Filgrastim (Monograph)

Drug class: Hematopoietic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Filgrastim is a biosynthetic (recombinant DNA origin) hematopoietic agent that principally affects the proliferation and differentiation of neutrophils within the bone marrow¹ ⁴ ⁷⁶ ⁷⁸ ⁷⁹ ⁸⁰ ⁸¹ ⁸² ¹⁴⁵ ¹⁵¹ ¹⁵⁷ and possibly other sites (e.g., spleen).²³ ⁴² ¹⁰⁵ 2

Filgrastim and tbo-filgrastim are structurally and pharmacologically similar drugs that contain a related drug substance.¹ ¹⁴⁵ ¹⁵¹ Tbo-filgrastim was licensed by the US Food and Drug Administration (FDA) through a biologics license application (BLA), not as a biosimilar to filgrastim.¹⁵¹ ¹⁵³ ¹⁵⁴

Filgrastim-sndz, filgrastim-aafi, and filgrastim-ayow are biosimilar to filgrastim (Neupogen).¹ ¹⁵⁷ ²⁰¹ ²⁰² A biosimilar is a biological that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.¹⁷⁰ ²⁰⁴ Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between a proposed biological and reference biological but does not independently establish safety and effectiveness of the proposed biological.²⁰⁴ In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product.¹⁶⁹ None of the currently available filgrastim biosimilars have interchangeable data at this time.²⁰⁵

Uses for Filgrastim

Chemotherapy-induced Neutropenia

Filgrastim, tbo-filgrastim, and biosimilars: reduces the incidence of infection, as seen by the presence of febrile neutropenia, in patients with non-myeloid malignancies administered myelosuppressive chemotherapeutic agents associated with a clinically significant incidence of febrile neutropenia.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
In adults receiving chemotherapy for a solid tumor or non-myeloid malignancy, guidelines recommend that colony stimulating factors (CSFs) be administered prophylactically when the risk of febrile neutropenia is high (exceeding 20%) and if equally effective treatments that do not require CSF support are unavailable.¹⁷¹ ¹⁷² ¹⁷³
For patients receiving chemotherapy regimens who have an intermediate risk of febrile neutropenia (10–20%), prophylactic use of CSFs can be considered, especially if the increased risk is due to patient factors (e.g., >65 years of age, coexisting illness) instead of the chemotherapy regimen.¹⁷² ¹⁷³
Prophylaxis is generally not recommended for patients with a low risk (<10%) of febrile neutropenia.¹⁷²

Acute Myeloid Leukemia - Induction and/or Consolidation Chemotherapy

Filgrastim and biosimilars: decreases the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).¹ ¹⁵⁷ ²⁰¹ ²⁰²

Bone Marrow Transplantation (BMT)

Filgrastim and biosimilars: decreases the duration of neutropenia and neutropenia-related clinical sequelae in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by BMT.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Autologous Peripheral Blood Progenitor Cell Collection and Therapy

Filgrastim and biosimilars (except filgrastim-ayow): mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.¹ ¹⁵⁷ ²⁰¹

Severe Chronic Neutropenia

Filgrastim and biosimilars: reduces the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital, cyclic, or idiopathic neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Acute Exposure to Myelosuppressive Doses of Radiation

Filgrastim (Neulasta): improves survival in patients acutely exposed to myelosuppressive radiation doses.¹

Filgrastim Dosage and Administration

General

Pretreatment Screening

Obtain a complete blood count (CBC) and platelet count at baseline.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
For patients with suspected chronic neutropenia, confirm the diagnosis prior to filgrastim therapy through evaluation of serial CBCs with differential, platelet counts, and bone marrow morphology and karyotype.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Patient Monitoring

Monitor for signs and symptoms of serious allergic reactions during therapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor platelet counts during therapy; frequency is indication-dependent.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor CBC during therapy; frequency is indication-dependent.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor for the development of left upper abdominal or shoulder pain during therapy and evaluate patients who develop these symptoms for splenic enlargement or rupture.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor for the development of fever and lung infiltrates or respiratory distress during therapy and evaluate patients who develop these signs and symptoms for acute respiratory distress syndrome.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor for signs and symptoms of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) in patients with breast and lung cancer who use filgrastim products concomitantly with chemotherapy and/or radiotherapy and in patients with severe chronic neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor for the development of sickle cell crisis in patients with sickle cell disorders.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor kidney function and evaluate for glomerulonephritis if it is suspected.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor closely for the development of signs and symptoms of capillary leak syndrome during therapy (e.g., hypotension, hypoalbuminemia, edema, hemoconcentration).¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Monitor for signs and symptoms of aortitis (e.g., fever, abdominal pain, malaise, back pain, increased inflammatory markers).¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Dispensing and Administration Precautions

Patients with latex allergies should not receive filgrastim (Neupogen) or filgrastim-sndz (Zarxio) via prefilled syringes as the needle cap contains dry natural rubber.¹ ¹⁵⁷
The filgrastim biosimilar prefilled syringe formulations do not allow for direct administration of doses <0.3 mL (180 mcg) to patients due to the potential for dosing errors.¹⁵⁷ ²⁰¹ ²⁰² For doses <0.3 mL, use of the single-dose vial is recommended.²⁰¹ ²⁰²
The Institute for Safe Medication Practices (ISMP) notes that the brand name Neupogen may be potentially confused with the brand name Neumega.²⁰⁶

Administration

Administer filgrastim products by sub-Q injection, short IV infusion (15 to 30 minutes), or continuous IV infusion, depending on the product and indication for use.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² May also be administered by continuous sub-Q infusion^{† [off-label]} .⁹ ¹⁶ ⁷²

If given sub-Q, inject into the outer area of the upper arms, abdomen (except for the 2-inch area around the navel), thighs, and the upper outer areas of the buttocks.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Rotate injection sites daily; avoid any area that is tender, red, bruised, scaly, hard, or has stretch marks or scars.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

If a filgrastim product is administered by a patient or caregiver and a dose is missed, contact the healthcare provider.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Discard any unused portion of filgrastim product in vials or prefilled syringes.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Do no re-enter the vial and do not save unused filgrastim product for administration at a later date.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Visually inspect for particulate matter and discoloration prior to administration. Do not administer if particulate matter or discoloration observed. ¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Avoid shaking filgrastim products.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Transport of filgrastim via a pneumatic tube system has not been evaluated.¹ ²⁰¹

Filgrastim (Neupogen)

Supplied in single-dose prefilled syringes (for sub-Q use) and single-dose vials (for both sub-Q use and IV infusion).¹

Dilution

If IV administration required, dilute filgrastim (vial only) in 5% Dextrose from a concentration of 300 mcg/mL to 5 mcg/mL.¹ Do not dilute to <5 mcg/mL.¹ Protect filgrastim, diluted to concentrations from 5 to 15 mcg/mL, from adsorption to plastic by adding Albumin (Human) to a final concentration of 2 mg/mL.¹

Filgrastim diluted in 5% Dextrose or 5% Dextrose plus Albumin (Human) is compatible with glass bottles, polyvinyl chloride and polyolefin IV bags, and polypropylene syringes.¹ Do not dilute with saline as precipitation may occur.¹ Store the diluted solution at room temperature for up to 24 hours, which includes time during storage and the duration of the infusion.¹

For continuous sub-Q infusion^{† [off-label]}, dilute in 10–50 mL of 5% dextrose injection and infuse at a rate not exceeding 10 mL/24 hours.⁹

Tbo-filgrastim (Granix)

Supplied in single-dose prefilled syringes and vials for sub-Q use.¹⁴⁵

Filgrastim biosimilars (Zarxio; Nivestym; Releuko)

Supplied in single-dose prefilled syringes for sub-Q use (Zarxio; Nivestym; Releuko) and single-dose vials for sub-Q or IV use (Nivestym; Releuko).¹⁵⁷ ²⁰¹ ²⁰²

Dilution

If IV administration is required, dilute Nivestym and Releuko (vial only) in 5% Dextrose from a concentration of 300 mcg/mL to 5 mcg/mL.²⁰¹ ²⁰² Do not dilute to <5 mcg/mL.²⁰¹ ²⁰² Protect these biosimilars, diluted to concentrations from 5 to 15 mcg/mL, from adsorption to plastic by adding Albumin (Human) to a final concentration of 2 mg/mL.²⁰¹ ²⁰²

Nivestym and Releukodiluted in 5% Dextrose or 5% Dextrose plus Albumin (Human) are compatible with glass bottles, polyvinyl chloride and polyolefin IV bags, and polypropylene syringes.²⁰¹ ²⁰² Do not dilute with saline as precipitation may occur.²⁰¹ ²⁰² Store the diluted solution at room temperature for up to 24 hours (Nivesytm) or up to 4 hours (Releuko), which includes time during storage and the duration of the infusion.²⁰¹ ²⁰²

Dosage

Chemotherapy-induced Neutropenia

Obtain CBC and platelet count at baseline and monitor twice weekly during therapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Administer at least 24 hours after cytotoxic chemotherapy; do not give within 24-hour period prior to chemotherapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow):

Sub-Q injection, short IV infusion (15 to 30 minutes), or continuous IV infusion: 5 mcg/kg/day.¹ ¹⁵⁷ ²⁰¹ ²⁰² Consider dose increases in increments of 5 mcg/kg for each chemotherapy cycle, based on duration and severity of ANC nadir.¹ ¹⁵⁷ ²⁰¹ ²⁰²

One to 2 days after initiation, transient increase in neutrophil count typically observed.¹ ¹⁵⁷ ²⁰¹ ²⁰² To ensure sustained response, administer for up to 2 weeks or until ANC has reached 10,000 cells/mm³ following expected chemotherapy-induced nadir.¹ ¹⁵⁷ ²⁰¹ ²⁰² Duration of therapy may be dependent on myelosuppressive potential of chemotherapy regimen.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Tbo-filgrastim:

Sub-Q injection: 5 mcg/kg/day.¹⁴⁵ Specifically labelled only for use in adults and pediatric patients ≥1 month of age.¹⁴⁵

.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Acute Myeloid Leukemia - Induction and/or Consolidation Chemotherapy

Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow):

Sub-Q injection, short IV infusion (15 to 30 minutes), or continuous IV infusion: 5 mcg/kg/day.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Consider dose increases in increments of 5 mcg/kg for each chemotherapy cycle, based on duration and severity of ANC nadir.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Obtain CBC and platelet count at baseline and monitor twice weekly during therapy.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Administer at least 24 hours after cytotoxic chemotherapy; do not give within 24-hour period prior to chemotherapy.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Bone Marrow Transplantation (BMT)

Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow):

IV: 10 mcg/kg/day infusion for no longer than 24 hours.¹ ¹⁵⁷ ²⁰¹ ²⁰² Give initial dose at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Monitor platelet counts and CBCs frequently after BMT.¹ ¹⁵⁷ ²⁰¹ ²⁰²

During neutrophil recovery, titrate daily dosage against the neutrophil response (See Table 1).¹ ¹⁵⁷ ²⁰¹ ²⁰²

If ANC reduces to <1000 cells/mm³ at any time while the patient is receiving 5 mcg/kg/day, increase the dosage to 10 mcg/kg/day, and then follow the steps in Table 1.

Table 1. Filgrastim Dosage Adjustment During Neutrophil Recovery.1157201202
Absolute Neutrophil Count	Dosage Adjustment
When ANC >1000 cells/mm³ for 3 consecutive days	Decrease to 5 mcg/kg/day
Then, if ANC remains >1000 cells/mm³ for 3 more consecutive days	Discontinue therapy
Then, if ANC decreases to <1000 cells/mm³	Reinitiate therapy at 5 mcg/kg/day

Autologous Peripheral Blood Progenitor Cell Collection and Therapy

Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi):

Sub-Q injection: 10 mcg/kg/day.¹ ¹⁵⁷ ²⁰¹

Give for at least 4 days before initial leukapheresis procedure and continue until last procedure.¹ ¹⁵⁷ ²⁰¹ Optimal duration of administration and leukapheresis schedule not established; administration for 6 to 7 days with leukaphereses on days 5, 6, and 7 has been found to be effective and safe.¹ ¹⁵⁷ ²⁰¹

Monitor neutrophil counts after 4 days of filgrastim and discontinue if WBC count rises to >100,000 cells/mm³.¹ ¹⁵⁷ ²⁰¹

Severe Chronic Neutropenia

Filgrastim and biosimilars (filgrastim-sndz, filgrastim-aafi, filgrastim-ayow):

Sub-Q injection: 6 mcg/kg twice daily (congenital neutropenia); 5 mcg/kg once daily (idiopathic or cyclic neutropenia)¹ ¹⁵⁷ ²⁰¹ ²⁰²

Chronic daily therapy required for continued benefit.¹ ¹⁵⁷ ²⁰¹ ²⁰² Individualize dosage based on ANC and clinical course.¹ ¹⁵⁷ ²⁰¹ ²⁰² Lower median daily dosages necessary for patients with idiopathic (1.2 mcg/kg) and cyclic (2.1 mcg/kg) neutropenia as compared to congenital (6 mcg/kg) neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰² Rarely, patients with congenital neutropenia may require dosages ≥100 mcg/kg/day.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Monitor CBCs with differential and platelet counts during initial 4 weeks of therapy, during the 2 weeks following any dosage adjustment, and monthly during first year of treatment once patient is clinically stable.¹ ¹⁵⁷ ²⁰¹ ²⁰² If patient remains clinically stable after initial year of treatment, less frequent routine monitoring is recommended.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Acute Exposure to Myelosuppressive Doses of Radiation

Filgrastim (Neupogen):

Sub-Q: 10 mcg/kg as a single daily injection.¹ Give dose as soon as possible after suspected or confirmed exposure to radiation doses >2 gray.¹ Continue until ANC is >1000 cells/mm³ for 3 consecutive CBCs or exceeds 10,000 cells/mm³ after a radiation-induced nadir.¹

Obtain a baseline CBC and subsequent serial CBCs approximately every third day until ANC is >1000 cells/mm³ for 3 consecutive CBCs.¹ Do not delay therapy if a CBC is not readily available.¹

Estimate the level of radiation exposure via clinical findings, biodosimetry (if available), and information from public health authorities.¹

Special Populations

Hepatic Impairment

Manufacturers of filgrastim and the biosimilars state dosage adjustment is not necessary.¹ ¹⁵⁷ ²⁰¹ ²⁰² Manufacturer of tbo-filgrastim makes no specific dosage recommendations.¹⁴⁵

Renal Impairment

Manufacturers of filgrastim and the biosimilars state dosage adjustment not necessary.¹ ¹⁵⁷ ²⁰¹ ²⁰² Manufacturer of tbo-filgrastim makes no specific dosage recommendations.¹⁴⁵

Geriatric Patients

No specific dosage recommendations.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Cautions for Filgrastim

Contraindications

History of serious allergic reactions to human granulocyte colony-stimulating factors such as pegfilgrastim or filgrastim products.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Warnings/Precautions

Splenic Rupture

Splenic rupture, including fatal cases, reported.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Monitor patients for left upper abdominal pain or shoulder pain as these may be suggestive of an enlarged spleen or splenic rupture.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) reported.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Monitor patients for fever and lung infiltrates or respiratory distress as these may be suggestive of ARDS.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Discontinue in patients with ARDS.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, reported.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Most occur upon initial exposure.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Serious allergic reactions, including anaphylaxis, can recur within days after discontinuing treatment for the initial reaction.¹ ¹⁵⁷ ²⁰¹ ²⁰² Permanently discontinue in patients with serious allergic reactions.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Do not administer to patients with a history of serious allergic reactions to these products or pegfilgrastim.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Sickle Cell Disorders

Severe sickle cell crises, including fatal cases, reported in patients with sickle cell disorders.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Discontinue therapy if a crisis occurs.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Glomerulonephritis

Glomerulonephritis reported with therapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² If suspected, assess for the underlying etiology.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² If a filgrastim product is the likely cause, consider reducing the dose or interrupting therapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Leukocytosis

To avoid risks associated with leukocytosis, discontinue therapy in patients with cancer receiving chemotherapy if ANC >10,000 cells/mm³after the chemotherapy-induced ANC nadir occurs.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Monitor CBCs at least twice weekly.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Filgrastim dosages that increase the ANC >10,000 cells/mm³ may not result in additional clinical benefit.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Discontinuation in these patients usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to baseline in 1 to 7 days.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

For patients with cancer undergoing PBPC mobilization, discontinue filgrastim if the leukocyte count increases to >100,000 cells/mm³.¹ ¹⁵⁷ ²⁰¹

Thrombocytopenia

Thrombocytopenia reported with therapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Monitor platelet counts.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Capillary Leak Syndrome

Symptoms of capillary leak syndrome (e.g., hypotension, hypoalbuminemia, edema, hemoconcentration) may occur.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² May be life-threatening if treatment delayed.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Closely monitor patients who develop capillary leak syndrome and initiate symptomatic treatment.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Tumor Growth Stimulatory Effects

May potentially act as growth factors for any tumor type.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Safety in the setting of chronic myeloid leukemia (CML) and myelodysplasia specifically has not been established.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

When used to mobilize PBPC, tumor cells may be collected in the leukapheresis product and subsequently reinfused.¹ ¹⁵⁷ ²⁰¹ Effects of reinfusion of tumor cells not well studied and available data are inconclusive.¹ ¹⁵⁷ ²⁰¹

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Patients with breast and lung cancer who receive filgrastim products in conjunction with chemotherapy and/or radiotherapy may potentially develop MDS and AML.¹ ¹⁵⁷ ²⁰¹ ²⁰² Monitor for signs and symptoms of MDS/AML.¹ ¹⁵⁷ ²⁰¹ ²⁰²

For patients with severe chronic neutropenia, confirm the diagnosis prior to filgrastim administration.¹ ¹⁵⁷ ²⁰¹ ²⁰² Patients with severe chronic neutropenia who received filgrastim have experienced cytogenetic abnormalities, MDS transformation, and AML.¹ ¹⁵⁷ ²⁰¹ ²⁰² Risk of MDS and AML development appears to be confined to the subset of patients with congenital neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰² Unknown what effect filgrastim has on the development of abnormal cytogenetics and the effect that continued administration has in patients with abnormal cytogenetics or MDS.¹ ¹⁵⁷ ²⁰¹ ²⁰² Monitor for signs and symptoms of MDS/AML in these settings.¹ ¹⁵⁷ ²⁰¹ ²⁰² Consider risks and benefits of continued therapy in patients with severe chronic neutropenia who develop abnormal cytogenetics or myelodysplasia.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Aortitis

Signs and symptoms of aortitis (e.g., fever, abdominal pain, malaise, back pain, and increased inflammatory markers) have been reported and may occur as soon as the initial week of treatment.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Discontinue if aortitis suspected.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Nuclear Imaging

Transient positive bone imaging changes may occur due to increased hematopoietic bone marrow activity.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Consider these changes when interpreting bone imaging results.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Alveolar Hemorrhage and Hemoptysis

Alveolar hemorrhage and hemoptysis necessitating hospitalization reported in patients undergoing PBPC collection mobilization.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Discontinuation of therapy resulted in hemoptysis resolution.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Use for PBPC mobilization in healthy donors is not an approved use.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Cutaneous Vasculitis

Cutaneous vasculitis reported; severity ranging from moderate to severe.¹ ¹⁵⁷ ²⁰¹ ²⁰² Majority of patients administered long-term therapy for severe chronic neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰² If cutaneous vasculitis occurs, hold filgrastim therapy.¹ ¹⁵⁷ ²⁰¹ ²⁰² When symptom resolution occurs and ANC decreases, may reinitiate at a reduced dosage.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Simultaneous Use with Chemotherapy and Radiation Therapy

Safety and efficacy of filgrastim products administered simultaneously with cytotoxic chemotherapy and/or radiotherapy have not been established.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Avoid simultaneous use.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Do not use in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Immunogenicity

Anti-drug antibodies have been detected with filgrastim product use.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Specific Populations

Pregnancy

No link between filgrastim use during pregnancy and the occurrence of major birth defects, miscarriage, or adverse maternal or fetal outcomes established.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Tbo-filgrastim should be used during pregnancy only if the potential benefit justifies the potential fetal risk.¹⁴⁵

Lactation

Case reports describe use of filgrastim in breast-feeding mothers; no adverse effects observed in exposed infants.¹ ¹⁵⁷ ²⁰¹ ²⁰² No data exist regarding effects on milk production.¹ ¹⁵⁷ ²⁰¹ ²⁰² Consider benefits of breast-feeding and mother’s need for filgrastim against any potential adverse effects on breast-feeding infant or underlying maternal condition.¹ ¹⁵⁷ ²⁰¹ ²⁰²

No data are available regarding presence of tbo-filgrastim in breastmilk, effects on the breastfed child, or effects on milk production.¹⁴⁵

Pediatric Use

In a study of patients with cancer administered myelosuppressive chemotherapy, 15 pediatric patients were administered filgrastim doses of 5, 10, or 15 mcg/kg/day for 10 days.¹ ¹⁵⁷ ²⁰¹ ²⁰² Pharmacokinetics of filgrastim in pediatric patients after chemotherapy administration comparable to those seen in adults.¹ ¹⁵⁷ ²⁰¹ ²⁰² Filgrastim also well tolerated with the only consistently reported adverse event being musculoskeletal pain.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Effectiveness and safety of filgrastim in pediatric patients with severe chronic neutropenia also established.¹ ¹⁵⁷ ²⁰¹ ²⁰² A postmarketing surveillance study included 429 pediatric patients with severe chronic neutropenia.¹ ¹⁵⁷ ²⁰¹ ²⁰² Results suggest that height and weight are not adversely affected in patients administered up to 5 years of filgrastim therapy.¹ ¹⁵⁷ ²⁰¹ ²⁰² Limited data do not suggest alterations in sexual maturation or endocrine function as well.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Development of cytogenetic abnormalities and transformation to MDS and AML have occurred in pediatric patients with congenital types of neutropenia given long-term therapy.¹ ¹⁵⁷ ²⁰¹ ²⁰² Relationship between filgrastim administration and these adverse events is unknown.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Administration of filgrastim to increase survival in pediatric patients acutely exposed to myelosuppressive radiation doses based on results from animal studies and clinical data supporting use in other indications.¹

Tbo-filgrastim is approved for use in pediatric patients >1 month old with non-myeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia, to reduce the duration of severe neutropenia.¹⁴⁵ Approval based on evidence from studies in adults and additional safety and pharmacokinetics data from a trial of 50 pediatric patients with solid tumors administered tbo-filgrastim.¹⁴⁵ ²⁰³

Geriatric Use

For patients administered myelosuppressive chemotherapy, no differences in effectiveness or safety observed between older and younger patients.¹ ¹⁵⁷ ²⁰¹ ²⁰²

For other approved indications, insufficient numbers of patients ≥65 years of age to determine whether response was different from younger patients.¹ ¹⁵⁷ ²⁰¹ ²⁰²

In clinical studies of tbo-filgrastim, no differences in effectiveness or safety observed between patients ≥65 years of age and younger patients.¹⁴⁵

Renal Impairment

Increased filgrastim concentrations noted in patients with end-stage renal disease as compared to healthy subjects and patients with moderate renal impairment.¹ ¹⁵⁷ ²⁰¹ ²⁰² Pharmacokinetics of tbo-filgrastim not studied in patients with moderate or severe renal impairment; mild renal impairment had no effect on tbo-filgrastim pharmacokinetics.¹⁴⁵

Hepatic Impairment

Pharmacokinetics and pharmacodynamics of filgrastim were comparable between healthy subjects and patients with hepatic impairment (mild to moderate).¹ ¹⁵⁷ ²⁰¹ ²⁰² Pharmacokinetics of tbo-filgrastim not evaluated in hepatic impairment.¹⁴⁵

Common Adverse Effects

Most common (≥5% difference compared to placebo) adverse reactions in patients with non-myeloid malignancies administered myelosuppressive chemotherapy receiving filgrastim and biosimilars include pyrexia, pain, rash, cough, dyspnea.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Most common (≥2% difference compared to placebo) adverse reactions in patients with AML receiving filgrastim and biosimilars include pain, epistaxis, rash.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Most common (≥5% difference compared to placebo) adverse reaction in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by BMT receiving filgrastim and biosimilars includes rash.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Most common (≥5%) adverse reactions in patients undergoing PBPC mobilization and collection receiving filgrastim and biosimilars include bone pain, pyrexia, headache.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Most common (≥5% difference compared to placebo) adverse reactions in patients with severe chronic neutropenia receiving filgrastim and biosimilars include pain, anemia, epistaxis, diarrhea, hypoesthesia, alopecia.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Most common (≥1%) adverse reaction for patients administered tbo-filgrastim is bone pain.¹⁴⁵

Drug Interactions

No formal drug interaction studies performed.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Filgrastim Pharmacokinetics

Absorption

Exhibits nonlinear pharmacokinetics.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Filgrastim is rapidly absorbed following sub-Q injection.⁹ ⁹² ⁹⁵ Peak serum concentrations generally are attained within 4–5 hours.⁴ ⁹ ⁹² ⁹⁵

Absolute bioavailability of filgrastim after sub-Q administration: 60–70%.¹ ¹⁵⁷ ¹⁹³ ²⁰¹ ²⁰²

Median time to peak plasma concentrations of sub-Q tbo-filgrastim in patients with cancer: approximately 4–6 hours.¹⁴⁵ ¹⁵³ Absolute bioavailability of tbo-filgrastim following sub-Q injection: approximately 33%.¹⁴⁵

Distribution

Filgrastim is rapidly distributed in animals, appearing in highest concentrations in bone marrow, adrenal glands, kidney, and liver.⁹⁵

Volume of distribution of filgrastim following a single IV or sub-Q dose averages 150 mL/kg (range: 46–384 mL/kg) in both healthy individuals and patients with cancer.¹ ⁹⁵

Unknown whether filgrastim is distributed into CSF.⁹⁵ Published literature exists documenting filgrastim transfer into human milk.¹ ¹⁵⁷ There have been reports of transplacental passage of filgrastim products in pregnant women when administered within 30 hours of preterm delivery.¹ ¹⁵⁷ ²⁰¹ ²⁰²

Elimination

Elimination Route

Eliminated by both renal elimination and specific degradation by G-CSF receptors and neutrophil elastase.¹ ¹⁹⁴

Clearance dependent on filgrastim concentration and neutrophil count; G-CSF receptor-mediated clearance saturated by high concentrations of filgrastim and diminished by neutropenia.¹

Half-life

Manufacturer states that the elimination half-life of filgrastim following sub-Q or IV administration averages 3.5 hours (range: 0.77–8.5 hours)¹ ⁹⁵ ¹⁵⁷ in healthy individuals or patients with cancer.¹

Median elimination half-life of tbo-filgrastim in patients with cancer receiving chemotherapy is 3.2–3.8 hours;¹⁴⁵ ¹⁵³ in healthy individuals, median half-life of the drug was approximately 8.9 hours.¹⁵³

Stability

Storage

Parenteral

Injection

Filgrastim (Neupogen): Store prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.¹ Prior to administration, remove from refrigeration and allow to reach room temperature for at least 30 minutes and no more than 24 hours.¹ Avoid freezing; however, if frozen, thaw in refrigerator prior to administration.¹ Discard any prefilled syringe or vial frozen more than once or left at room temperature for >24 hours.¹

Tbo-filgrastim (Granix): Store prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.¹⁴⁵ Prior to administration, remove from refrigeration and allow to reach room temperature for at least 30 minutes.¹⁴⁵ May be removed from refrigeration for a single period of up to 5 days between 23° to 27°C and returned to refrigeration, up to product expiration date, if not used during the 5 day period.¹⁴⁵ Exposure to -1° to -5°C for up to 72 hours and temperatures as low as -15° to -25°C for up to 24 hours do not adversely affect stability.¹⁴⁵

Filgrastim biosimilars (Zarxio; Nivestym; Releuko): Store prefilled syringe or vial under refrigeration (2° to 8°C); protect from light.¹⁵⁷ ²⁰¹ ²⁰² Prior to administration, remove the Zarxio prefilled syringe from refrigeration and allow to reach room temperature for at least 30 minutes and for a maximum of 4 days.¹⁵⁷ Avoid freezing; however, if frozen, thaw in refrigerator prior to administration.¹⁵⁷ Discard any prefilled syringe frozen more than once or left at room temperature for >4 days.¹⁵⁷ Prior to administration, remove the Nivestym and Releukoprefilled syringe or vial from refrigeration and allow to reach room temperature for at least 30 minutes and no more than 24 hours.²⁰¹ ²⁰² Avoid freezing; however, if Nivestym is frozen, thaw in refrigerator prior to administration.²⁰¹ Do not freeze Releuko.²⁰² Discard any prefilled syringe or vial frozen more than once or left at room temperature for >24 hours.²⁰¹ ²⁰²

Actions

Filgrastim, tbo-filgrastim, and biosimilars are hematopoietic agents that principally influence leukopoiesis.¹ ⁴ ²³ ³² ⁷⁶ ⁷⁸ ⁸⁴ ⁸⁵ ⁸⁶ ⁸⁷ ⁸⁸ ⁸⁹ ⁹⁰ ¹⁰³ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Appear to elicit the same pharmacologic effects produced by endogenous human granulocyte colony-stimulating factor (G-CSF).¹ ⁴ ²³ ³² ⁷⁶ ¹⁵⁷
Endogenous G-CSF, a growth factor, is a lineage-restricted CSF that principally affects the proliferation, differentiation, and activation of committed progenitor cells of the neutrophil-granulocyte lineage.¹ ⁴ ²⁶ ³² ⁴² ⁴⁵ ⁵⁰ ⁷⁶ ⁸⁴ ⁸⁵ ⁸⁷ ¹⁰³
In addition, endogenous G-CSF enhances certain functions of mature neutrophils, including phagocytosis, chemotaxis, and antibody-dependent cellular cytotoxicity (ADCC).¹ ⁴ ¹⁷ ³² ³³ ⁴² ⁵⁰ ⁷⁶ ⁸⁷ ⁹⁶ ¹⁰³

Advice to Patients

Instruct patients who self-administer filgrastim products as to the proper administration and disposal procedures.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Advise patients of the potential risk of serious allergic reactions.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Symptoms may include rash, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast heart rate, and sweating.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients of the potential risk for rupture or enlargement of the spleen.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Patients should report any pain in the left upper stomach area or left shoulder to their healthcare provider.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Advise patients of the risk for acute respiratory distress syndrome.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Advise patients to contact their healthcare provider if any shortness of breath (with or without a fever), trouble breathing, or fast breathing occurs.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients with sickle cell disease to report any symptoms of sickle cell crisis (e.g., pain, difficulty breathing) to their healthcare provider.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Advise patients of the potential for kidney injury.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Advise patients to contact their healthcare provider if any swelling of the face or ankles, blood in the urine or dark colored urine, or urination less frequently than normal occurs.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Advise patients to report any unusual bleeding or bruising to their healthcare provider.¹ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients of the potential risk of capillary leak syndrome.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Advise patients to contact emergency medical services if any of the following symptoms occur: trouble breathing, swelling of the stomach area and feeling of fullness, dizziness or feeling faint, swelling or puffiness, a reduction in urination, and a general feeling of tiredness.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients of the potential for aortitis (inflammation of the aorta).¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Advise patients to report any symptoms of aortitis (e.g., fever, abdominal pain, feeling tired, back pain) to their healthcare provider.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Advise patients with breast or lung cancer of the increased risk of development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with therapy when used in conjunction with chemotherapy and/or radiotherapy and inform patients with congenital neutropenia who receive filgrastim of this potential increased risk as well.¹ ¹⁵⁷ ²⁰¹ ²⁰² These patients should report any tiredness, fever, and easy bruising or bleeding to their healthcare provider.¹ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients of the potential risk of cutaneous vasculitis.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰² Advise patients to report signs or symptoms of vasculitis (e.g., purpura, erythema) to their healthcare provider immediately.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Importance of females informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²
Inform patients of other important precautionary information.¹ ¹⁴⁵ ¹⁵⁷ ²⁰¹ ²⁰²

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Filgrastim (Recombinant DNA Origin)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV or subcutaneous use	300 mcg/mL (300 and 480 mcg)	Neupogen (available in single-dose vials)	Amgen
		600 mcg/mL (300 and 480 mcg)	Neupogen (available in prefilled syringes with UltraSafe needle guard)	Amgen

Filgrastim-sndz (biosimilar)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV or subcutaneous use	600 mcg/mL (300 and 480 mcg)	Zarxio (available in prefilled syringes with UltraSafe Passive needle guard)	Sandoz

Filgrastim-aafi (biosimilar)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV or subcutaneous use	600 mcg/mL (300 and 480 mg)	Nivestym (available in prefilled syringes with UltraSafe Passive needle guard)
		300 mcg/mL (300 and 480 mcg)	Nivestym (available in single-dose vials)

Filgrastim-ayow (biosimilar)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	600 mg/mL (300 mcg and 480 mcg)	Releuko (available in prefilled syringes with UltraSafe Passive needle guard)	Amneal Pharmaceuticals
		300 mcg/mL (300 mcg and 480 mcg)	Releuko (available in single-dose vials)

Tbo-filgrastim (Recombinant DNA Origin)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	600 mcg/mL (300 and 480 mcg)	Granix (available in prefilled syringes with or without UltraSafe Passive needle guard)	Teva
		300 mcg/mL (300 and 480 mg)	Granix (available in single-dose vials)	Teva

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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81. Nagata S, Tsuchiya M, Asano S et al. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature. 1986; 319:415-8. http://www.ncbi.nlm.nih.gov/pubmed/3484805?dopt=AbstractPlus

82. Cohen AM, Zsebo KM, Inoue H et al. In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor. Proc Natl Acad Sci USA. 1987; 84:2484-8. http://www.ncbi.nlm.nih.gov/pubmed/3550811?dopt=AbstractPlus

84. Watari K, Asano S, Shirafuji N et al. Serum granulocyte colony-stimulating factor levels in healthy volunteers and patients with various disorders as estimated by enzyme immunoassay. Blood. 1989; 73:117-22. http://www.ncbi.nlm.nih.gov/pubmed/2462934?dopt=AbstractPlus

85. Kawakami M, Tsutsumi H, Kumakawa T et al. Levels of serum granulocyte colony-stimulating factor in patients with infections. Blood. 1990; 76:1962-4. http://www.ncbi.nlm.nih.gov/pubmed/1700729?dopt=AbstractPlus

86. Morstyn G, Campbell L, Souza LM et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988; 1:667-72. http://www.ncbi.nlm.nih.gov/pubmed/2895212?dopt=AbstractPlus

87. Lindemann A, Herrmann F, Oster W et al. Hematologic effects of recombinant human granulocyte colony-stimulating factor in patients with malignancy. Blood. 1989; 74:2644-51. http://www.ncbi.nlm.nih.gov/pubmed/2479425?dopt=AbstractPlus

88. Lord BI, Bronchud MH, Owens S et al. The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci USA. 1989; 86:9499-503. http://www.ncbi.nlm.nih.gov/pubmed/2480603?dopt=AbstractPlus

89. Gabrilove JL, Jakubowski A, Fain K et al. Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium. J Clin Invest. 1988; 82:1454-61. http://www.ncbi.nlm.nih.gov/pubmed/2459163?dopt=AbstractPlus

90. Dührsen U, Villeval JL, Boyd J et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood. 1988; 72:2074-81. http://www.ncbi.nlm.nih.gov/pubmed/3264199?dopt=AbstractPlus

91. Bronchud MH, Potter MR, Morgenstern G et al. In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients. Br J Cancer. 1988; 58:64-9. http://www.ncbi.nlm.nih.gov/pubmed/2458748?dopt=AbstractPlus

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94. Nicola NA, Metcalf D. Binding of¹²⁵I-labeled granulocyte colony-stimulating factor to murine hemopoietic cells. J Cell Physiol. 1985; 124:313-21. http://www.ncbi.nlm.nih.gov/pubmed/3876343?dopt=AbstractPlus

95. Amgen. Neupogen (filgrastim) product monograph. Thousand Oaks, CA; 1992 Jan. (Publication No. P40106)

96. Wang JM, Chen ZG, Colella S et al. Chemotactic activity of recombinant human granulocyte colony-stimulating factor. Blood. 1988; 72:1456-60. http://www.ncbi.nlm.nih.gov/pubmed/2460152?dopt=AbstractPlus

97. Finley RS. Measuring the cost-effectiveness of hematopoietic growth factor therapy. Cancer. 1991; 67(Suppl):2727-30. http://www.ncbi.nlm.nih.gov/pubmed/1901757?dopt=AbstractPlus

98. Stein RS. G-CSF for fever and neutropenia induced by chemotherapy. N Engl J Med. 1992; 326:269. http://www.ncbi.nlm.nih.gov/pubmed/1370182?dopt=AbstractPlus

102. Faulds D, Lewis NJW, Milne RJ. Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemotherapy-induced neutropenia. Pharmacoeconomics. 1992; 1:231-49. http://www.ncbi.nlm.nih.gov/pubmed/10147015?dopt=AbstractPlus

103. Lang CH, Bagby GJ, Dobrescu C et al. Effect of granulocyte colony-stimulating factor on sepsis-induced changes in neutrophil accumulation and organ glucose uptake. J Infect Dis. 1992; 166:336-43. http://www.ncbi.nlm.nih.gov/pubmed/1378872?dopt=AbstractPlus

104. Migliaccio AR, Migliaccio G, Dale DC et al. Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo. Blood. 1990; 75:1951-9. http://www.ncbi.nlm.nih.gov/pubmed/1692489?dopt=AbstractPlus

105. Dale DC, Hammond WP, Gabrilove J et al. Long term treatment of severe chronic neutropenia with recombinant human granulocyte factor (r-metHuG-CSF). Blood. 1990; 76(Suppl 1):139.

111. Geissler K, Forstinger C, Kalhs P et al. Effect of interleukin-3 on responsiveness to granulocyte-colony-stimulating factor in severe aplastic anemia. Ann Intern Med. 1992; 117:223-5. http://www.ncbi.nlm.nih.gov/pubmed/1377461?dopt=AbstractPlus

114. Furman WL, Crist WM. Biology and clinical applications of hemopoietins in pediatric practice. Pediatrics. 1992; 90:716-28. http://www.ncbi.nlm.nih.gov/pubmed/1383919?dopt=AbstractPlus

115. Katz R, Chuang LC, Sutton JD. Use of granulocyte colony-stimulating factor in the treatment of pancytopenia secondary to colchicine overdosage. Ann Pharmacother. 1992; 26:1087-8. http://www.ncbi.nlm.nih.gov/pubmed/1384817?dopt=AbstractPlus

116. Gerson SL, Gullion G, Yeh HS et al. Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis. Lancet. 1992; 340:1097. http://www.ncbi.nlm.nih.gov/pubmed/1383662?dopt=AbstractPlus

117. Tajiri J, Noguchi S, Okamura S et al. Granulocyte colony-stimulating factor treatment of antithyroid drug-induced granulocytopenia. Arch Intern Med. 1993; 153:509-14. http://www.ncbi.nlm.nih.gov/pubmed/7679571?dopt=AbstractPlus

118. Chia HM, Kalra L, Lakhani AK et al. Filgrastim for low-dose, captopril-induced agranulocytosis. Lancet. 1993; 342:304. http://www.ncbi.nlm.nih.gov/pubmed/8101328?dopt=AbstractPlus

119. Wyatt S, Joyner MV, Daneshmend TK. Filgrastim for mesalazine-associated neutropenia. Lancet. 1993; 341:1476. http://www.ncbi.nlm.nih.gov/pubmed/8099166?dopt=AbstractPlus

120. Lyman GH, Lyman CG, Sanderson RA et al. Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst. 1993; 85:488-93. http://www.ncbi.nlm.nih.gov/pubmed/8445677?dopt=AbstractPlus

121. Lorber C, Willfort A, Ohler L et al. Granulocyte colony-stimulating factor (rh G-CSF) as an adjunct to interferon alpha therapy of neutropenic patients with hairy cell leukemia. Ann Hematol. 1993; 67:13-6. http://www.ncbi.nlm.nih.gov/pubmed/7687471?dopt=AbstractPlus

122. 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; 11:198-208. http://www.ncbi.nlm.nih.gov/pubmed/1381218?dopt=AbstractPlus

123. Saven A, Piro LD. Treatment of hairy cell leukemia. Blood. 1992; 79:1111-20. http://www.ncbi.nlm.nih.gov/pubmed/1371410?dopt=AbstractPlus

124. Jaiyesimi IA, Kantarjian HM, Estey EH. Advances in therapy for hairy cell leukemia. A review. Cancer. 1993; 72:5-16. http://www.ncbi.nlm.nih.gov/pubmed/7685243?dopt=AbstractPlus

125. Stahel RA, Jost LM, Cerny T et al. Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies. J Clin Oncol. 1994; 12:1931-8. http://www.ncbi.nlm.nih.gov/pubmed/7521907?dopt=AbstractPlus

126. Spitzer G, Deisseroth A, Ventura G et al. Use of recombinant human hematopoietic growth factors and autologous bone marrow transplantation to attenuate the neutropenic trough of high-dose therapy. Int J Cell Cloning. 1990; 8(Suppl 1):249-61. http://www.ncbi.nlm.nih.gov/pubmed/1691246?dopt=AbstractPlus

127. Teitelbaum AH, Bell AJ, Brown SL. Filgrastim (r-metHuG-CSF) reversal of drug induced agranulocytosis. Am J Med. 1993; 95:245-6. http://www.ncbi.nlm.nih.gov/pubmed/7689297?dopt=AbstractPlus

128. Weide R, Koppler H, Heymanns J et al. Successful treatment of clozapine induced agranulocytosis with granulocyte-colony stimulating factor (G-CSF). Br J Haematol. 1992; 80:557-9. http://www.ncbi.nlm.nih.gov/pubmed/1374635?dopt=AbstractPlus

129. Maher DW, Lieschke GJ, Green M et al. Filgrastim in patients with chemotherapy-induced febrile neutropenia: a double-blind, placebo-controlled trial. Ann Intern Med. 1994; 121:492-501. http://www.ncbi.nlm.nih.gov/pubmed/7520676?dopt=AbstractPlus

132. Hermans P, Rozenbaum W, Jou A et al. Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection. G-CSF 92105 Study Group. AIDS. 1996; 10:1627-33. http://www.ncbi.nlm.nih.gov/pubmed/8970682?dopt=AbstractPlus

133. Riikonen P, Rahiala J, Salonvaara M et al. Prophylactic administration of granulocyte colony-stimulating factor (Filgrastim) after conventional chemotherapy in children with cancer. Stem Cells. 1995; 13:289-94. http://www.ncbi.nlm.nih.gov/pubmed/7542114?dopt=AbstractPlus

136. Heil G, Hoelzer D, Sanz MA et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia: the International Acute Myeloid Leukemia Study Group. Blood. 1997; 90(12):4710-4718. http://www.ncbi.nlm.nih.gov/pubmed/9389686?dopt=AbstractPlus

137. Godwin JE, Kopecky KJ, Head DR et al. A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood. 1998; 91(10):3607-3615. http://www.ncbi.nlm.nih.gov/pubmed/9572995?dopt=AbstractPlus

138. Moore JO, Dodge RK, Amrein PC et al. Granulocyte-colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoquinone and mitoxantrone: Cancer and Leukemia Group B study 9022. Blood. 1997; 89(3)780-788.

139. Ogata K, An E, Kamikubo K et al. Repeated cycles of G-CSF-combined postremission chemotherapy for acute myeloid leukemia in a first complete remission: a pilot study. Stem Cells. 1998; 16(4):280-7. http://www.ncbi.nlm.nih.gov/pubmed/9708450?dopt=AbstractPlus

140. Jakubowski A, Gordon M, Tafuri A et al. A pilot study of the biologic and therapeutic effects of granulocyte colony-stimulating factor (filgrastim) in patients with acute myelogenous leukemia. Leukemia. 1995; 9(11):1799-1804. http://www.ncbi.nlm.nih.gov/pubmed/7475265?dopt=AbstractPlus

142. Kuritzkes 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; 30:256-60. http://www.ncbi.nlm.nih.gov/pubmed/10671324?dopt=AbstractPlus

143. Wong RJ. Treatment of HIV-related neutropenia. Am J Health Syst Pharm. 1999; 56(Suppl 5):S17-20. http://www.ncbi.nlm.nih.gov/pubmed/10613382?dopt=AbstractPlus

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154. Abraham I, Tharmarajah S, Macdonald K. Clinical safety of biosimilar recombinant human granulocyte colony-stimulating factors. Expert Opin Drug Saf. 2013; 12:235-46. http://www.ncbi.nlm.nih.gov/pubmed/23419039?dopt=AbstractPlus

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171. Smith TJ, Bohlke K, Lyman GH et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015; 33:3199-212. http://www.ncbi.nlm.nih.gov/pubmed/26169616?dopt=AbstractPlus

172. Crawford J, Becker PS, Armitage JO, et al. NCCN Myeloid growth factors, version 2.2017. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15:1520-41.

173. Bennett CL, Djulbegovic B, Norris LB et al. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med. 2013; 368:1131-9. http://www.ncbi.nlm.nih.gov/pubmed/23514290?dopt=AbstractPlus

174. Clark OA, Lyman GH, Castro AA et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol. 2005; 23:4198-214. http://www.ncbi.nlm.nih.gov/pubmed/15961767?dopt=AbstractPlus

175. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol. 2014; 90:190-9. http://www.ncbi.nlm.nih.gov/pubmed/24434034?dopt=AbstractPlus

176. Schmitz N, Dreger P, Zander AR et al. Results of a randomised, controlled, multicentre study of recombinant human granulocyte colony-stimulating factor (filgrastim) in patients with Hodgkin's disease and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation. Bone Marrow Transplant. 1995; 15:261-6. http://www.ncbi.nlm.nih.gov/pubmed/7539668?dopt=AbstractPlus

177. Schmitz N, Linch DC, Dreger P et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet. 1996; 347:353-7. http://www.ncbi.nlm.nih.gov/pubmed/8598700?dopt=AbstractPlus

178. Dale DC, Bonilla MA, Davis MW et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993; 81:2496-502. http://www.ncbi.nlm.nih.gov/pubmed/8490166?dopt=AbstractPlus

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