected
patients with measured endogenous serum erythropoietin
levels ≤ 500 mUnits/mL and receiving zidovudine doses of
4,200 mg or less per week; at initiation of therapy, Hgb
concentration must be less than 10 g/dL2,3,19 (Class I, Level
of Evidence A)
d. Religious beliefs prohibiting blood transfusions (Class IIb, Level of
Evidence C)
i. Elective surgical patients who decline blood-derived
products because of religious beliefs, epoetin may be used if
clinically indicated (i.e., anticipated blood loss, etc.) as
several cases have been reported where recombinant
human erythropoietin has been successfully administered to
critically ill Jehovah’s Witnesses; however time to start of
treatment, dosages, route of administration and treatment
duration varied widely among case reports; thus if clinically
indicated a standardized dosing regimen may be
considered25 (Class IIb, Level of Evidence C)25
4. Epoetin Dosing and Administration
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

a. Zidovudine-treated HIV-infected patients
i. The starting dose of 100 units/kg subcutaneously three times
weekly is recommended19(Class I, Level of Evidence A)
ii. Prior to starting epoetin therapy, an endogenous serum
erythropoietin level should be drawn as patients with levels >
500 mUnits/mL are unlikely to respond to epoetin therapy35
(Class I, Level of Evidence A)
iii. Dose Adjustments
1. If Hgb does not increase after 8 weeks of therapy,
recommend increasing epoetin dose by approximately
50 to 100 Units/kg at 4 to 8 week intervals until Hgb
reaches a level needed to avoid RBC transfusions or
300 Units/kg19 (Class I, Level of Evidence A)
2. Withholding epoetin if Hgb exceeds 12 g/dL is
indicated; recommend resuming therapy at a dose
25% below the previous dose when Hgb declines to
less than 11 g/dL19 (Class I, Level of Evidence A)
3. No added clinical benefit has been demonstrated if
epoetin doses exceed 300 units/kg three times
weekly; epoetin should be discontinued if an increase
in Hgb is not achieved at a dose of 300 units/kg three
times weekly for 8 weeks19 (Class I, Level of Evidence
A)
5. Monitoring Parameters
a. Iron Status
i. Evaluate iron status in all patients before and during
treatment and maintain iron repletion1,2,19 (Class I, Level of
Evidence A)
ii. Goals of therapy for ESAs include serum ferritin ≥ 100 ng/mL
and transferrin saturation is ≥ 20% saturation1 (Class I, Level
of Evidence A)
b. Blood Pressure
i. Blood pressure should be controlled prior to initiating ESA
therapy and monitor periodically during therapy 1,19 (Class I,
Level of Evidence A)
c. Hemoglobin
i. Hemoglobin should be monitored weekly until it has
stabilized and maintenance dose has been established1,19
(Class I, Level of Evidence A)
ii. After an adjustment in dose, Hgb should be monitored
weekly for at least four weeks until stabilized; following
stabilization Hgb may be monitored monthly1,19 (Class I,
Level of Evidence A)
iii. Targeted Hgb concentrations should not exceed 10 g/dL in
oncology patients as adverse outcomes have been noted in
trials when Hgb concentrations exceed 12 g/dL; clinical trial
data evaluating patients with head and neck cancer
documented accelerated tumor progression with ESA
therapy compared to placebo36 and a subsequent trial
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

evaluating metastatic breast cancer patients receiving
chemotherapy noted an increase in mortality due to disease
progression and decreased overall survival37 (Class III, Level
of Evidence A)
iv. Lack or loss of hemoglobin response
1. Initiate a search for causative factors causing
refractoriness prior to increasing dose, including:
infection, inflammatory processes, occult blood loss,
hemolysis or severe aluminum toxicity1-3 (Class I,
Level of Evidence A)
2. In absence of another etiology, the patient should be
evaluated for evidence of pure red cell aplasia and
serum should be tested for the presence of antibody
to recombinant erythropoietins1-3 (Class I, Level of
Evidence A)
6. Warnings/Cautions
a. ESAs increase the risk for death, myocardial infarction, stroke,
venous thromboembolism, thrombosis of vascular access and
tumor progression or recurrence, particularly when administered to
target a Hgb of >12 g/dL thus it is recommended to use the lowest
dose of ESA that will gradually increase the Hgb concentration to
the lowest level sufficient to avoid the need for RBC
transfusion1,19,26-28 (Class I, Level of Evidence A)
b. Given use of ESAs in cancer patients has shortened overall
survival and/or increased risk of tumor progression in patients with
advanced head and neck, breast, non-small cell lung, and cervical
cancers when administered to target a Hgb of >12 g/dL, ESAs
should not be used for the treatment of anemia in cancer patients
other than those with non-myeloid malignancies where anemia is
due to the effect of concomitant myelosuppressive
chemotherapy1,19 (Class I, Level of Evidence A)
c. ESAs are contraindicated in patients with uncontrolled hypertension
as approximately 40% of patients required initiation or
intensification of antihypertensive therapy during early phase of
treatment and hypertensive encephalopathy and seizures have
been reported; ESAs may need to be reduced or withheld if blood
pressure is difficult to control and patients should be advised
regarding importance of compliance with antihypertensive
therapy1,19,26 (Class I, Level of Evidence A)
7. Eligibility Period
a. For patients receiving chemotherapy, ESAs should be discontinued
following completion of a chemotherapy course1-3,19 (Class I, Level
of Evidence A)
8. Special Considerations for Oncology Indication1,19
a. Prescribing of ESAs for patients with chemotherapy-induced
anemia is restricted to UW Heath prescribers who have completed
training and are currently enrolled in the ESA APPRISE Oncology
Program1,19,29 (Class I, Level of Evidence A)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

b. Approved prescribers must counsel each patient regarding risks of
ESA therapy prior to new course1,19,29 (Class I, Level of Evidence
A)
c. Prescriber and patient must sign approved ESA APPRISE
acknowledgement form (available from website) prior to initiation
and administration of ESAs; a copy of the signed acknowledgement
form must be made available in patient’s medical record and given
to patient1,19,29 (Class I, Level of Evidence A)
d. Prior to each administration of an ESA, a medication guide should
be distributed to the patient per product labeling1,19,29 (Class I, Level
of Evidence A)
Pediatric Use
1. Darbepoetin Indications
a. Use of darbepoetin in pediatric patients is not indicated as safety
and effectiveness have not been established19 (Class III, Level of
Evidence A)
2. Epoetin Indications
a. Treatment of anemia in patients 5 to 18 years old due to
concomitant myelosuppressive chemotherapy19 (Class I, Level of
Evidence A)
b. Anemia due to zidovudine in HIV-infected pediatric patients based
off increases in Hgb levels and decreases in blood transfusions19
(Class I, Level of Evidence A)
c. Reduction of blood transfusions in pediatric patients with acute
kidney injury30-32 (Class IIb, Level of Evidence C)
i. Pediatric nephrology service should be consulted for use in
this population30-32 (Class I, Level of Evidence A)
ii. Use may be considered but effectiveness is not well
established30-32 (Class IIb, Level of Evidence C)
iii. Continuation of therapy after resolution of renal insufficiency
is not recommended as it exposes the patient to
unnecessary risks of drug adverse effects and increases the
cost of therapy30-32 (Class III, Level of Evidence C)
iv. Patients should be evaluated for the need for epoetin on a
daily basis and upon hospital discharge based on Hgb,
serum creatinine, urine output and renal function30-32 (Class
I, Level of Evidence A)
3. Epoetin Dosing and Administration
a. Pediatric cancer patients (5 to 18 years) receiving chemotherapy
i. The starting dose of epoetin 600 units/kg intravenously
weekly until completion of a chemotherapy course is
recommended19 (Class I, Level of Evidence A)
ii. The following dose adjustments are recommended17 (Class
I, Level of Evidence A)
1. If Hgb does not increase by >1 g/dL and remains <10
g/dL after initial 4 weeks; increase to 900
units/kg/dose (maximum dose: 60,000 units)
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2. If Hgb exceeds a level needed to avoid RBC
transfusion: Withhold dose; resume treatment with a
25% dose reduction when Hgb approaches a level
where transfusions may be required
3. If Hgb increases >1 g/dL in any 2-week period or Hgb
reaches a level sufficient to avoid RBC transfusion;
reduce dose by 25%
4. Discontinue after 8 weeks of treatment if RBC
transfusions are still required or there is no Hgb
response
b. Pediatric patients with HIV infection receiving zidovudine
i. The starting dose of epoetin 50 to 400 units/kg
subcutaneously or intravenously 2 to 3 times per week is
recommended19 (Class I, Level of Evidence A)
ii. The following dose adjustments are recommended17 (Class
I, Level of Evidence A)
1. Withhold dose if Hgb exceeds 12 g/dL, may resume
treatment with a 25% dose reduction once Hgb <11
g/dL; titrate to minimum effective dose to maintain a
Hgb sufficient to avoid RBC transfusions
c. Reduction of blood transfusions in patients with acute kidney injury
i. Initiation of therapy may be considered if Hgb is less than 10
g/dL30-32 (Class IIb, Level of Evidence C)
ii. No specific pediatric dosing recommendations are present
with acute kidney injury; initial dosing strategies and dose
adjustments may be based on anemia in chronic kidney
disease; reduce or interrupt treatment if Hgb approaches or
exceeds 11 g/dL17,30-32 (Class IIb, Level of Evidence C)
iii. It is not recommended to continue epoetin beyond resolution
of renal insufficiency or in admitted patients with Hgb >12
g/dL regardless of renal function30-32 (Class III, Level of
Evidence C)
iv. Epoetin alfa may be discontinued once acute kidney injury
has resolved and renal function has returned to baseline30-32
(Class IIb, Level of Evidence C)
4. See adult section for monitoring parameters, warnings/cautions and
documentation requirements
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Consider anemia of chronic inflammation or
due to myelosuppressive chemotherapy
Cancer Patient
Hgb ≤ 10 g/dL or ≥2 g/dL below baseline
Titrate ESA dose to maintain
lowest Hb level sufficient to
avoid transfusion (see Dosing
and Administration)
Measure Hbg at least weekly
until it has stabilized and
maintenance dose
established
Targeted hemoglobin
concentrations should not
exceed 10 g/dL in oncology
patients and 12 g/dL for all
other indications
Initiate ESA Therapy
Observe
Iron Stores - Achieve and maintain
ξ Ferritin ≥ 100 ng/mL
ξ Transferrin Saturation ≥ 20%
ESA Therapy; Risk - Benefit consideration:
May be considered for patient on an active chemotherapy regimens
(or within 8 weeks of completing chemotherapy) for a non myeloid
malignancy for non-curative intent
Not receiving
chemotherapy or
receiving chemotherapy
with curative intent
ξ ESAs are not approved and are not
recommended for use in this patient
population
ξ Clinical trials have demonstrated that
ESAs negatively impact cancer treatment
outcomes and have been shown to
increase mortality in this patient population
Appendix A: ESA Algorithm for the Treatment of Anemia in Cancer Patients
Initiate anemia evaluation
(CBC with indices, peripheral smear, etc.)
Evaluate for other sources of anemia
(bleeding, hemolysis, iron deficiency, renal
involvement etc.) and treat as indicated
No Cause Identified
Treat as indicated
Asymptomatic
without significant
comorbidities
Asymptomatic with comorbidites or high risk (CAD,
chronic pulmonary disease, cerebral vascular disease,
progressive decline in Hb with recent intensive
chemotherapy or radiation
Symptomatic (sustained tachycardia, tachypnea, chest
pain, syncope, severe fatigue preventing work and
usual activity)
Red blood cell transfusion per guidelines Consider red blood cell transfusion per guidelines
Transfusion goal Hb
8-10 g/dL as needed
to prevent symptoms
Symptomatic anemia
(tachycardia,
tachypnea)
Acute coronary
symptoms or acute
MI
Transfusion goal Hb
≥ 10 g/dL
Trasfusion goal Hb 7-9 g/dL for asymptomatic
hemodynamically stable cancer patients without acute
coronary syndrome
Periodic re-valuation (interval
dependent
upon myelosuppressive
potential
and other patient specific
characteristics
Appendix A: ESA Algorithm: Treatment of Anemia in Adult Cancer Patients
Modified from NCCN Cancer- and Chemotherapy-Induced Anemia Guidelines V.2.2015
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

MDS with symptomatic
anemia
Treat coexisting causes, replace iron, folate, vitamin B
12
if
necessary. Red blood cell transfusion support (standard of care)
< 15% ringed sideroblasts and
serum EPO ≤ 500 mU/mL
Epoetin 40,000 - 60,000 units
1-3x per week subcutaneously
OR
Darbepoetin 150-300 mcg/week
subcutaneously
Consider adding G-CSF 1-2
mcg/kg 1-3x per week
subcutaneously
Decrease dose to tolerance
Refer to NCCN guidelines for
MDS Low INT-1 (MDS-10)
≥ 15% ringed sideroblasts and
serum EPO ≤ 500 mU/mL
Epoetin 40,000 - 60,000 units
1-3x per week subcutaneously plus
G-CSF 1-2 mcg/kg 1-3x per week subcutaneously
OR
Darbepoetin 150-300 mcg/week subcutaneously plus
G-CSF 1-2 mcg/kg 1-3x per week subcutaneously
Decrease dose to tolerance
Refer to NCCN guidelines for
MDS Low INT-1 (MDS-10)
Response
No Response
No response despite
adequate iron stores
Response No Response
Continue ESA, decrease
dose to tolerance
Response
Appendix B: Algorithm for the Treatment of Symptomatic Anemia in Adult Patients with Myelodysplastic Syndrome
Modified from NCCN MDS Guidelines V. 2.2015
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
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UW Health Implementation
Potential Benefits:
This guideline has been developed based on best evidence based
recommendations. By implementing the parameters set forth in the guideline,
non-nephrology adult and pediatric patients will receive ESAs appropriately and
safely.
Potential Harms:
Side effects and adverse events associated with various medical/drug
treatments.
Implementation Tools/Plan
1. Guideline will be housed on UConnect in a dedicated folder for Clinical
Practice Guidelines.
2. Links to this guideline will be created in appropriate HealthLink or equivalent
tools.
3. Pharmacists will be educated about these guidelines via department
inservices.
Disclaimer
CPGs are described to assist clinicians by providing a framework for the
evaluation and treatment of patients. This Clinical Practice Guideline outlines the
preferred approach for most patients. It is not intended to replace a clinician’s
judgment or to establish a protocol for all patients. It is understood that some
patients will not fit the clinical condition contemplated by a guideline and that a
guideline will rarely establish the only appropriate approach to a problem.
References
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Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

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Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org