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filgrastim

( fill-GRA-stim )
Funding:
ODB - General Benefit
  • filgrastim - Grastofil brand is a general benefit
ODB Limited Use
  • filgrastim - (Neupogen brand) - Pre-Stem Cell Transplant Mobilization: For peripheral blood progenitor cell collection for peripheral stem cell transplant as treatment for malignant disease. Approval for Neupogen 300 mcg and 480 mcg vial format only.
  • filgrastim - (Neupogen brand) For pediatric patients (less than 18 years age) who are unable to achieve the appropriate dose of granulocyte colony-stimulating factor with the formulary listed formats of pre-filled syringes. Approval for Neupogen 300 mcg vial format only.
  • filgrastim - (Neupogen brand) For patients who are unable to use available formats of Grastofil due to a documented latex allergy. Approval for Neupogen 300 mcg and 480 mcg vial format only.
Other Name(s): Neupogen®, Grastofil®
Appearance: Clear, colourless solution
A - Drug Name

filgrastim

SYNONYM(S):   G-CSF; Granulocyte-Colony Stimulating Factor

COMMON TRADE NAME(S):   Neupogen®; Grastofil®

 
B - Mechanism of Action and Pharmacokinetics

Filgrastim is a human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology – but unlike the endogenous form, filgrastim is unglycosylated. Endogenous G-CSF is a lineage-restricted colony-stimulating factor that principally affects the proliferation, differentiation, and activation of committed progenitor cells of the neutrophil-granulocyte linage.  In addition, endogenous G-CSF enhances certain functions of mature neutrophils, including phagocytosis, chemotaxis, and antibody-dependent cellular cytotoxicity. G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. It has been shown to have minimal direct in vivo or in vitro effects on the production of other hematopoietic cell types. 



Absorption
Bioavailability oral: no

Distribution

Filgrastim is rapidly distributed, appearing in highest concentration in bone marrow, adrenal glands, kidney and liver.  Pharmacokinetics are linear.

Cross blood brain barrier? Unknown
PPB Unlikely
Metabolism

The metabolic fate of filgrastim has not been fully determined and it is not known whether the drug is metabolized or how it is eliminated from the body. 

Active metabolites Unlikely
Inactive metabolites Unlikely
Elimination
Half-life 3.5 hours (average).
Clearance 0.5-0.7 mL/min/kg
 
C - Indications and Status
Health Canada Approvals:

Both Neupogen® and Grastofil® * brands are approved for the following cancer-related indications:

  • to decrease incidence of febrile neutropenia and its sequelae in patients with
    • non-myeloid malignancies receiving myelosuppressive chemotherapy
    • following induction and consolidation treatment for acute myeloid leukemia
    • myeloablative chemotherapy followed by bone marrow transplantation (BMT)
       
  • to mobilize autologous peripheral blood progenitor cells for patients undergoing peripheral blood progenitor cell (PBPC) collection.
     
    *Grastofil® is a subsequent entry biologic drug. Comparability has been established with the reference product, Neupogen®; however, Grastofil® is not interchangeable with the reference product.


 
D - Adverse Effects

Emetogenic Potential:  

Not applicable

Extravasation Potential:   None

The following table contains adverse effects reported in small cell lung cancer patients where the incidence was higher than placebo, unless indicated otherwise.

 

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arrhythmia (3%) E
Hypotension (mild, transient, rare) I
Dermatological Erythema nodosum (rare) E
Other (Sweet's syndrome - acute febrile neutrophilic dermatosis: rare) E
Pruritus (rare) E
General Fever (12%) E
Hematological Leukocytosis (2%) E
Sickle cell crisis (in patients with sickle cell anemia) L
Splenic rupture (+/- splenomegaly; rare) D
Hypersensitivity Hypersensitivity (rare) I
Injection site Injection site reaction E
Metabolic / Endocrine ↑ ALP (27-58%, transient) E
Hyperuricemia (27-58%, transient) L
↑ LDH (27-58%, transient) L
Musculoskeletal Bone pain (medullary, 22%) E
Other - Chondrocalcinosis (rare) E
Neoplastic Leukemia (secondary) (2%) (in congenital neutropenia) D
Renal Nephritis (glomerulonephritis) (rare) E
Respiratory Adult respiratory distress syndrome (ARDS) (rare) E
Vascular Capillary leak syndrome (rare) E  D
Vasculitis (cutaneous; rare) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

Filgrastim generally is well tolerated, and only rarely have adverse effects been severe enough to require discontinuation of the drug.  The adverse effect reported most frequently is mild to moderate (occasionally severe) medullary bone pain (24%).   The bone pain appears to be dependent on the dose and/or route of administration.  In most reported cases, bone pain appeared to occur at sites containing bone marrow in the 2 to 3 day period preceding the increase in peripheral neutrophil count and to be particularly severe in patients with marked leukocytosis.  Filgrastim-induced bone pain usually can be effectively prevented or treated with non-opioid oral analgesics (e.g. acetaminophen).   In severe cases, opioid analgesics may be used.  Bone pain generally resolves spontaneously with continued filgrastim therapy.    

Intensified doses of chemotherapy may result in increased rates of toxicity for those agents (including secondary leukemias with alkylating agents).

Cutaneous vasculitis has been reported most frequently in patients with severe chronic neutropenia receiving long-term filgrastim therapy.  Adverse cutaneous effects appeared to be related to high neutrophil counts and resultant infiltration at sites of vascular inflammation that occurred as a result of filgrastim therapy.

Capillary leak syndrome (CLS, signs include hypotension, hypoalbuminemia, edema, hemoconcentration) has been reported and may be life-threatening. Prompt treatment is required.

Acute Respiratory Distress Syndrome (ARDS) may develop in patients with sepsis due to migration of neutrophils to lung inflammation sites; discontinue filgrastim if signs of ARDS develop. 

Marked leukocytosis (> 100 x 109 /L) occurs occasionally. 

Although a direct causal relationship has not been established, development of myelodysplasia or myeloid leukemia has been reported in patients with chronic neutropenia receiving filgrastim therapy.  The effects of filgrastim on the development of abnormal cytogenetics and the effect of continued filgrastim therapy in patients with abnormal cytogenetics are unknown.   

Rare instances of hypersensitivity reactions have been reported with rash, urticaria, wheezing and hypotension, usually occurring within 30 minutes of exposure.  These reactions generally respond rapidly to antihistamine and corticosteroid treatment, but recur in more than 50% of patients who are rechallenged.  

Cases of glomerulonephritis have been reported in patients receiving filgrastim, usually resolving after dose reductions or withdrawal.

Splenomegaly has been reported in patients who had received long-term therapy of filgrastim.  Increases in spleen size were not associated with clinical manifestation in most patients, and partially resolved in some patients during continued therapy with the drug. Rarely, rapid increase in spleen size occurs and may lead to rupture. 

Three percent of patients develop binding, but not neutralizing, antibodies.

 
E - Dosing

Refer to protocol by which patient is being treated.

Different filgrastim products are not interchangeable.

Filgrastim should be started at least 24 hours after the last chemotherapy dose and or marrow/stem cell transfusion, and discontinued at least 24 hours before chemotherapy. In general, treatment should be continued daily until post-nadir counts reach 10 x 109/L.

 



Adults:

Chemotherapy-induced neutropenia (including post-stem cell transplant):  

  • 5 μg/kg/day (SC, IV infusion, SC infusion, or CIV)
  • Doses may be increased in increments of 5 μg/kg for each chemotherapy cycle, according to the duration and severity of ANC nadir. (for post-stem cell transplant, use Table 1 for titration)
Patients receiving myeloablative chemotherapy followed by bone marrow transplantation:
  • 10 μg/kg/day IV infusion over 4-24 hrs, or continuous SC infusion over 24 hrs.
  • Doses may be adjusted according to ANC response as shown in Table 1:

 

Table 1: 
 

ANC (X 109/L)

Dose (μg/kg/day)

If >1 for 3 consecutive days

Reduce to 5 μg/kg/day. If ANC falls to < 1, increase to  10 μg/kg/day

Then:

If >1 for 3 more consecutive days

Discontinue Filgrastim

Then:

If return to <1

Resume at 5 μg/kg/day

 PBPC mobilization (cancer patients only):

  • Mobilization: 10 μg/kg/day SC or continuous SC 24-hour infusion, given for at least 4 days before the first leukapheresis and continued to the day of the last leukapheresis.

 

 


Dosage with Toxicity:

Toxicity
Filgrastim dose
Severe hypersensitivity
Discontinue
Capillary leak syndrome/ARDS
Discontinue
Alveolar Hemorrhage
Hold until resolution or discontinue
Glomerulonephritis Consider dose reduction or discontinue


Dosage with Hepatic Impairment:

No information found



Dosage with Renal Impairment:

No information found



Dosage in the elderly:

Pharmacokinetic information is unavailable.



Children:

  • The recommended dose in pediatric oncology patients receiving myelosuppressive chemotherapy is 5 μg/kg/day SC. The safety profile of filgrastim in pediatric patients appears similar to that reported in adults.
  • Safety in neonates has not been established.


 
F - Administration Guidelines

Different filgrastim products are not interchangeable.

  • Refrigerate but do not freeze. Avoid vigorous shaking.
  • For Neupogen, vials or pre-filled synringes may be allowed to reach room temperature for a maximum of 14 days. Discard drug if it is left at room temperature beyond this time period.
  • For Grastofil, pre-filled syringes may be stored at room temperature for one single period of up to 15 days. Discard drug if it is left at room temperature beyond this time period.
  • Subcutaneous self-administration (or administered by home caregiver); drug available by outpatient prescription.
  • The pre-filled syringe of both Neupogen and Grastofil contains a derivative of latex. It should not be handled by individuals who are sensitive to latex.
  • May also be given as IV infusion, continuous SC or IV infusion.  See "Dosing" section.
  • If required, filgrastim may be diluted in 5% dextrose. DO NOT dilute with saline as precipitation may occur.
  • For IV, CIV, or SC infusions, dilute filgrastim to produce a final concentration 5-15 µg/mL.  Human albumin should be added to the solution at a final concentration of 2 mg/mL, to minimize adsorption of the drug to infusion containers or equipment.  Do not dilute filgrastim to < 5µg/mL, even if human albumin is present in the solution.
  • Compatible with PVC, glass, or polyolefin containers, and polypropylene syringes when filgrastim is diluted in 5% dextrose or 5% dextrose plus albumin
  • For IV administration, infuse over 15-30 minutes or as CIV. 


 
G - Special Precautions
Contraindications:

  • Patients with known hypersensitivity to E. coli derived products or to any constituent of the product
  • PBPC mobilization in health donors (not approved)

Other Warnings/Precautions:

  • Patients with sickle cell anemia because of the risk of sickle cell crisis
  • Patients with known autoimmune disease or cardiac conditions
  • Simultaneous administration of radiation or chemotherapy (within 24 hours)
  • Patients with CML or MDS (tumour growth factor potential; no data available)
  • Since patients are more likely to receive full dose chemotherapy with filgrastim support, they may be at greater risk of thrombocytopenia, anemia and non-hematologic adverse effects of chemotherapy. Regular CBC and clinical toxicity monitoring are recommended.
  • Response to filgrastim may be diminished in patients with decreased neutrophil precursors, such as those who have extensive pre-treatment with chemotherapy or radiotherapy.


Other Drug Properties:

  • Carcinogenicity: Unknown
    The carcinogenic potential of filgrastim has not been studied; the possibility that filgrastim can stimulate growth of any tumour  type cannot be excluded.

Pregnancy and Lactation:
  • Mutagenicity: No
  • Embryotoxicity: Probable
    Filgrastim is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).
  • Excretion into breast milk: Probable
    Breastfeeding is not recommended. Women who become pregnant or who breastfeed while receiving filgrastim may enroll in Amgen's pregnancy or lactation surveillance programs, respectively.
  • Fertility effects: Unlikely
 
H - Interactions

 

 

AGENT EFFECT MECHANISM MANAGEMENT
Cytokines (hematopoietic growth factors) Additive myeloproliferative effect Synergistic stimulation Caution (unknown)
Antineoplastics with delayed myelosuppression (e.g. nitrosourea derivatives) or mitomycin or myelosuppressive doses of antimetabolite Reduced effect or additive myeloproliferative effect (unknown) Theoretically antagonistic mechanism Caution (unknown)
Lithium Additive myeloproliferative effect Potentially release neutrophils Caution
cytotoxics ↑ neutropenia ↑ sensitivity of neutrophils Do not start Filgrastim treatment within 24 hours before or after chemotherapy
Bone imaging transient positive bone imaging changes ↑ hematopoietic activity in bone marrow Consider when interpreting bone imaging results.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and 2-3 times a week during filgrastim therapy

Clinical assessment of bone pain, hypersensitivity, pulmonary, cutaneous effects and cardiac status

At each visit

Urinalysis

Baseline and as clinically indicated

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Bone marrow and trephines in patients receiving chronic filgrastim for SCN Annual
 
J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

  • filgrastim - Grastofil brand is a general benefit
ODB Limited Use (ODB Formulary )
  • filgrastim - (Neupogen brand) - Pre-Stem Cell Transplant Mobilization: For peripheral blood progenitor cell collection for peripheral stem cell transplant as treatment for malignant disease. Approval for Neupogen 300 mcg and 480 mcg vial format only.
  • filgrastim - (Neupogen brand) For pediatric patients (less than 18 years age) who are unable to achieve the appropriate dose of granulocyte colony-stimulating factor with the formulary listed formats of pre-filled syringes. Approval for Neupogen 300 mcg vial format only.
  • filgrastim - (Neupogen brand) For patients who are unable to use available formats of Grastofil due to a documented latex allergy. Approval for Neupogen 300 mcg and 480 mcg vial format only.

 
K - References

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p.1592-600.

Nemunaitis J. A comparative review of colony-stimulating factors. Drugs 1997; 54(5): 709-29.

Product Monograph: Grastofil® (filgrastim). Apotex Inc. October 7, 2016.

Product Monograph: Neupogen® (Filgrastim). Amgen Canada Inc., October 31, 2016.


September 2019 Added additional info on biosimilars

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.