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Utilization Review Policy
Subject:
Date revised:
filgrastim injection (Neupogen®)
12/9/2009; selected revision 12/16/2009
Description
Filgrastim is a human granulocyte colony stimulating factor (G-CSF) which acts on
hematopoietic cells and has various functions such as stimulating the production of neutrophils
within the bone marrow. It is approved by the Food and Drug Administration (FDA) for the
following indications.1
Cancer patients receiving myelosuppressive chemotherapy
Patients with acute myeloid leukemia (AML) receiving induction or consolidation
chemotherapy
Cancer patients receiving bone marrow transplant (BMT)
Patients undergoing peripheral blood progenitor cell (PBPC) collection and cancer
patients receiving PBPC transplantation
Patients with severe chronic neutropenia
Filgrastim is also used for many off-label (not FDA approved) indications.
The National Comprehensive Cancer Network (NCCN) recommends use for filgrastim for
prophylaxis of febrile neutropenia based on the patient’s risk of developing febrile neutropenia
(high, intermediate, and low) and the intent of chemotherapy (curative/adjuvant, prolong
survival/quality of life, and symptom management/quality of life).2 This is in adults with solid
tumors and nonmyeloid malignancies. NCCN also has recommendations for secondary
prophylaxis and to treat febrile neutropenia.
Filgrastim is available as a preservative free solution in single use vials and prefilled syringes.
The single use vials contain either 300 mcg or 480 mcg of filgrastim in 1.0 mL or 1.6 mL,
respectively. The single use syringes contain either 300 mcg or 480 mcg of filgrastim in 0.5 mL
or 0.8 mL, respectively. Depending on the indication, filgrastim is given by subcutaneous (SC)
bolus injection, by short intravenous (IV) infusion (15 to 30 minutes), or by continuous SC or
continuous IV infusion.1
Indications, Medically Necessary
1. Cancer patients receiving myelosuppressive chemotherapy: Indicated in cancer
patients (adults and children) receiving myelosuppressive chemotherapy who meet all of
the following criteria.

Filgrastim is prescribed by an oncologist or hematologist, and

Patient has a nonmyeloid malignancy, and
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filgrastim (Neupogen)

Patient is receiving myelosuppressive anti-cancer drugs that are associated with a significant
incidence of severe neutropenia with fever, that is, the risk of febrile neutropenia is at least
20% based on the chemotherapy regimen. Note: Myelosuppressive chemotherapy regimens
associated with a significant incidence of severe neutropenia are listed in the NCCN
guidelines2 and in ASCO guidelines3. These references may not be a complete list, as new
regimens are being developed.
OR
Patient is receiving myelosuppressive anti-cancer drugs that are associated with a significant
incidence of severe neutropenia with fever but the risk is less than 20% based on the
chemotherapy regimen if the patient has one or more risk factors for febrile neutropenia
which includes the following:
 Older patient, especially aged ≥ 65 years
 History of previous chemotherapy or radiation therapy
 Pre-existing neutropenia
 Bone marrow involvement with tumor
 Open wounds or active infection
 Recent surgery
 Poor performance status
 Poor renal function
 Liver dysfunction, most notably elevated bilirubin
 Previous episodes of febrile neutropenia
 Poor nutritional status
 Other serious comorbidities as determined by the physician
OR
Patient has had a neutropenic complication from prior chemotherapy and did not receive
prophylaxis with a CSF and a reduced dose may compromise treatment outcome.
OR
Patient has febrile neutropenia AND is at high risk for infection associated complications OR
has any one of the following factors that predict clinical deterioration:2-3
 Neutropenia expected to be > 10 days in duration2
 Profound neutropenia [absolute neutrophil count [ANC] < 100 cells/mm3]2
 Age greater than 65 years2
 Uncontrolled primary disease
 Pneumonia2
 Hypotension and multiorgan dysfunction (sepsis syndrome)2
 Invasive fungal infection2
 Hospitalization at the time of the development of fever2
 Other clinically documented infections2
Note: This includes using filgrastim to maintain dose intensity (dose intense chemotherapy)
and to support dose dense (treatment is given more frequently such as every 2 weeks instead
of every 3 weeks) chemotherapy. Filgrastim is used to prevent neutropenia (primary
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filgrastim (Neupogen)
prophylaxis) and may also be used for treatment of neutropenia once it has occurred
(secondary treatment).
Dosing in cancer patients receiving myelosuppressive chemotherapy: In adults and
children, the recommended starting dose of filgrastim is 5 mcg/kg/day, administered as a
single daily injection by SC bolus injection, by short IV infusion (15 to 30 minutes), or by
continuous SC or continuous IV infusion.1 The preferred route of administration is SC.2
Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle, according
to the duration and severity of the ANC nadir.1 Filgrastim should be given no earlier than 24
hours after the administration of cytotoxic chemotherapy.1-2 Filgrastim should not be
administered in the period 24 hours before the administration of chemotherapy. Dosing is
continued until an ANC is adequate (2000-3000/mm3 or 2-3 X 109/L).3 The product labeling
states filgrastim should be administered daily for up to 2 weeks, until the ANC has reached
10,000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of
filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent
on the myelosuppressive potential of the chemotherapy regimen employed.
Product labeling for filgrastim states that therapy should be discontinued if the ANC
surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir. In phase 3
trials, efficacy was observed at doses of 4 to 8 mcg/kg/day. Because the duration of
neutropenia often increases with each cycle of chemotherapy, longer periods of filgrastim
therapy may be required for later chemotherapy cycles than for early cycles.4
Filgrastim has been used in children aged 3 months to 18 years without unusual adverse
effects.4 However, safety and efficacy in neonates or patients with autoimmune neutropenia
of infancy have not been established.
Initial approval/extended approval in cancer patients receiving myelosuppressive
chemotherapy: Initial approval is for 6 months.
Duration of therapy in cancer patients receiving myelosuppressive chemotherapy:
therapy may be continued as long as the patient is on myelosuppressive chemotherapy.
Labs/Diagnostics required: Baseline complete blood count (CBC) and platelet count as
needed to follow guidelines for filgrastim use.
Waste management: Single use vials and syringes contain 300 mcg and 480 mcg. Initial
doses are 5 mcg/kg daily, and should be rounded to the nearest vial size per weight limits.
Doses are usually given daily for 6 to 10 days after chemotherapy. The dose can be
increased from 5 mcg/kg to 10 mcg/kg in patients who had an inadequate response during the
previous cycle.
Exclusions: cancer patients receiving myelosuppressive chemotherapy. See more below.
 Afebrile neutropenic patients who do not meet the criteria above.3
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

Prophylactic use in patients on concurrent chemotherapy and radiation therapy.2
Use before or concurrently with chemotherapy.
2. AML: Indicated for adults with AML receiving induction or repeat induction or after
consolidation chemotherapy treatment who meet all of the following criteria.

Filgrastim is prescribed by an oncologist or hematologist.
Note: Some patients with AML may receive PBPC transplantation and require filgrastim.
Use criteria number 4, if applicable.
Dosing in AML: Dosing is the same as in cancer patients receiving myelosuppressive
chemotherapy. See above. Following induction chemotherapy, 5 mcg/kg is given daily from
24 hours after the last dose of chemotherapy until neutrophil recovery (ANC 1000/mm3 for 3
consecutive days or 10,000/mm3 for 1 day or a maximum of 35 days). Also used in
consolidation chemotherapy (post remission chemotherapy).
Initial approval/extended approval in AML: Initial approval is for 6 months.
Duration of therapy in AML: therapy may be continued as long as the patient is on
consolidation chemotherapy. Some patients will receive an autologous or allogeneic
hematopoietic stem cell transplantation and may require filgrastim after PBPC. See Criteria
4 below.
Labs/Diagnostics required: Baseline CBC and platelet count and as needed to follow
guidelines for filgrastim use.
Waste management: Single-use vials and syringes contain 300 mcg and 480 mcg. Initial
doses are 5 mcg/kg daily. Doses are usually given daily for 6 to 10 days after chemotherapy.
The dose can be increased from 5 mcg/kg to 10 mcg/kg in patients who had an inadequate
response during the previous cycle.
Exclusions: AML. See more below.
 Administration prior to or concurrently with chemotherapy for AML (use is
considered after chemotherapy is complete).
 Use for priming effects in AML.2
 Prophylactic use in patients on concurrent chemotherapy and radiation therapy.
 Use before or concurrent with chemotherapy and radiotherapy.
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3. Bone marrow transplant (BMT) in patients with nonmyeloid malignancies
undergoing myeloablative chemotherapy followed by autologous or allogeneic BMT.
These patients are not addressed in this document.
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4. PBPC collection or cancer patients who have received therapy with PBPC
(autologous). Indicated in patients (adults and children) with cancer or healthy donors
who are undergoing mobilization of hematopoietic progenitor cells and in cancer patients
(adults and children) post autologous PBPC transplantation who meet all of the following
criteria.

Filgrastim is prescribed by an oncologist or hematologist.
Dosing in cancer patients or healthy donors undergoing mobilization of PBPC: The
recommended dose of filgrastim for the mobilization of PBPC is 10 mcg/kg/day SC, either as
a bolus or continuous infusion. However, some patients may require higher doses of
filgrastim (e.g., up to 20 mcg/kg/day SC). Filgrastim is given for at least 4 days before the
first leukapheresis procedure and continued until the last leukapheresis. According to the
package insert, although the optimal duration of filgrastim administration and leukapheresis
schedule have not been established, administration of filgrastim for 6 to 7 days with
leukapheresis on days 5, 6, and 7 was found to be safe and effective in the pivotal clinical
trials where cancer patients were undergoing PBPC collection for autologous transplantation.
Neutrophil counts should be monitored after 4 days of filgrastim, and filgrastim dose
modification should be considered for patients who develop a white blood cell (WBC) count
> 100,000/mm3.1 Recent reviews indicate 5 days of filgrastim 10 mcg/kg/day is adequate.5-6
Some patients may require a longer duration of therapy (see duration of therapy section).
Poor mobilizers (e.g., patients who fail to mobilize an adequate number of stem cells on the
first attempt; patients with Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and
preleukemic syndromes; recent chemotherapy or radiation), may benefit from using
filgrastim 12.5 to 50 mcg/kg/day, adding sargramostim (Leukine) to filgrastim, adding
plerixafor (Mozobil) injection, or mobilization with chemotherapy plus filgrastim.6
Dosing in cancer patients post autologous PBPC transplantation: In the pivotal trials of
filgrastim reported in the package insert for mobilization of PBPC, filgrastim was also
administered after reinfusion of collected cells.1 In these studies doses were 5 to 24
mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (> 500/mm 3) were
attained. The median number of days to attaining ANC > 500/mm3 were 9 to 11 days but
ranged from 7 to 63 days. Most patients achieved engraftment (defined as platelet count ≥
20,000/mm3) by day 28; the range was 7 to 63 days. A few patients did not achieve
engraftment.
Initial approval/extended approval in PBPC:
Cancer patients or healthy donors undergoing mobilization of PBPC: For unrelated
healthy donors, 5 days of therapy with filgrastim 10 mcg/kg/day are used. 1,5-6 For cancer
patients, 5 to 7 days of filgrastim 10 mcg/kg/day are given once daily. Exceptions may
be made based upon transplant center protocols.
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filgrastim (Neupogen)
Cancer patients post autologous PBPC transplantation: 14 days or until the ANC is
> 1500 cells/mm3 for 3 consecutive days.1 Exceptions may be made based upon
transplant center protocols.
Duration of therapy:
Cancer patients or healthy donors undergoing PBPC collection: 5 days. The
National Marrow Donor Program protocol gives filgrastim for 4 (in patients weighing
< 35 kg) or 5 consecutive days in unrelated donors (allogeneic transplantation).5 In some
instances, patients may require a longer duration of therapy (e.g., cancer patients heavily
pretreated with chemotherapy, healthy patients in which a higher number of cells are
needed due to the type of transplantation). Exceptions may be made based on transplant
center protocols.
Cancer patients post autologous PBPC transplantation: 14 days. Approve for
another 14 days if ANC is not at a sustainable level.1 Most patients have a response after
28 days of filgrastim.
Labs/Diagnostics required: Baseline CBC and platelet count as needed for filgrastim use.
In persons undergoing PBPC collection, neutrophil counts should be monitored after 4 days
of filgrastim, and filgrastim dose modification should be considered for those patients who
develop a WBC count > 100,000/mm3.1
Waste management: Single use vials and syringes contain 300 mcg and 480 mcg. Since
the agent is based on mcg/kg, assess the dosage and the vial or syringe.
Exclusions: PBPC. See more below.
 Use post allogeneic PBPC transplantation.
5. Severe chronic neutropenia. Indicated for symptomatic patients (adults, infants,
children, and adolescents) with congenital neutropenia (e.g., Kostmann’s syndrome,
Shwachmann-Diamond syndrome, myelokathexis), cyclic neutropenia, or idiopathic
neutropenia who meet all of the following.

Filgrastim is prescribed by or in consultation with a hematologist, and

Other diseases associated with neutropenia have been ruled out.
Dosing in severe chronic neutropenia: The starting dose in congenital neutropenia is 6
mcg/kg twice daily (BID) by SC injection.1,7 For idiopathic or cyclic neutropenia, the
starting dose is 5 mcg/kg once daily. The dose is adjusted based on the clinical response and
the ANC. Dose Adjustments: Chronic daily administration is required to maintain clinical
benefit.1 ANC should not be used as the sole indication of efficacy. The dose should be
individually adjusted based on the patients' clinical course, such as reduced number of
infections and frequency of fever, as well as ANC. In the severe chronic neutropenia
postmarketing surveillance study, the median daily doses of filgrastim were: 6.0 mcg/kg
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filgrastim (Neupogen)
(congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic
neutropenia).1 In rare instances, patients with congenital neutropenia have required doses of
filgrastim > 100 mcg/kg/day. In the phase 3 pivotal trial, filgrastim doses were 2.3 to 40
mcg/kg/day in patients with congenital neutropenia; 0.6 to 11.5 mcg/kg/day in idiopathic
neutropenia; and 0.5 to 6 mcg/kg/day in cyclic neutropenia.1 NCCN guidelines state that
observational studies show that patients with idiopathic and cyclic neutropenia generally
respond to low-dose daily, alternative day, or thrice-per-week filgrastim (1 to 3 mcg/kg/day
SC).2 Patients with congenital neutropenia generally require somewhat higher doses of 3 to
10 mcg/kg/day.
Initial approval/extended approval in severe chronic neutropenia: Initial approval is for
2 months to allow adjustment of dosage and to assess for response. Approve for an
additional 12 months of therapy if the patient has responded (e.g., ANC has increased;
reduced frequency of fever, inflammation, and infections; reduced antibiotic use) as
determined by the prescribing physician.
Duration of therapy in patients with severe chronic neutropenia: therapy is chronic.
Labs/Diagnostics required: Prior to starting filgrastim therapy, serial CBCs with
differential and platelet counts and an evaluation of bone marrow morphology and karyotype
must be performed.1 The use of filgrastim prior to confirmation of severe chronic
neutropenia may impair diagnostic efforts and may thus impair or delay evaluation and
treatment of an underlying condition, other than severe chronic neutropenia, causing the
neutropenia.
Waste management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in severe chronic neutropenia is based on mcg/kg of body weight and the dose may need to
be adjusted with changes in weight.
Exclusions: severe chronic neutropenia. See below.
6. Neutropenia associated with HIV or AIDS. Indicated in adults with HIV or AIDS with
neutropenia who meet all of the following criteria.8-14 [NOT FDA-APPROVED
INDICATION]

Prescribed by, or in consultation with, an infectious disease physician, a hematologist, or a
physician that specializes in the management of HIV/AIDS, and

Patient is neutropenic, and

Medications that cause neutropenia have been assessed for discontinuation, dose reduction,
or possible alteration.
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filgrastim (Neupogen)
Dosing in patients with HIV or AIDS: 5 to 10 mcg/kg/day for 2 to 4 weeks.4
Initial approval/extended approval for neutropenia in HIV/AIDS: Approve for a one
month time period.
Duration of therapy for neutropenia in HIV or AIDS: use may be long-term due to the
nature of the disease/and or the need to continue medication therapy.
Labs/Diagnostics required: CBC and ANC as required for filgrastim use.
Waste management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in based on mcg/kg body weight and the dose may need to be adjusted.
Exclusions: neutropenia in HIV or AIDS. See more below.
 Routine long-term use in HIV/AIDS without neutropenia.
7. Myelodysplastic syndrome (MDS). Indicated in adults with MDS who meet all of the
following criteria. [NOT FDA-APPROVED INDICATION]

Filgrastim is prescribed by an oncologist or hematologist.
Dosing in MDS: The dose range is 1 to 2 mcg/kg 1 to 3 times per week subcutaneously15 or
5 mcg/kg once daily SC or IV.16
Initial approval/extended approval in MDS:
neutropenia resolves and then as needed.
Approval is for up to one month until
Duration of therapy in patients with MDS: duration of therapy will vary per the response
and is usually intermittent vs. chronic.
Labs/Diagnostics required: Monitor CBC and ANC as required for filgrastim use.
Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in MDS is based on mcg/kg of body weight and the dose may need to be adjusted with
changes in weight.
Exclusions: MDS. See more below.
 Routine long-term use in MDS.15
8. Aplastic anemia. Indicated in patients (adults and children) with aplastic anemia who
meet all of the following criteria.17-22 [NOT FDA-APPROVED INDICATION]
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filgrastim (Neupogen)

Filgrastim is prescribed by an oncologist or hematologist, and

Patient is severely neutropenic OR if the patient has a severe systemic infection that is not
responding to intravenous antibiotics and anti-fungal drugs.17
Dosing in aplastic anemia: The dose range is 5 mcg/kg/day SC once daily or 1-3 times per
week SC.17
Initial approval/extended approval in aplastic anemia: Approval is for one week.17 If
there is no increase to the neutrophil count, then the agent should be discontinued. If there is
a response approve for up to one month.
Duration of therapy in patients with aplastic anemia: the duration of therapy will vary per
the response and is usually intermittent vs. chronic.
Labs/Diagnostics required: Monitor CBC and ANC as needed for filgrastim use.
Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in aplastic anemia is based on mcg/kg of body weight and the dose may need to be adjusted
with changes in weight.
Exclusions: aplastic anemia. See more below.
 Routine long-term use in aplastic anemia.17
 Patients are not neutropenic or do not have a severe systemic infection that is not
responding to intravenous antibiotics or antifungals.
 Use after neutropenia has resolved.
9. Medication-induced (non-chemotherapy) neutropenia (agranulocytosis): Indicated
in patients with medication-induced neutropenia (agranulocytosis) who meet all of the
following criteria.23-30 [NOT FDA-APPROVED INDICATION]

Patients has an neutropenia, defined as an ANC < 500 cells/mm3 or < 0.5 X 109 cells/L, and

The drug that is believed to have caused the neutropenia has been discontinued. Some of the
more frequently associated causes of medication-induced neutropenia in the literature include
carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide,
prophylthiouracil, rituximab, sulfasalazine, and ticlopidine.23-25
Dosing in medication-induced neutropenia (agranulocytosis): The dose range is 5 to 10
mcg/kg/day SC or 300 mcg/day SC once daily.
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filgrastim (Neupogen)
Initial
approval/extended
approval
in
medication-induced
neutropenia
(agranulocytosis): Approval is for two weeks, as most times the ANC recovers in about one
week. If there is a response, approve for an additional 2 weeks.
Duration of therapy in patients with medication-induced neutropenia (agranulocytosis):
the duration of therapy should not be on a chronic basis.
Labs/Diagnostics required: Monitor CBC and ANC as needed for filgrastim use.
Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in aplastic anemia is based on mcg/kg of body weight and the dose may need to be adjusted
with changes in weight.
Exclusions: medication-induced neutropenia (agranulocytosis). See more below.
 Routine long-term use in medication-induced neutropenia.2
 Use after neutropenia has resolved.
10. Acute lymphocytic leukemia (ALL). Filgrastim is indicated in patients with ALL after
the completion of the initial first few days of chemotherapy of the initial induction or first
post remission course and for those who meet the criteria below.3 [NOT FDAAPPROVED INDICATION]

Filgrastim is prescribed by an oncologist or hematologist.
Dosing in ALL: The dose seems to vary but in general is in the range of 5-10 mcg/kg/d
SC.31
Initial approval/extended approval in ALL: Approval is for up to one month.
Duration of therapy in patients with ALL: the recommendation is to administer for the
initial first few days after the completion of the chemotherapy of the initial induction or first
post remission course.2
Labs/Diagnostics required: Monitor CBC and ANC as needed for filgrastim use.
Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in aplastic anemia is based on mcg/kg of body weight and the dose may need to be adjusted
with changes in weight.
Exclusions: ALL. See below.
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11. Radiation injury. Indicated in patients (adults and children) with acute intentional or
accidental radiation injury who meet all of the following criteria.2,32-33 [NOT FDAAPPROVED INDICATION]

Filgrastim is prescribed by a physician with expertise in treating acute radiation syndrome,
and

The estimated whole body or significant partial-body exposure is at least 3 Grays in adults
aged < 60 years; OR at least 2 Grays in children (aged < 12 years) and in adults aged ≥ 60
years OR in those who have major trauma injuries or burns.32-33
Dosing in radiation injury: Filgrastim 5 mcg/kg/day SC.32-33
Initial approval/extended approval in radiation injury: Initial approval is for 1 month.
Duration of therapy in radiation injury: Filgrastim may be withdrawn when the ANC
reaches > 1000 cells/mm3 or > 1.0 X 109 cells/L after recovery from the nadir.
Labs/Diagnostics required: Monitor CBC and ANC as needed for filgrastim use.
Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in radiation injury is based on mcg/kg of body weight and the dose may need to be adjusted
with changes in weight.
Exclusions: radiation injury. See more below.
 Radiation dose is less than 2 Grays in children and adults ≥ 60 years or in those who
have had major trauma injuries or burns.33
 Radiation dose is less than 3 Grays in adults aged < 60 years.33
12. Radiation therapy. Indicated in patients (adults and children) receiving radiation
therapy alone if prolonged delays secondary to neutropenia are expected if the patient
meets all of the following criteria.3,34-36 [NOT FDA-APPROVED INDICATION]

Filgrastim is prescribed by an oncologist, radiologist, or radiation oncologist.
Dosing in radiation therapy: Filgrastim 5 mcg/kg/day SC or 300 mcg SC daily.
Initial approval/extended approval in radiation therapy: Initial approval is for 6 months.
Duration of therapy in radiation therapy: filgrastim may be withdrawn when the ANC
reaches > 1000 cells/mm3 or > 1.0 x 109 cells/L after recovery from the nadir.
Labs/Diagnostics required: Monitor CBC and ANC as needed for filgrastim use.
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Waste Management: Single use vials and syringes contain 300 mcg and 480 mcg. Dosage
in radiation injury is based on mcg/kg of body weight and the dose may need to be adjusted
with changes in weight.
Exclusions: in radiation therapy. See more below.
 Patient is also receiving chemotherapy.
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Exclusions for all:
 Patients with a known hypersensitivity to Escherichia coli-derived protein.
 Use in routine infection prophylaxis.
 Patients receiving concomitant chemotherapy and radiation therapy.1-2
 Use in Acute Promyelocytic Leukemia (APL).37
Abbreviations
AIDS = Acquired Immunodeficiency Virus
AML = acute myelogenous leukemia
ANC = Absolute neutrophil count
ASCO = American Society of Clinical Oncology
BID = twice daily
BMT = bone marrow transplant
CBC = complete blood count
CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone
CSF = colony stimulating factor
FDA = Food and Drug Administration
G-CSF = granulocyte colony stimulating factor
HIV = human immunodeficiency virus
IV = intravenous
MDS = myelodysplastic syndrome
mL = milliliter
MDS = myelodysplastic syndrome
NCCN = National Comprehensive Cancer Network
PBPC = peripheral blood progenitor cell
SC = subcutaneous
WBC = White Blood Cell
References
Neupogen® [package insert]. Thousand Oaks, CA: Amgen, Inc.; September 2007.
NCCN Clinical Practice Guidelines in Oncology™.
Myeloid growth factors.
V.I.2010. Available at:
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed 9/3/2009.
3. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendations for the Use of White Blood Cell Growth
Factors: An Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2006;24:3187-3205. Accessed on September 22,
2009 online at http://www.jco.org/cgi/reprint/JCO.2006.06.4451v2.pdf
4. AHFS Drug Information. Filgrastim pages 1592-1600.
5. Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408 unrelated donors of peripheral blood stem
cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113:3604-3611.
6. Pusic I, DiPersio JF. The use of growth factors in hematopoietic stem cell transplantation. Curr Pharm Des.
2008;14(20):1950-1961.
7. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colonystimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993;81:2496-2502.
HIV/AIDS [NOT FDA-APPROVED INDICATION]
8. Kuritzkes DR, Parenti D, Ward DJ, et al, and the G-CSF 930101 study group. Filgrastim prevents severe neutropenia and
reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter controlled trial.
AIDS. 1998;12:65-71.
9. Jaresko GS. Etiology of neutropenia in HIV-infected patients. Am J Health Syst Pharm. 1999;56(Suppl 5):S5-S8.
1.
2.
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filgrastim (Neupogen)
10. Mitsuyasu R. Prevention of bacterial infections in patients with advanced HIV infection. AIDS. 1999;13(Suppl 2):S19S23.
11. Kurizkes DR. Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus
disease: the role of granulocyte colony-stimulating factor. Clin Infect Dis. 2000;30:256-260.
12. Hermans P, Rozenbaum W, Joy A, et al, and the G-CSF 92105 Study Group. Filgrastim to treat neutropenia and support
myelosuppressive medication dosing in HIV infection. AIDS. 1996;10:1627-1633.
13. Nielsen SD, Sorensen TU, Aladdin H, et al. The effect of long-term treatment with granulocyte colony-stimulating factor on
hematopoiesis in HIV-infected individuals. Scand J Immunol. 2000;52:298-303.
14. Kaplan JE, Benson C, Holmes KH Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC);
National Institutes of Health; HIV Medicine Association for the Infectious Diseases Society of America. Guidelines for
prevention and treatment of opportunistic infection in HIV-infected adults and adolescents. Recommendations from the
CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.
MMWR Recomm Rep. 2009; April 10;58(RR-4):1-207.
MDS [NOT FDA-APPROVED INDICATION]
15. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes.
Version 2.2010.
16. Jadersten M, Montgomery SM, Dybedal I, et al. Long-term outcome of treatment of anemia in MDS with erythropoietin
and G-CSF. Blood. 2005;106:803-811.
Aplastic anemia [NOT FDA-APPROVED INDICATION]
17. Marsh JCW, Ball SE, Cavenagh J, et al, Writing Group: British Committee for Standards in Haematology. Guidelines for
the diagnosis and management of aplastic anemia. Br J Haematol. 2009;147:43-70.
18. Imamura M, Kobayashi M, Kobayashi S, et al. Combination therapy with recombinant human granulocyte colony
stimulating factor and erythropoietin in aplastic anemia. Am J Hematol. 1995;48:29-33.
19. Bessho M, Hirashima K, Asano S, et al. Treatment of the anemia of aplastic anemia patients with recombinant human
erythropoietin in combination with granulocyte colony-stimulating factor: a multicenter, randomized controlled study. Eur J
Haematol. 1997;58:265-272.
20. Meidlinger P, Knobl P, Jager U, et al. Granulocyte colony-stimulating factor-supported combined immunosuppressive
therapy (antilymphocyte globulin, cyclosporine, and methylprednisolone) in patients with aplastic anemia: tolerability,
efficacy and changes in the progenitor cell compartment. Ann Hematol. 1999;78:299-304.
21. Matsuo Y, Iwanaga M, Mori H, et al. Recovery of hematopoietic progenitor cells in patients with severe aplastic anemia
who obtained good clinical response with a combination therapy of immunosuppressive agents and recombinant human
granulocyte colony-stimulating factor. Int J Hematol. 2000;72:37-43.
22. Fuhrer M, Rampf U, Baumann I, et al, for the German/Austrian Aplastic Anemia Working Group. Immunosuppressive
therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood. 2005;106:2102-2104.
Medication-induced neutropenia [NOT FDA-APPROVED INDICATION]
23. Andersohn F, Konzen C, Garbe E. Systematic review: Agranulocytosis induced by nonchemotherapy drugs. Ann Intern
Med. 2007;146:657-665.
24. Beaushesne MF, Shalansky SJ. Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with
colony-stimulating factors. Pharmacother. 1999;19(3):299-305.
25. Bhatt V, Saleem A. Review: Drug-induced neutropenia-pathophysiology, clinical features, and management. Ann Clin Lab
Sci. 2004;34(2):131-136.
26. Wickramanayake PD, Scheid C, Josting A, et al. Use of granulocyte colony-stimulating factor (filgrastim) in the treatment
of non-cytotoxic drug-induced agranulocytosis. Eur J Med Res. 1995;1996;1:153-156.
27. Mani S, Barry M, Concato J. Granulocyte-colony stimulating factor therapy in drug-induced agranulocytosis. Arch Intern
Med. 1993;153:2500-2501.
28. Tesfa D, Keisu M, Palblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanism and management. Am J
Hematol. 2009;84:428-434.
29. Castanheira D, Marzella M, Skirvin JA. Administration of filgrastim in two patients with drug-induced agranulocytosis.
Pharmacother. 1998;18(6):1347-1351.
30. Hagg S, Rosenius S, Spigset O. Long-term combination treatment with clozapine and filgrastim in patients with clozapineinduced agranulocytosis. Int Clin Psychopharmacol. 2003;18:173-174.
Acute Leukemia [NOT FDA-APPROVED INDICATION]
31. Holdsworth, MT, Mathew P. Efficacy of colony-stimulating factors in acute leukemia. Ann Pharmacother. 2001;35:92108.
Radiation Injury [NOT FDA-APPROVED INDICATION]
32. Radiation Injury Transplant Network. Acute Radiation Syndrome Treatment guidelines. November 16, 2006. Accessed
11/13/2009 at http://www.nmdp.org/RITN/GUIDELINES/DOCS/ars_treatment_guidel.pdf
33. Waselenko JK, Macvittie TJ, Bladely WF, et al. Medical management of the acute radiation syndrome: recommendations of
the strategic national stockpile radiation working group. Ann Intern Med. 2004;140:1037-1051.
12/9/2009
15
filgrastim (Neupogen)
Radiation Therapy [NOT FDA-APPROVED INDICATION]
34. Starr S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of
simultaneous chemotherapy—results of a multicentric randomized, German trial in advanced head-and-neck cancer. Int J
Radiat Oncol Biol Phys. 2001;50(5):1161-1171.
35. Su YB, Vickers AJ, Zelefsky NJ, et al. Double-blind, placebo-controlled, randomized trial of granulocyte-colony
stimulating factor during postoperative radiotherapy for squamous head and neck cancer. Cancer J. 2006;12(3):182-188.
36. Kolotas C, Zamboglou N, Schnabel T, et al. Effect of recombinant human granulocyte colony stimulating factor (RmetHuG-CSF) as an adjunct to large-field radiotherapy: a phase I study. Int J Radiat Oncol Biol Phys. 1996;35(1):137-142.
Acute Myeloid Leukemia
37. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. V.1.2010.
Acute radiation injury (other articles) [NOT FDA-APPROVED INDICATION]

Weisdorf D, Chao N, Waselenko JK, et al. Acute radiation injury: contingency planning for triage, supportive care, and
transplantation. Biol Blood Marrow Transplantat. 2006;12:672-682.
Aplastic anemia [NOT FDA-APPROVED INDICATION]

Locasciulli A, Bruno B, Rambaldi A, et al. Treatment of severe aplastic anemia with antilymphocyte globulin, cyclosporine
and two different granulocyte colony-stimulating factor regimens: a GITMO prospective randomized study.
Haematologica. 2004;89:1052-1061
Adjunctive therapy for diabetic foot infections [NOT FDA-APPROVED INDICATION]

Cruciani M, Lipsky Ba, Mengoli C, de Lalla F. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic
foot infections (Review). Cochrane Database Syst Rev. 2009 July 8;(3):CD0068810.
Cancer

Bennett CL, Stinson TJ, Laver JH, et al. Cost analyses of adjunct colony stimulating factors for acute leukemia: can they
improve clinical decision making? Leukemia Lymphoma. 2000;37(1-2):65-70.

Crawford J, Green M, McGuire B, Shahin S. A combined analysis of average relative dose intensity in the chemotherapy of
solid tumors with pegfilgrastim or filgrastim support. Supportive Cancer Ther. 2005;2(4):229-233.

Greil R, Psenak O, Roila R, on behalf of the ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO
recommendations for the applications. Ann Oncol. 2008;19(Suppl 2):ii116-ii118.

Frangoul H, Nemecek ER, Billheimer D, et al. A prospective study of G-CSF-primed bone marrow as a stem cell source for
allogeneic bone marrow transplantation in children: a Pediatric Blood and Marrow Transplant Consortium (PMBTC) study.
Blood. 2007;110:4584-4587.

Kouroukis CT, Chia S, Verma S, et al. Canadian supportive care recommendations for the management of neutropenia in
patients with cancer. Curr Oncology. 2008;15(1):9-23.

Lyman GH, Kuderer NM. Filgrastim in patients with neutropenia. Potential effects on quality of life. Drugs.
2002;62(Suppl 1):65-78.

Lyman G, Lalla A, Barron R, Dubois RW. Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis
in patients with non-Hodgkin’s lymphoma receiving CHOP-21 in United States. Curr Med Res Opinion. 2009;25:401-411.

Ozkaynak MF, Krailo M, Chen Z, Feusner J. Randomized comparison of antibiotics with and without granulocyte colonystimulating factor in children with chemotherapy-induced febrile neutropenia: a report from the Children’s Oncology Group.
Pediatr Blood Cancer. 2005;45:274-280.

Renwick A, Pettengell R, Green M. use of filgrastim and pegfilgrastim to support delivery of chemotherapy. Twenty years
of clinical experience. Biodrugs. 2009;23(3):175-186.

Rueda A, Sevilla I, Guma J, et al. Secondary prophylactic G-CSF (filgrastim) administration in chemotherapy of Stage I and
II Hodgkin’s lymphoma with ABVD. Leukemia Lymphoma. 2001;41(3-4)353-358.

Schiffer CA. Commentary. Use of myeloid growth factors for patients with febrile neutropenia. Pediatric Blood Cancer.
2005;45:242-243.

Sung L, Nathan PC, Lange B, et al. Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony
stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized
controlled trials. J Clin Oncol. 2004;22(16):3350-3356.

Weycker D, Malin J, Kim J, et al. Risk of hospitalization for neutropenic complications of chemotherapy in patients with
primary solid tumors receiving pegfilgrastim or filgrastim prophylaxis: a retrospective cohort study. Clin Ther.
2009;31(5):1069-1080.
Chronic hepatitis C [NOT FDA-APPROVED INDICATION]

Danish FA, Koul SS, Subhani FR, et al. Role of hematopoietic growth factors as adjuncts in the treatment of chronic
hepatitis C patients. Saudi J Gastroenterol. 2008;14(3):151-157.

Gonzalez SA, Jacobson IM. The role of hematopoietic growth factors in special populations with chronic hepatitis C:
patients with HIV coinfection, end-stage renal disease, or liver transplantation. Cleve Clin J Med. 2004;71(3):S22-S26.
HIV disease [NOT FDA-APPROVED INDICATION]
12/9/2009
16
filgrastim (Neupogen)

Davidson M, Min Y-I, Holbrook JT, et al. Influence of filgrastim (granulocyte colony-stimulating factor) on human
immunodeficiency virus type 1 RNA in patients with cytomegalovirus retinitis. J Infect Dis. 2002;186:1013-1018.

Moore DAJ, Benepal T, Portsmouth S, et al. Etiology and natural history of neutropenia in human immunodeficiency virus
disease: a prospective study. Clin Infect Dis. 2001;32:469-476.
Non-Hodgkin’s Lymphoma in the elderly [NOT FDA-APPROVED INDICATION]

Doorduijn JK, Buijt I, van der Holt B, et al. Economic evaluation of prophylactic granulocyte colony-stimulating factor
during chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma. Haematologica. 2004;89:1109-1117.

Doorduinn JK, van der Holt B, van Imhoff GW, et al. CHOP compared with CHOP plus granulocyte colony stimulating
factor in elderly patients with aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:3041-3050.
Glycogen storage disease [NOT FDA-APPROVED INDICATION]

Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b – European
study on glycogen storage disease type 1. Eur J Pediatr. 2002;161:S120-S123.

Visser G, Rake J, Labrune P, et al. Granulocyte colony stimulating factor in glycogen storage disease type 1b. Results of
the European Study on glycogen storage disease type 1. Eur J Pediatr. 2002;161:S83-S87.

Chou JY, Jun HS, Mansfield BC. Neutropenia in type Ib glycogen storage disease. Curr Opin Hematol. 2010;17(1):36-42.
Severe Chronic Neutropenia

Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia: treatment and follow-up of patients in the severe chronic
neutropenia international registry. Am J Hematol. 2003;72:82-93.

Zeidler C, Schwinzer B, Welte K. Congenital neutropenia. Rev Clin Exp Hematol. 2003;7(1):72-83.
Hairy Cell Leukemia [NOT FDA-APPROVED INDICATION]

Cannon T, Mobarek D, Wegge J, Tabbara IA. Hairy cell leukemia: current concepts. Cancer Invest. 2008;26(8):860-865.

Gidron A, Tallman MS. Hairy cell leukemia: towards a curative strategy. Hematol Oncol Clin N Am. 2006;20(5):11531162.

Swords R, Giles F. Hairy cell leukemia. Medical Oncol. 2007;24(1):7-15.

Glaspy JA, Souza L, Scates S, et al. Treatment of hairy cell leukemia with granulocyte colony-stimulating factor and
recombinant consensus interferon or recombinant interferon-alpha-2b. J Immunother. 1992;11(3):198-208.

Glaspy JA, Baldwin GC, Robertson RA, et al. Therapy for neutropenia in hairy cell leukemia with recombinant human
granulocyte colony-stimulating factor. Ann Intern Med. 1988;109(10):789-795.

Saven A, burian C, Adusumalli J, Koziol JA. Filgrastim for cladribine-induced neutropenia fever in patients with hairy cell
leukemia. Blood. 1999;93(8):2471-2477.
Medication-induced agranulocytosis [NOT FDA-APPROVED INDICATION]

Marinella MA. Agranulocytosis associated with ticlopidine: a possible benefit with filgrastim. Ann Clin Laboratory Sci.
1997;27(6):418-421.

Taher A, Ammash Z, Dabajah B, et al. Ticlopidine-induced aplastic anemia and quick recovery with G-CSF: case report
and literature review. Am J Hematol. 2000;63:90-93.
Radiation therapy [NOT FDA-APPROVED INDICATION]

Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718-726.

MacManus MP, MoCormick D, Trimble A, Abram WP. Value of granulocyte colony stimulating factor in radiotherapy
induced neutropenia: clinical and laboratory studies. Eur J Cancer. 1995;31A(3):302-307.

Mascarin M, Franchin G, Minatel E. et al. The effect of granulocyte colony-stimulating factor on oral mucositis in head and
neck cancer patients treated with hyperfractionated radiotherapy. Oral Oncol. 1999;35:203-208.

Knox SJ, Fowler S, Marquez C, Hoppe RT. Effect of filgrastim (G-CSF) in Hodgkin’s disease patients treated with
radiation therapy. Int J Radiation Oncol Biol. 1993;28:445-450.

Schmidberger H, Hess CF, Hoffmann W, et al. Granulocyte colony-stimulating factor treatment of leucopenia during
fractionated radiotherapy. Eur J Cancer. 1993;29A(14):1927-1931.

Schneider SB, Nishimura RD, Zimmerman RP, et al. Filgrastim (r-metHuG-CSF) and its potential use in the reduction of
radiation-induced oropharyngeal mucositis: an interim look at a randomized, double-blind, placebo-controlled trial.
Cytokines Cell Mol Ther. 1999;5(3):175-180.
Chemotherapy and radiation therapy [NOT FDA-APPROVED INDICATION]

Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor
in the treatment of limited-stage small cell lung cancer: a prospective phase III randomized study of the Southwest
Oncology Group. J Clin Oncol. 1995;13:1632-1641.

Fyles AW, Manchul L, Levin W, et al. Effect of filgrastim (G-CSF) during chemotherapy and abdomino-pelvic radiation
therapy in patients with ovarian carcinoma. Int J Radiation Oncol Biol Phys. 1998;41(4):843-847.
Transplant

Arslan O, Moog R. Mobilization of peripheral blood stem cells. Transfusion Apheresis Sci. 2007;37:179-185.
12/9/2009
17
filgrastim (Neupogen)










Battiwalla M, McCarthy PL. Filgrastim support in allogeneic HSCT for myeloid malignancies: a review of the role of GCSF and the implications for current practice. Bone Marrow Transplantation. 2009;43:351-356.
Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow
Transplantation. 2009;43:181-195.
Bishop MR, Tarantolo SR, Geller RB, et al. A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating
factor) versus placebo following allogeneic blood stem cell transplantation. Blood. 2000;96:80-85.
Klumpp TR, Mangan KF, Goldberg SL, et al. Granulocyte colony-stimulating factor accelerates neutrophil engraftment
following peripheral-blood stem cell transplantation: a prospective randomized trial. J Clin Oncol. 1995;13:1323-1327.
Miller JP, Perry EH, Price TH, et al. Recovery and safety profiles of marrow and PBSC donors: experience of the National
Marrow Donor Program. Biol Blood and Marrow Transplant. 2008;14:29-36.
Moog R. Management strategies for poor peripheral blood stem cell mobilization. Transfusion Apheresis Sci.
2008;38:229-236.
Ojeda E, Garcia-Bustos J, Aguado MJ, et al. A prospective randomized trial of granulocyte colony-stimulating factor
therapy after autologous blood stem cell transplantation in adults. Bone Marrow Transplantation. 1999;24:601-607.
Ozcan M, Ustun C, Akcaglayan E, et al. Recombinant human granulocyte colony-stimulating factor (rh-G-CSF) may
accelerate hematopoietic recovery after HLA-identical sibling allogeneic peripheral blood stem cell transplantation. Bone
Marrow Transplantation. 2001;27:499-505.
Quittet P, Ceballos P, Lopez E, et al. Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after
cyclophosphamide (4 g/m2) enhances the periperhal blood progenitor cell harvest: results of two randomized studies
including 120 patients. Bone Marrow Transplantation. 2006;38:275-284.
Waxman IM, Militano O, Baldinger L, et al. Sequential administration of sargramostim and filgrastim in pediatric
allogeneic stem cell transplantation recipients undergoing myeloablative conditioning.
Pediatr Transplantation.
2009;13:464-474.
12/9/2009
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