Filgrastim

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Neupogen: filgrastim 300 mcg/mL (1 mL); filgrastim 480 mcg/1.6 mL (1.6 mL) [contains polysorbate 80]

Solution, Injection [preservative free]:

Nivestym: filgrastim-aafi 300 mcg/mL (1 mL); filgrastim-aafi 480 mcg/1.6 mL (1.6 mL) [contains polysorbate 80]

Solution, Subcutaneous [preservative free]:

Granix: tbo-filgrastim 300 mcg/mL (1 mL); tbo-filgrastim 480 mcg/1.6 mL (1.6 mL) [contains polysorbate 80]

Solution Prefilled Syringe, Injection [preservative free]:

Neupogen: filgrastim 300 mcg/0.5 mL (0.5 mL); filgrastim 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Nivestym: filgrastim-aafi 300 mcg/0.5 mL (0.5 mL); filgrastim-aafi 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Zarxio: filgrastim-sndz 300 mcg/0.5 mL (0.5 mL); filgrastim-sndz 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Granix: tbo-filgrastim 300 mcg/0.5 mL (0.5 mL); tbo-filgrastim 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSFs stimulate the production, maturation, and activation of neutrophils to increase both their migration and cytotoxicity.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 150 mL/kg; Continuous infusion: No evidence of drug accumulation over a 11- to 20-day period

Metabolism

Systemically degraded

Onset of Action

Filgrastim: 1 to 2 days

Tbo-filgrastim: Time to maximum ANC: 3 to 5 days

Time to Peak

Serum: Filgrastim: SubQ: 2 to 8 hours; Tbo-filgrastim: 4 to 6 hours

Duration of Action

Filgrastim: Neutrophil counts generally return to baseline within 4 days

Tbo-filgrastim: ANC returned to baseline by 21 days after completion of chemotherapy

Half-Life Elimination

Neonates: 4.4 ± 0.4 hours (Gillan 1994)

Adults: Filgrastim: ~3.5 hours; Tbo-filgrastim: 3 to 3.5 hours

Use in Specific Populations

Special Populations: Renal Function Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (ESRD) (n = 4 per group), higher serum concentrations were observed in subjects with ESRD.

Use: Labeled Indications

Chemotherapy-induced myelosuppression in nonmyeloid malignancies:

Neupogen and filgrastim biosimilars: To decrease the incidence of infection (neutropenic fever) in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever

Tbo-filgrastim: To decrease the duration of severe neutropenia in adult and pediatric patients ≥1 month of age with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of neutropenic fever

Acute myeloid leukemia (AML) following induction or consolidation chemotherapy (Neupogen and filgrastim biosimilars): To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in adults with AML

Bone marrow transplantation (Neupogen and filgrastim biosimilars): To reduce the duration of neutropenia and neutropenia-related events (eg, neutropenic fever) in patients with nonmyeloid malignancies receiving myeloablative chemotherapy followed by marrow transplantation

Hematopoietic radiation injury syndrome, acute (Neupogen only): To increase survival in patients acutely exposed to myelosuppressive doses of radiation

Peripheral blood progenitor cell collection and therapy (Neupogen and filgrastim biosimilars): Mobilization of autologous hematopoietic progenitor cells into the peripheral blood for apheresis collection

Severe chronic neutropenia (Neupogen and filgrastim biosimilars): Long-term administration to reduce the incidence and duration of neutropenic complications (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital, cyclic, or idiopathic neutropenia

Note: Nivestym (filgrastim-aafi) and Zarxio (filgrastim-sndz) are approved as biosimilars to Neupogen (filgrastim). In Canada, Grastofil is a biosimilar to Neupogen (filgrastim).

Use: Off Label

Alcoholic hepatitis (severe)c

Data from a small randomized, non-blinded pilot study suggest filgrastim may be safe and effective therapy and may improve liver function as well as survival in patients with severe alcoholic hepatitis Singh 2014.

Anemia in myelodysplastic syndromeyes

Based on the European LeukemiaNet guidelines for the management of primary myelodysplastic syndromes in adults, filgrastim (in combination with epoetin) is effective and recommended for the management of this condition Malcovati 2013.

Hematopoietic stem cell mobilization for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma or multiple myelomaa

Data from two phase III prospective, randomized, double-blind, placebo-controlled trials support the use of filgrastim (in combination with plerixafor) in the mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma DiPersio 2009a, DiPersio 2009b.

Neutropenia in advanced HIV infectionb

Data from a randomized, controlled, open-label, multicenter study support the use of filgrastim in prevention and treatment of neutropenia in patients >13 years of age with advanced HIV infection Kuritzkes 1998.

Neutropenia (hepatitis C treatment-associated)yes

Based on the American Association for the Study of Liver Diseases (AASLD) guidelines for the diagnosis, management, and treatment of hepatitis C, filgrastim is effective and recommended in the management of hepatitis C treatment-associated neutropenia AASLD [Ghany 2009].

Contraindications

History of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim, or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Known hypersensitivity to E. coli-derived products

Dosage and Administration

Dosing: Adult

Note: Do not administer in the period 24 hours before to 24 hours after cytotoxic chemotherapy. May round the dose to the nearest vial size for convenience and cost minimization (ASCO [Ozer 2000]). Nivestym (filgrastim-aafi) and Zarxio (filgrastim-sndz) are approved as biosimilars to Neupogen (filgrastim). In Canada, Grastofil is a biosimilar to Neupogen (filgrastim). International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Hoglund 1998).

Acute myeloid leukemia (AML) following induction or consolidation chemotherapy (Neupogen and filgrastim biosimilars): SubQ, IV: 5 mcg/kg/day; doses may be increased by 5 mcg/kg (for each chemotherapy cycle) according to the duration and severity of the neutropenia; continue for up to 14 days until the ANC reaches 10,000/mm³. Discontinue if the ANC surpasses 10,000/mm³ after the expected chemotherapy-induced neutrophil nadir.

Alcoholic hepatitis (severe) (off-label use): SubQ: 5 mcg/kg every 12 hours for 5 consecutive days in combination with standard medical therapy (pentoxifylline and nutritional therapy) and supportive care (Singh 2014).

Anemia in myelodysplastic syndrome (off-label use; in combination with epoetin): SubQ: 300 mcg weekly in 2 to 3 divided doses (Malcovati 2013) or 1 mcg/kg once daily (Greenberg 2009) or 75 mcg, 150 mcg, or 300 mcg per dose 3 times weekly (Hellstrom-Lindberg 2003)

Bone marrow transplantation (Neupogen and filgrastim biosimilars): IV infusion: 10 mcg/kg/day (administer ≥24 hours after chemotherapy and ≥24 hours after bone marrow infusion); adjust the dose according to the duration and severity of neutropenia; recommended steps based on neutrophil response:

When ANC >1,000/mm³ for 3 consecutive days: Reduce dose to 5 mcg/kg/day.

If ANC remains >1,000/mm³ for 3 more consecutive days: Discontinue.

If ANC decreases to <1,000/mm³: Resume at 5 mcg/kg/day.

If ANC decreases to <1,000/mm³ during the 5 mcg/kg/day dose: Increase dose to 10 mcg/kg/day and follow the above steps.

Chemotherapy-induced myelosuppression in nonmyeloid malignancies (Neupogen and filgrastim biosimilars): SubQ, IV: 5 mcg/kg/day; doses may be increased by 5 mcg/kg (for each chemotherapy cycle) according to the duration and severity of the neutropenia; continue for up to 14 days until the absolute neutrophil count (ANC) reaches 10,000/mm³. Discontinue if the ANC surpasses 10,000/mm³ after the expected chemotherapy-induced neutrophil nadir.

Chemotherapy-induced myelosuppression in nonmyeloid malignancies (tbo-filgrastim): SubQ: 5 mcg/kg/day; continue until anticipated nadir has passed and neutrophil count has recovered to normal range.

Hematopoietic radiation injury syndrome, acute (Neupogen only): SubQ: 10 mcg/kg once daily; begin as soon as possible after suspected or confirmed radiation doses >2 gray (Gy) and continue filgrastim until ANC remains >1,000/mm³ for 3 consecutive CBCs or ANC exceeds 10,000/mm³ after the radiation-induced nadir. ASCO guidelines recommend initiating within 24 hours of exposure of a dose ≥2 Gy and/or significant decrease in absolute lymphocyte count, or for anticipated neutropenia <500/mm³ for ≥7 days (ASCO [Smith 2015]).

Hematopoietic stem cell mobilization in autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma (in combination with plerixafor; off-label combination): SubQ: 10 mcg/kg once daily; begin 4 days before initiation of plerixafor; continue G-CSF on each day prior to apheresis for up to 8 days (DiPersio 2009a; DiPersio 2009b)

Hepatitis C treatment-associated neutropenia (off-label use): SubQ: 150 mcg once weekly to 300 mcg 3 times weekly; titrate to maintain ANC between 750 and 10,000/mm³ (Younossi 2008)

Neutropenia in advanced HIV infection (off-label use): SubQ: Initial: 1 mcg/kg once daily or 300 mcg one to three times per week; titrate to maintain ANC 2,000 to 10,000/mm³; doses up to 10 mcg/kg/day or 600 mcg daily were studied (Kuritzkes 1998).

Peripheral blood progenitor (PBPC) cell collection and therapy (Neupogen and filgrastim biosimilars): SubQ: 10 mcg/kg daily, usually for 6 to 7 days (with apheresis occurring on days 5, 6, and 7). Begin at least 4 days before the first apheresis and continue until the last apheresis; discontinue for WBC >100,000/mm³

Severe chronic neutropenia (Neupogen and filgrastim biosimilars): SubQ:

Congenital: Initial: 6 mcg/kg/day in 2 divided doses; adjust the dose based on ANC and clinical response; mean dose: 6 mcg/kg/day.

Idiopathic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 1.2 mcg/kg/day

Cyclic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 2.1 mcg/kg/day

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Höglund 1998). Dosing may vary by protocol; refer to specific treatment protocol. For larger doses (eg, adolescents), rounding doses to the nearest vial size may enhance patient convenience and reduce costs without compromising clinical response.

Bone marrow transplantation: Filgrastim and filgrastim biosimilars: Children and Adolescents: IV infusion: 10 mcg/kg/day (administer ≥24 hours after chemotherapy and ≥24 hours after bone marrow infusion); adjust the dose according to the duration and severity of neutropenia; dosage adjustment recommended based on neutrophil response:

When ANC >1,000/mm³ for 3 consecutive days: Reduce dose to 5 mcg/kg/day

If ANC remains >1,000/mm³ for 3 more consecutive days: Discontinue

If ANC decreases to <1,000/mm³: Resume at 5 mcg/kg/day

If ANC decreases to <1,000/mm³ during the 5 mcg/kg/day dose, increase dose to 10 mcg/kg/day and follow the above steps

Bone marrow transplantation, slow engraftment: Filgrastim: Infants, Children, and Adolescents: Limited data available: IV, SubQ: 5 mcg/kg/day administered ≥24 hours after cytotoxic chemotherapy and ≥24 hours after bone marrow infusion (Schaison 1998; Wagner 2001)

Chemotherapy-induced neutropenia (myelosuppressive chemotherapy recipients with non-myeloid malignancies):

Filgrastim and filgrastim biosimilars: Infants, Children, and Adolescents: IV, SubQ: 5 mcg/kg/day once daily beginning ≥24 hours after chemotherapy; recommendations for duration of therapy vary: Manufacturer labeling is for up to 14 days or until ANC reaches 10,000/mm³; others have suggested a lower target ANC of 5,000/mm³ (Schaison 1998; Wagner 2001); review treatment-specific protocol for guidance. For subsequent chemotherapy cycles, dose may be increased by 5 mcg/kg based upon patient's previous response to therapy along with duration and severity of neutropenia.

Tbo-Filgrastim (Granix): Infants, Children, and Adolescents: SubQ: 5 mcg/kg/day once daily; begin ≥24 hours after chemotherapy and continue until anticipated nadir has passed and neutrophil count has recovered to normal range.

Hematopoietic syndrome of acute radiation syndrome, acute: Filgrastim: Infants, Children, and Adolescents: SubQ: 10 mcg/kg/day once daily; begin as soon as possible after suspected or confirmed radiation doses >2 gray (Gy) and continue filgrastim until ANC remains >1,000/mm³ for 3 consecutive CBCs or ANC exceeds 10,000/mm³ after the radiation-induced nadir. ASCO guidelines recommend initiating within 24 hours of exposure of a dose ≥2 Gy and/or significant decrease in absolute lymphocyte count, or for anticipated neutropenia <500/mm³ for ≥7 days (ASCO [Smith 2015]).

Neutropenia, severe, chronic: Filgrastim and filgrastim biosimilars: Infants, Children, and Adolescents: SubQ:

Congenital: Initial: 6 mcg/kg/day in 2 divided doses; adjust the dose based on ANC and clinical response; median dose: 6 mcg/kg/day

Idiopathic: Initial: 5 mcg/kg/day in 1 or 2 divided doses; adjust the dose based on ANC and clinical response; median dose: 1.2 mcg/kg/day

Cyclic: Initial: 5 mcg/kg/day in 1 or 2 divided doses; adjust the dose based on ANC and clinical response; median dose: 2.1 mcg/kg/day

Neutropenia in HIV infection (eg, drug induced): Limited data available:

Note: Trials performed with Neupogen product

Infants and Children: SubQ: Initial: 1 mcg/kg/day, titrate every 3 days to maintain desired ANC. Doses as high as 20 mcg/kg/day have been described (Mueller 1992).

Adolescents:

Weight-based dosing: SubQ: Initial: 1 mcg/kg/day, titrate every 3 days to maintain desired ANC. Doses as high as 20 mcg/kg/day have been described (Kuritzkes 1998; Mueller 1992).

Fixed dosing: SubQ: Initial: 300 mcg 1 to 3 times weekly, titrate to desired ANC. Maximum daily dose: 600 mcg/day (Kuritzkes 1998).

Peripheral blood progenitor cell collection and therapy: Filgrastim and filgrastim biosimilars: Infants, Children, and Adolescents: Limited data in infants: SubQ, IV: 10 mcg/kg/day; begin at least 4 days prior to first apheresis and continue until apheresis; discontinue if WBC >100,000/mm³ (Díaz 2000; Wagner 2001).

Reconstitution

Visually inspect prior to use; discard if discolored (all products should be colorless; Zarxio should be colorless to slightly yellowish) or if particulates are present.

IV: Neupogen and filgrastim biosimilars: Do not dilute with saline at any time; product may precipitate. May be diluted with D5W for IV infusion administration. Do not shake.

Neupogen, Nivestym: May be diluted with D5W to a concentration of 5 to 300 mcg/mL (do not dilute to <5 mcg/mL); concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Use vial only when preparing for IV use; do not use prefilled syringe for IV preparation. May be prepared in glass bottles, polyvinyl chloride (PVC) or polyolefin bags, and polypropylene syringes. Discard unused portion of vial.

Zarxio: May be diluted with D5W to a concentration of 5 to 15 mcg/mL (do not dilute to <5 mcg/mL); concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. May be prepared in glass bottles, polyvinyl chloride (PVC) or polyolefin bags, and polypropylene syringes. Discard unused portion of syringe.

Grastofil [Canadian product]: May be prepared in glass if diluted with D5W or in PVC or polyolefin IV bags if diluted in D5W plus albumin. Discard unused portion of syringe.

SubQ: Do not shake.

Neupogen and filgrastim biosimilars: May use vial or prefilled syringe for subcutaneous administration.

Granix: For subcutaneous use only. Remove needle shield from prefilled syringe with needle guard device. Expel extra volume from prefilled syringe if needed (depending on dose). Prefilled syringe and vial are for single use only; discard unused portion.

Administration

Do not administer earlier than 24 hours after or in the 24 hours prior to cytotoxic chemotherapy.

IV (Neupogen and filgrastim biosimilars): May be administered IV as a short infusion over 15 to 30 minutes (chemotherapy-induced neutropenia) or by continuous infusion (chemotherapy-induced neutropenia) or as an infusion of no longer than 24 hours (bone marrow transplantation).

SubQ: May be administered SubQ (chemotherapy-induced neutropenia, peripheral blood progenitor cell collection, severe chronic neutropenia, hematopoietic radiation injury syndrome). Administer into the outer upper arm, abdomen (except within 2 inches of navel), front middle thigh, or the upper outer buttocks area. Rotate injection site; do not inject into areas that are tender, red, bruised, hardened, scaly, or scarred, or sites with stretch marks.

Some patients (or caregivers) may be appropriate candidates for subQ self-administration with proper training; patients/caregivers should follow the manufacturer instructions for preparation and administration. Do not skip doses, change schedule, or discontinue without consulting with health care provider. Granix is available in prefilled syringes with and without a needle guard; the prefilled syringe without a safety needle guard is intended for patient/caregiver self-administration. Nivestym is available in a prefilled syringe with a safety needle guard and is not designed to allow for direct administration of doses <0.3 mL (180 mcg); use single-dose vials for doses <0.3 mL (180 mcg). Zarxio is only available in a prefilled syringe with a safety needle guard and is not designed to allow for direct administration of doses <0.3 mL (180 mcg). If filgrastim comes in contact with the skin, wash area thoroughly with soap and water; if eye contact occurs, flush exposed eye(s) with water.

Dietary Considerations

Some products may contain sodium.

Storage

Store at 2°C to 8°C (36°F to 46°F). Protect from light. Do not shake.

Neupogen, Nivestym, Zarxio: Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard if frozen more than once. Transport via a pneumatic tube has not been studied. Prior to injection, allow to reach room temperature for 30 minutes up to a maximum of 24 hours. Discard any vial or prefilled syringe left at room temperature for more than 24 hours. Solutions diluted for infusion in D5W may be stored at room temperature for up to 24 hours (infusion must be completed within 24 hours of preparation).

Neupogen: Store in original carton. Protect from direct sunlight. Extended storage information may be available for undiluted filgrastim; contact product manufacturer to obtain current recommendations. Sterility has been assessed and maintained for up to 7 days when prepared under strict aseptic conditions (Jacobson 1996; Singh 1994). The manufacturer recommends using within 24 hours due to the potential for bacterial contamination.

Nivestym: Store in original carton. Protect from direct sunlight.

Grastofil [Canadian product]: Accidental one-time exposure to temperatures up to 30ºC (86°F) or exposure to freezing temperatures <0ºC (32°F) does not adversely affect stability. If exposure at >30ºC or <0ºC has been greater than 24 hours or frozen more than once, do not use. May be removed from the refrigerator and stored at room temperature (≤25°C) for a single period of up to 7 days. Do not return to refrigerator.

Granix: May be removed from 2°C to 8°C (36°F to 46°F) storage for a single period of up to 5 days between 23°C to 27°C (73°F to 81°F). If not used within 5 days, the product may be returned to 2°C to 8°C (36°F to 46°F) up to the expiration date. Dispose of syringes or vials if stored at room temperature for more than 5 days. Exposure to -1°C to -5°C (23°F to 30°F) for up to 72 hours and temperatures as low as -15°C to -25°C (5°F to -13°F) for up to 24 hours do not adversely affect stability.

Drug Interactions

Belotecan: Granulocyte Colony-Stimulating Factors may enhance the neutropenic effect of Belotecan. Consider therapy modification

Bleomycin: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of bleomycin. Consider therapy modification

Cyclophosphamide: Filgrastim may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

Tisagenlecleucel: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Tisagenlecleucel. Avoid combination

Topotecan: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Topotecan. Specifically, the risk for the development of interstitial lung disease may be increased. Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of topotecan. Additionally, monitor patients closely for the development of interstitial lung disease with this combination. Consider therapy modification

Test Interactions

May interfere with bone imaging studies; increased hematopoietic activity of the bone marrow may appear as transient positive bone imaging changes

Adverse Reactions

>10%:

Cardiovascular: Chest pain (5% to 13%)

Central nervous system: Fatigue (20%), dizziness (14%), pain (12%)

Dermatologic: Skin rash (2% to 14%)

Gastrointestinal: Nausea (43%)

Hematologic & oncologic: Thrombocytopenia (5% to 38%), splenomegaly (≥5%; severe chronic neutropenia: 30%)

Hepatic: Increased serum alkaline phosphatase (6% to 11%)

Neuromuscular & skeletal: Ostealgia (11% to 30%), back pain (2% to 15%)

Respiratory: Epistaxis (≥5%), cough (14%), dyspnea (13%)

Miscellaneous: Fever (8% to 48%)

1% to 10%:

Cardiovascular: Peripheral edema (≥5%), hypertension (≥5%)

Central nervous system: Headache (6% to 10%), hypoesthesia (≥5%), insomnia (≥5%), malaise (≥5%), mouth pain (≥5%)

Dermatologic: Alopecia (≥5%), erythema (≥2%), maculopapular rash (≥2%)

Endocrine & metabolic: Increased lactate dehydrogenase (6%)

Gastrointestinal: Vomiting (≥5%), decreased appetite (≥5%), constipation (≥2%), diarrhea (≥2%)

Genitourinary: Urinary tract infection (≥5%)

Hematologic & oncologic: Anemia (≥5%), decreased hemoglobin (≥5%), leukocytosis (≤2%)

Hypersensitivity: Transfusion reaction (≥2%), hypersensitivity reaction (≥5%)

Immunologic: Antibody development (2% to 3%; no evidence of neutralizing response)

Infection: Sepsis (≥5%)

Neuromuscular & skeletal: Arthralgia (5% to 9%), limb pain (2% to 7%), muscle spasm (≥5%), musculoskeletal pain (≥5%) asthenia (≥5%)

Respiratory: Bronchitis (≥5%), oropharyngeal pain (≥5%), upper respiratory tract infection (≥5%)

<1%, postmarketing, and/or case reports: Acute respiratory distress syndrome, anaphylaxis, capillary leak syndrome, decreased bone mineral density, glomerulonephritis, hemoptysis, hypersensitivity angiitis, myalgia, osteoporosis, pulmonary alveolar hemorrhage, pulmonary infiltrates, sickle cell crisis, splenic rupture, Sweet syndrome, vasculitis (aortitis)

Warnings/Precautions

Concerns related to adverse reactions:

• Allergic reactions: Serious allergic reactions (including anaphylaxis) have been reported, usually with the initial exposure; may be managed symptomatically with administration of antihistamines, steroids, bronchodilators, and/or epinephrine. Allergic reactions may recur within days after the initial allergy management has been stopped. Do not administer filgrastim products to patients who have experienced serious allergic reaction to filgrastim or pegfilgrastim. Permanently discontinue filgrastim products in patients with serious allergic reactions.
• Alveolar hemorrhage: Reports of alveolar hemorrhage, manifested as pulmonary infiltrates and hemoptysis (requiring hospitalization), have occurred in healthy donors undergoing PBPC mobilization (off-label for use in healthy donors); hemoptysis resolved upon discontinuation.
• Aortitis: Aortitis has been reported in patients receiving filgrastim; aortitis may occur as early as the first week after treatment initiation. Manifestations of aortitis may include generalized fever, abdominal pain, malaise, back pain, and increased inflammatory markers (eg, c-reactive protein, WBC count). Consider aortitis in patients who develop related signs/symptoms of unknown etiology. Discontinue filgrastim if aortitis is suspected.
• Capillary leak syndrome: Capillary leak syndrome (CLS), characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration, may occur in patients receiving human granulocyte colony-stimulating factors (G-CSF). CLS episodes may vary in frequency and severity. If CLS develops, monitor closely and manage symptomatically (may require intensive care). CLS may be life-threatening if treatment is delayed.
• Cutaneous vasculitis: Moderate or severe cutaneous vasculitis has been reported, generally occurring in patients with severe chronic neutropenia on chronic therapy. Withhold treatment if cutaneous vasculitis occurs; may be restarted with a dose reduction once symptoms resolve and the ANC has decreased.
• Hematologic effects: White blood cell counts of ≥100,000/mm³ have been reported with filgrastim doses >5 mcg/kg/day. When filgrastim products are used as an adjunct to myelosuppressive chemotherapy, discontinue when ANC exceeds 10,000/mm³ after the ANC nadir has occurred (to avoid potential excessive leukocytosis). Doses that increase the ANC beyond 10,000/mm³ may not result in additional clinical benefit. Monitor complete blood cell count (CBC) twice weekly during therapy. In patients receiving myelosuppressive chemotherapy, filgrastim discontinuation generally resulted in a 50% decrease in circulating neutrophils within 1 to 2 days, and a return to pretreatment levels in 1 to 7 days. When used for peripheral blood progenitor cell collection, discontinue filgrastim products if leukocytes >100,000/mm³. Thrombocytopenia has also been reported with filgrastim products; monitor platelet counts.
• Nephrotoxicity: Based on findings of azotemia, hematuria (micro- and macroscopic), proteinuria, and renal biopsy, glomerulonephritis has occurred in patients receiving filgrastim. Glomerulonephritis usually resolved after filgrastim dose reduction or discontinuation. If glomerulonephritis is suspected, evaluate for cause; if likely due to filgrastim, consider dose reduction or treatment interruption.
• Respiratory distress syndrome: Acute respiratory distress syndrome (ARDS) has been reported. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS; discontinue in patients with ARDS.
• Splenic rupture: Rare cases of splenic rupture have been reported (may be fatal); in patients with upper abdominal pain, left upper quadrant pain, or shoulder tip pain, withhold treatment and evaluate for enlarged spleen or splenic rupture. Discontinue with confirmed or suspected splenic rupture.

Disease-related concerns:

• Severe chronic neutropenia: Establish diagnosis of severe chronic neutropenia (SCN) prior to initiation; use prior to appropriate diagnosis of SCN may impair or delay proper evaluation and treatment for neutropenia due to conditions other than SCN. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported to occur in the natural history of congenital neutropenia (without cytokine therapy). Cytogenetic abnormalities and transformation to MDS and AML have been observed with filgrastim when used to manage SCN, although the risk for MDS and AML appears to be in patients with congenital neutropenia. Abnormal cytogenetics and MDS are associated with the development of AML. The effects of continuing filgrastim products in patients who have developed abnormal cytogenetics or MDS are unknown; consider risk versus benefits of continuing treatment.
• Sickle cell disorders: Severe and sometimes fatal sickle cell crises may occur in patients with sickle cell disorders receiving filgrastim products. Discontinue if sickle cell crisis occurs.

Concurrent drug therapy issues:

• Cytotoxic chemotherapy: Do not use filgrastim products in the period 24 hours before to 24 hours after administration of cytotoxic chemotherapy because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. Transient increase in neutrophil count is seen 1 to 2 days after filgrastim initiation; however, for sustained neutrophil response, continue until post-nadir ANC reaches 10,000/mm³.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly patients: The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update recommend that prophylactic colony-stimulating factors be used in patients ≥65 years of age with diffuse aggressive lymphoma treated with curative chemotherapy (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), especially if patients have comorbid conditions (ASCO [Smith 2015]).
• Pediatric patients: Colony-stimulating factor (CSF) use in pediatric patients is typically directed by clinical pediatric protocols. The ASCO Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update states that CSFs may be reasonable as primary prophylaxis in pediatric patients when chemotherapy regimens with a high likelihood of febrile neutropenia are employed. Likewise, secondary CSF prophylaxis should be limited to high-risk patients. In pediatric cancers in which dose-intense chemotherapy (with a survival benefit) is used, CSFs should be given to facilitate chemotherapy administration. CSFs should not be used in the pediatric population for non-relapsed acute lymphoblastic or myeloid leukemia when no infection is present (ASCO [Smith 2015]).
• Radiation therapy recipients: Avoid concurrent radiation therapy with filgrastim products; safety and efficacy have not been established with patients receiving radiation therapy.

Dosage form specific issues:

• Latex: The packaging of some dosage forms may contain latex.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Filgrastim products should not be routinely used in the treatment of established neutropenic fever. CSFs may be considered in cancer patients with febrile neutropenia who are at high risk for infection-associated complications or who have prognostic factors indicative of a poor clinical outcome (eg, prolonged and severe neutropenia, age >65 years of age, hypotension, pneumonia, sepsis syndrome, presence of invasive fungal infection, uncontrolled primary disease, hospitalization at the time of fever development) (ASCO [Smith 2006]; IDSA [Freifeld 2011]). CSFs should not be routinely used for patients with neutropenia who are afebrile. Dose-dense regimens that require CSFs should only be used within the context of a clinical trial or if supported by convincing evidence (ASCO [Smith 2015]).
• International issues: Some products available internationally may have vial strength and dosing expressed as units (instead of as micrograms). Refer to prescribing information for specific strength and dosing information.
• Nuclear imaging: Increased bone marrow hematopoietic activity due to colony-stimulating factor use has been associated with transient positive bone-imaging changes; interpret results accordingly.
• Tumor growth effects: The G-CSF receptor through which filgrastim products act has been found on tumor cell lines. May potentially act as a growth factor for any tumor type (including myeloid malignancies and myelodysplasia). When used for stem cell mobilization, may release tumor cells from marrow, which could be collected in leukapheresis product; potential effect of tumor cell reinfusion is unknown.

Monitoring Parameters

Chemotherapy-induced neutropenia: Complete blood cell count (CBC) with differential and platelets prior to chemotherapy and twice weekly during growth factor treatment.

Bone marrow transplantation: CBC with differential and platelets frequently.

Hematopoietic radiation injury syndrome (acute): CBC at baseline (do not delay filgrastim for baseline CBC) and approximately every 3 days until ANC remains >1,000/mm³ for 3 consecutive CBCs. Estimate absorbed radiation dose (radiation exposure) based on information from public health authorities, biodosimetry (if available), or clinical findings (eg, onset of vomiting or lymphocyte depletion kinetics).

Peripheral progenitor cell collection: Neutrophil counts after 4 days of filgrastim treatment.

Severe chronic neutropenia: CBC with differential and platelets twice weekly during the first month of therapy and for 2 weeks following dose adjustments; once clinically stable, monthly for 1 year and quarterly thereafter. Monitor bone marrow and karyotype prior to treatment; and monitor marrow and cytogenetics annually throughout treatment.

Neutropenia in advanced HIV infection (off-label use): ANC 3 times weekly for 1st week then weekly thereafter (Kuritzkes 1999).

All patients: Monitor for signs/symptoms of allergic reactions, aortitis, capillary leak syndrome, cutaneous vasculitis, respiratory distress syndrome, and splenic rupture.

Pregnancy

Pregnancy Considerations

Filgrastim crosses the placenta.

Available data do not suggest an association between the use of filgrastim during pregnancy and an increased risk of miscarriage, preterm labor, or adverse fetal outcomes (birth weight or infection) following maternal use for severe chronic neutropenia. Information related to the use of granulocyte-colony stimulating factor (G-CSF) in pregnant patients with congenital, cyclic, or idiopathic neutropenia (Boxer 2015; Zeidler 2014) and G-CSF-induced allogeneic peripheral blood stem cells donation is limited (Leitner 2001; Shibata 2003).

Data collected from the Severe Chronic Neutropenia International Registry (SCNIR) note dosing for chronic conditions may need adjusted in pregnant women; the lowest effective dose to maintain the absolute neutrophil count is recommended (Zeidler 2014). An international consensus panel has published guidelines for hematologic malignancies during pregnancy that suggest that although data are limited, administration of granulocyte growth factors during pregnancy may be acceptable (Lishner 2016). One review suggests when utilizing for hematopoietic stem cell mobilization (in healthy donors; not a labeled use) avoiding use during the first trimester until additional outcome information is available (Pessach 2013).

Patient Education

What is this drug used for?

• It is used to lower the chance of getting an infection in people with bone marrow problems caused by chemo.
• It is used to raise the number of white blood cells in certain patients.
• It is used in patients who have been exposed to certain doses of radiation.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Bone pain
• Headache
• Muscle pain
• Joint pain
• Diarrhea
• Hair loss
• Nausea
• Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Capillary leak syndrome like abnormal heartbeat; chest pain; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; unable to pass urine or change in amount of urine passed; or blood in the urine
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Dark urine
• Chest pain
• Fast heartbeat
• Dizziness
• Passing out
• Sweating a lot
• Fast breathing
• Coughing up blood
• Severe loss of strength and energy
• Bruising
• Bleeding
• Purple spots or redness of skin
• Abdominal pain
• Swelling
• Back pain
• Numbness or tingling
• Left upper abdominal pain
• Left shoulder pain
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.