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Filgrastim

Pronunciation

Pronunciation

(fil GRA stim)

Index Terms

  • Filgrastim-Sndz
  • G-CSF
  • Granulocyte Colony Stimulating Factor
  • Tbo-Filgrastim
  • Tevagrastim

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 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]

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]

Brand Names: U.S.

  • Granix
  • Neupogen
  • Zarxio

Pharmacologic Category

  • Colony Stimulating Factor
  • Hematopoietic Agent

Pharmacology

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

Distribution

Vd: 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 4 hours

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

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies:

Neupogen (filgrastim), Zarxio (filgrastim-sndz; biosimilar), Grastofil [Canadian product]: 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.

Granix (tbo-filgrastim): To decrease the duration of severe neutropenia in patients 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, Zarxio, Grastofil [Canadian product]): 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, Zarxio, Grastofil [Canadian product]): 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): To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Peripheral blood progenitor cell collection and therapy (Neupogen, Zarxio, Grastofil [Canadian product]): Mobilization of autologous hematopoietic progenitor cells into the peripheral blood for apheresis collection.

Severe chronic neutropenia (Neupogen, Zarxio, Grastofil [Canadian product]): 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.

Use: Unlabeled

Treatment of anemia in myelodysplastic syndrome (in combination with epoetin); mobilization of hematopoietic stem cells (HSC) for collection and subsequent autologous transplantation (in combination with plerixafor) in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM); treatment of neutropenia in HIV-infected patients receiving zidovudine; hepatitis C treatment-associated neutropenia; treatment of radiation-induced myelosuppression of the bone marrow

Contraindications

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

Granix: There are no contraindications listed in the manufacturer’s labeling

Canadian labeling: Neupogen, Grastofil: Hypersensitivity to E. coli derived products, filgrastim, pegfilgrastim or any component of the formulation.

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 (Ozer 2000). International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Hoglund 1998).

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Neupogen [filgrastim], Zarxio [filgrastim-sndz; biosimilar], Grastofil [Canadian product]): 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.

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Granix [tbo-filgrastim]): SubQ: 5 mcg/kg/day; continue until anticipated nadir has passed and neutrophil count has recovered to normal range.

Acute myeloid leukemia (AML) following induction or consolidation chemotherapy (Neupogen, Zarxio, Grastofil [Canadian product]): 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.

Bone marrow transplantation (Neupogen, Zarxio, Grastofil [Canadian product]): 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.

Hematopoietic radiation injury syndrome, acute (Neupogen): 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 (Smith 2015).

Peripheral blood progenitor (PBPC) cell collection and therapy (Neupogen, Zarxio, Grastofil [Canadian product]): 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, Zarxio, Grastofil [Canadian product]): 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

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)

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).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Do not administer in the period 24 hours before to 24 hours after cytotoxic chemotherapy. International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Hoglund 1998).

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Neupogen [filgrastim], Zarxio [filgrastim-sndz; biosimilar], Gastrofil [Canadian product]): 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.

Bone marrow transplantation (Neupogen, Zarxio): 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

Hematopoietic radiation injury syndrome, acute (Neupogen): 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 (Smith 2015).

Peripheral blood progenitor cell collection and therapy (Neupogen, Zarxio): 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, Zarxio, Grastofil [Canadian product]): Infants ≥1 month, Children, and Adolescents: 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

Neutropenia in advanced HIV infection (off-label use): Adolescents >13 years: SubQ: Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment at treatment initiation:

Neupogen, Zarxio: No dosage adjustment necessary.

Granix:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied).

Renal toxicity during treatment: Glomerulonephritis due to filgrastim: Consider dose reduction or treatment interruption.

Dosing: Hepatic Impairment

Neupogen, Zarxio: No dosage adjustment necessary.

Granix: There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied).

Reconstitution

Visually inspect prior to use; discard if discolored or if particulates are present.

Neupogen: Do not dilute with saline at any time; product may precipitate. Filgrastim (vial only; do not use prefilled syringe for IV preparation) may be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration (minimum concentration: 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. Dilution to <5 mcg/mL is not recommended. Do not shake. May be prepared in glass bottles, polyvinyl chloride (PVC) or polyolefin bags, and polypropylene syringes. Discard unused portion of vial.

Granix: Remove needle shield and expel extra volume if needed (depending on dose). Prefilled syringe is single use; discard unused portion.

Grastofil [Canadian product]: Do not dilute with saline at any time; product may precipitate. May be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration. Concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Dilution to <5 mcg/mL is not recommended. Do not shake. 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.

Zarxio: Do not dilute with saline at any time; product may precipitate. Filgrastim-sndz may be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration. Concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Do not shake. May be prepared in glass, PVC, polyolefin, and polypropylene. Discard unused portion of syringe.

Administration

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

IV (Neupogen, Zarxio, Grastofil [Canadian product]): 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, 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. 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.

Dietary Considerations

Some products may contain sodium.

Compatibility

Stable in D5W; incompatible with NS.

Y-site administration: Incompatible with amphotericin B, cefepime, cefotaxime, cefoxitin, ceftriaxone, cefuroxime, clindamycin, etoposide, fluorouracil, furosemide, heparin, mannitol, methylprednisolone sodium succinate, metronidazole, mitomycin, piperacillin, prochlorperazine edisylate, thiotepa.

Storage

Neupogen: Store at 2°C to 8°C (36°F to 46°F). Store in the original carton. Protect from light. Protect from direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard if frozen more than once. Do not shake. Transport via a pneumatic tube has not been studied. Prior to injection, allow to reach room temperature for up to 30 minutes and 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).

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.

Granix: Store prefilled syringes at 2°C to 8°C (36°F to 46°F). Protect from light. Do not shake. 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. 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. Discard unused product.

Zarxio: Store at 2°C to 8°C (36°F to 46°F). Store in the original carton. Protect from light. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard if frozen more than once. Do not shake. Transport via a pneumatic tube has not been studied. Prior to injection, allow to reach room temperature for up to 30 minutes and a maximum of 24 hours. Discard any prefilled syringe left at room temperature for more than 24 hours. Solutions diluted for infusion may be stored at room temperature for up to 24 hours (infusion must be completed within 24 hours of preparation).

Grastofil [Canadian product]: Store at 2ºC to 8ºC (36°F to 46°F). Protect from light. Do not shake. 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.

Drug Interactions

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

Bleomycin: Filgrastim may enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Monitor therapy

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

Topotecan: Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. 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%)

Endocrine & metabolic: Increased lactate dehydrogenase (6% to ≤58%; reversible mild to moderate elevations), increased uric acid (≤58%; reversible mild to moderate elevations)

Gastrointestinal: Nausea (10% to 43%)

Hematologic & oncologic: Thrombocytopenia (5% to 38%), splenomegaly (≥5%; severe chronic neutropenia: 30%), petechia (17%)

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

Neuromuscular & skeletal: Ostealgia (5% to 33%; dose and cycle related), back pain (2% to 15%)

Respiratory: Epistaxis (2% to 15%), cough (14%), dyspnea (13%)

Miscellaneous: Fever (12% to 48%; dose and cycle related)

1% to 10%:

Cardiovascular: Peripheral edema (≥5%), hypertension (≥4% ), cardiac arrhythmia (≤3%), myocardial infarction (≤3%)

Central nervous system: Headache (7% to 10%), hypoesthesia (≥5%), insomnia (≥5%), malaise (≥5%), mouth pain (≥5%)

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

Gastrointestinal: Vomiting (5% to 7%), decreased appetite (≥5%), constipation (≥2%), diarrhea (≥2% )

Genitourinary: Urinary tract infection (≥5%)

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

Hypersensitivity: Transfusion reaction (2% to 10%), hypersensitivity reaction (≥5%)

Immunologic: Antibody development (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%) weakness (≥5%)

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

<1% (Limited to important or life-threatening): Acute calcium pyrophosphate deposition disease (in patients treated for cancer), calcium pyrophosphate deposition disease (in patients treated for cancer), capillary leak syndrome, cerebral hemorrhage, decreased bone mineral density, decreased hemoglobin, erythema nodosum, exacerbation of psoriasis, glomerulonephritis, hematuria, hemoptysis, hepatomegaly, hypersensitivity angiitis, proteinuria, pulmonary hemorrhage, pulmonary infiltrates, renal insufficiency, respiratory distress syndrome, severe sickle cell crisis, splenic rupture, Sweet syndrome, tachycardia

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.

• 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 absolute neutrophil count (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.

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: May precipitate severe sickle cell crises, sometimes resulting in fatalities, in patients with sickle cell disorders (sickle cell trait or sickle cell disease); carefully evaluate potential risks and benefits. Discontinue in patients undergoing sickle cell crisis.

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 with diffuse aggressive lymphoma treated with curative chemotherapy (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), especially if patients have comorbid conditions (Smith 2015).

• Pediatric patients: Colony-stimulating factor (CSF) use in pediatric patients is typically directed by clinical pediatric protocols. The American Society of Clinical Oncology (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 (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, hypotension, pneumonia, sepsis syndrome, presence of invasive fungal infection, uncontrolled primary disease, hospitalization at the time of fever development) (Freifeld 2011; Smith 2006). 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 (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 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).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Filgrastim has been shown to cross the placenta in humans. 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). One review suggests avoiding use during the first trimester until additional outcome information is available (Pessach 2013). 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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, bone pain, joint pain, cough, or nausea. Have patient report immediately to prescriber signs of capillary leak syndrome (abnormal heartbeat; angina; 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; blood in the urine), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), dark urine, tachycardia, dizziness, passing out, sweating a lot, shortness of breath, fast breathing, coughing up blood, severe loss of strength and energy, bruising, bleeding, purple spots or redness of skin, severe headache, edema, left upper abdominal pain, or left shoulder pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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