PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Colony-stimulating Factors

    DEA CLASS

    Rx

    DESCRIPTION

    Filgrastim is a human granulocyte colony-stimulating factor, available as Neupogen or the biosimilar product, Zarxio
    Indicated to reduce the duration of neutropenia and incidence of infection in patients receiving myelosuppressive chemotherapy and in patients undergoing myeloablative chemotherapy followed by a bone marrow transplant, for the mobilization of peripheral blood progenitor cells for collection by leukapheresis, and for the treatment of severe chronic neutropenia; Neupogen is also indicated to improve survival following acute radiation exposure
    Serious adverse reactions such as splenic rupture, acute respiratory distress syndrome, and allergic reactions (e.g., anaphylaxis) have been reported with filgrastim use

    COMMON BRAND NAMES

    Neupogen, Zarxio

    HOW SUPPLIED

    Filgrastim (E. coli)/Neupogen/Zarxio Intravenous Inj Sol: 0.5mL, 0.8mL, 1mL, 1.6mL, 300mcg, 480mcg
    Filgrastim (E. coli)/Neupogen/Zarxio Subcutaneous Inj Sol: 0.5mL, 0.8mL, 1mL, 1.6mL, 300mcg, 480mcg

    DOSAGE & INDICATIONS

    For the treatment of neutropenia.
    For the treatment of HIV-induced† or drug therapy-induced† neutropenia (e.g., ganciclovir-induced neutropenia† or zidovudine-induced neutropenia†) in patients with HIV disease to decrease the risk of bacterial infections.
    Subcutaneous dosage
    Adults, Adolescents, and Children

    Doses of filgrastim 5 to 10 mcg/kg/day (300 to 600 mcg/day) 1 to 3 times weekly have been given to maintain absolute neutrophil counts of 2000 to 10,000 cells/mm3. Filgrastim use has been associated with a decreased incidence of severe neutropenia and bacterial infection and allows tolerance of myelosuppressive agents (e.g., ganciclovir or zidovudine). The CDC does not routinely recommend this dosage.

    For the treatment of severe chronic congenital neutropenia.
    NOTE: Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults, Adolescents, Children, and Infants 7 months and older

    6 mcg/kg subcutaneously twice daily is recommended initially. Individualize the dosage to maintain clinical benefit based on patient clinical course and absolute neutrophil count (ANC). In a postmarketing surveillance study in 731 patients (adults, n = 302; pediatric patients, n = 429), the median filgrastim dose was 6 mcg/kg/day. Rarely, doses of 100 mcg/kg/day or greater have been required. The starting dose for congenital neutropenia was 11.5 mcg/kg/day (based on actual body weight) given subcutaneously in 2 divided doses in a randomized, phase III study in patients with chronic severe neutropenia (n = 123; median age of 12.1 years; range, 7 months to 76 years). In this study, the filgrastim dosage was adjusted to a level that maintained a median monthly ANC between 1,500 cells/mm3 and 10,000 cells/mm3. The dosage was increased if the median ANC was below 1,500 cells/mm3 for 2 weeks. The dosage was decreased if the median ANC was 10,000 cells/mm3 or greater for 4 weeks. The median ANC was significantly improved in 62 patients who received 4 months of filgrastim compared with 60 patients who received 4 months of observation only (6.1 cells/mm3 vs. 0.21 cells/mm3; p-value of 0.001 or less). In patients with congenital neutropenia, the median ANC was 3.45 cells/mm3 in the filgrastim arm (n = 31; median age of 7.7 years; range, 1.1 to 32.9 years) and 0.15 cells/mm3 in the observation only arm (n = 29; median age of 8 years; range, 0.6 to 33.8 years).

    For the treatment of severe chronic cyclic neutropenia.
    NOTE: Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults, Adolescents, Children, and Infants 7 months and older

    5 mcg/kg subcutaneously once daily is recommended initially. Individualize the dosage to maintain clinical benefit based on patient clinical course and absolute neutrophil count (ANC). In a postmarketing surveillance study in 731 patients (adults, n = 302; pediatric patients, n = 429), the median filgrastim dose was 2.1 mcg/kg/day in patients with cyclic neutropenia. The starting dose for cyclic neutropenia 5.75 mcg/kg/day (based on actual body weight) given subcutaneously in a randomized, phase III study in patients with chronic severe neutropenia (n = 123; median age of 12.1 years; range, 7 months to 76 years). In this study, the filgrastim dosage was adjusted to a level that maintained a median monthly ANC between 1,500 cells/mm3 and 10,000 cells/mm3. The dosage was increased if the median ANC was below 1,500 cells/mm3 for 2 weeks. The dosage was decreased if the median ANC was 10,000 cells/mm3 or greater for 4 weeks The median ANC was significantly improved in 62 patients who received 4 months of filgrastim compared with 60 patients who received 4 months of observation only (6.1 cells/mm3 vs. 0.21 cells/mm3; p-value of 0.001 or less). In patients with cyclic neutropenia, the median ANC was 9.88 cells/mm3 in the filgrastim arm (n = 10; median age of 10.7 years; range, 2.5 to 47.2 years) and 0.67 cells/mm3 in the observation only arm (n = 11; median age of 27.4 years; range, 10.5 to 59.1 years).

    In patients with myelodysplastic syndrome†.
    Intravenous or Subcutaneous dosage
    Adults

    5 mcg/kg/day IV/subcutaneous, rounded to the nearest vial size. Although data supporting the routine, long-term use of filgrastim is lacking, intermittent administration may be considered in patients with severe neutropenia and recurrent infection.

    For the treatment of severe chronic idiopathic neutropenia.
    NOTE: Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults, Adolescents, Children, and Infants 7 months and older

    5 mcg/kg subcutaneously once daily is recommended initially. Individualize the dosage to maintain clinical benefit based on patient clinical courses and absolute neutrophil count (ANC). In a postmarketing surveillance study in 731 patients (adults, n = 302; pediatric patients, n = 429), the median filgrastim dose was 1.2 mcg/kg/day in patients with idiopathic neutropenia. The starting dose for idiopathic neutropenia was 3.45 mcg/kg/day (based on actual body weight) given subcutaneously in a randomized, phase III study in patients with chronic severe neutropenia (n = 123). In this study, the filgrastim dosage was adjusted to a level that maintained a median monthly ANC between 1,500 cells/mm3 and 10,000 cells/mm3. The dosage was increased if the median ANC was below 1,500 cells/mm3 for 2 weeks. The dosage was decreased if the median ANC was 10,000 cells/mm3 or greater for 4 weeks The median ANC was significantly improved in 62 patients who received 4 months of filgrastim compared with 60 patients who received 4 months of observation only (6.1 cells/mm3 vs. 0.21 cells/mm3; p-value of 0.001 or less). In patients with idiopathic neutropenia, the median ANC was 9.72 cells/mm3 in the filgrastim arm (n = 21; median age of 28.5 years; range, 2.1 to 69.1 years) and 0.23 cells/mm3 in the observation only arm (n = 20; median age of 30.8 years; range, 1.3 to 75.7 years).

    For chemotherapy-induced neutropenia prophylaxis, to decrease the incidence of febrile neutropenia, in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.
    As primary prophylaxis in patients with nonmyeloid malignancies.
    Subcutaneous dosage
    Adults

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recommend the use of colony-stimulating factors (CSFs) for primary prophylaxis in patients who are at high-risk of developing febrile neutropenia (e.g., age greater than 65 years, prior episodes of febrile neutropenia, poor nutritional status, poor performance status, open wounds or active infections, combined chemoradiotherapy, history of extensive treatment including large radiation ports, tumor bone marrow involvement resulting in cytopenias, and advanced cancer), have other comorbidities, or who are receiving dose-dense chemotherapy with the intention of cure or a chemotherapy regimen with an expected incidence of febrile neutropenia of 20% or greater.

    Adolescents and Children

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recognize that the use of colony-stimulating factors are guided by clinical protocols. Filgrastim may be considered as primary prophylaxis in children who are at high-risk for febrile neutropenia.

    Intravenous dosage
    Adults

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recommend the use of colony-stimulating factors (CSFs) for primary prophylaxis in patients who are at high-risk of developing febrile neutropenia (e.g., age greater than 65 years, prior episodes of febrile neutropenia, poor nutritional status, poor performance status, open wounds or active infections, combined chemoradiotherapy, history of extensive treatment including large radiation ports, tumor bone marrow involvement resulting in cytopenias, and advanced cancer), have other comorbidities, or who are receiving dose-dense chemotherapy with the intention of cure or a chemotherapy regimen with an expected incidence of febrile neutropenia of 20% or greater.

    Adolescents and Children

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recognize that the use of colony-stimulating factors are guided by clinical protocols. Filgrastim may be considered as primary prophylaxis in children who are at high-risk for febrile neutropenia.

    Following induction or consolidation therapy in patients with acute myelogenous leukemia.
    Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size . Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology (ASCO) clinical guidelines suggest that colony-stimulating factors (CSFs) may be used after initial induction therapy; acute myelogenous leukemia (AML) patients aged greater than 55 years may benefit the most from post-induction CSF therapy. The benefit of shortening the duration of neutropenia has been demonstrated with post-consolidation CSF use in AML patients in remission; therefore, the ASCO guidelines recommend the use of CSFs in this setting.

    Adolescents and Children

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology (ASCO) clinical guidelines suggest that colony-stimulating factors (CSFs) may be used after initial acute myelogenous leukemia (AML) induction therapy. The benefit of shortening the duration of neutropenia has been demonstrated with post-consolidation CSF use in AML patients in remission; therefore, the ASCO guidelines recommend the use of CSFs in this setting.

    Intravenous dosage
    Adults

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size . Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology (ASCO) clinical guidelines suggest that colony-stimulating factors (CSFs) may be used after initial induction therapy; acute myelogenous leukemia (AML) patients aged greater than 55 years may benefit the most from post-induction CSF therapy. The benefit of shortening the duration of neutropenia has been demonstrated with post-consolidation CSF use in AML patients in remission; therefore, the ASCO guidelines recommend the use of CSFs in this setting.

    Adolescents and Children

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology (ASCO) clinical guidelines suggest that colony-stimulating factors (CSFs) may be used after initial acute myelogenous leukemia (AML) induction therapy. The benefit of shortening the duration of neutropenia has been demonstrated with post-consolidation CSF use in AML patients in remission; therefore, the ASCO guidelines recommend the use of CSFs in this setting.

    Following induction or consolidation therapy for acute lymphocytic leukemia†.
    Intravenous or Subcutaneous dosage
    Adults, Adolescents, and Children

    5 mcg/kg IV or subcutaneously daily, rounded to the nearest vial size, beginning 24 to 72 hours after completion of chemotherapy. Administration of filgrastim may shorten the duration of neutropenia (ANC less than 1,000/mm3) by approximately 1 week. Filgrastim may be given along with corticosteroid/antimetabolite therapy; concurrent therapy does not appear to prolong the myelosuppressive effect of the chemotherapy.

    As secondary prophylaxis in patients with nonmyeloid malignancies.
    Subcutaneous dosage
    Adults

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recommend the use of colony-stimulating factors (CSFs) for secondary prophylaxis in patients who had a neutropenic complication after a prior cycle of chemotherapy (when a CSF was not given as primary prophylaxis) and in situations that a chemotherapy dose reduction may compromise the disease-free or overall survival or treatment outcome.

    Adolescents and Children

    5 mcg/kg/day administered as a subcutaneous injection. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recognize that use of colony-stimulating factors is guided by clinical protocols. Filgrastim may be considered as secondary prophylaxis in children who are at high-risk for febrile neutropenia.

    Intravenous dosage
    Adults

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Consider rounding the dose to the nearest vial size. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recommend the use of colony-stimulating factors (CSFs) for secondary prophylaxis in patients who had a neutropenic complication after a prior cycle of chemotherapy (when a CSF was not given as primary prophylaxis) and in situations that a chemotherapy dose reduction may compromise the disease-free or overall survival or treatment outcome.

    Adolescents and Children

    5 mcg/kg/day administered as an IV infusion over 15 to 30 minutes or by continuous IV infusion. Based on the duration and severity of the absolute neutrophil count (ANC) nadir, the filgrastim dose may be escalated in increments of 5 mcg/kg for each cycle of chemotherapy. Discontinue filgrastim if the ANC is increased to greater than 10,000 cells/mm3. Treatment with filgrastim should be started between 24 and 72 hours after chemotherapy and continued until the ANC is at least 2,000 to 3,000 cells/mm3. The American Society of Clinical Oncology clinical guidelines recognize that use of colony-stimulating factors is guided by clinical protocols. Filgrastim may be considered as secondary prophylaxis in children who are at high-risk for febrile neutropenia.

    Following bone marrow transplantation in patients with nonmyeloid malignancies.
    Filgrastim has been designated an orphan drug by the FDA for this indication.
    Intravenous dosage
    Adults

    10 mcg/kg/day administered as an IV infusion; infuse over no longer than 24 hours. Treatment with filgrastim should be started no sooner than 24 hours after chemotherapy and 24 hours after bone marrow infusion. Titrate the daily dose according to the absolute neutrophil count (ANC) response. When the ANC is greater than 1000 cells/mm3 for 3 consecutive days, reduce the dose to 5 mcg/kg/day. After this dose reduction, discontinue filgrastim when the ANC remains greater than 1,000 cells/mm3 for 3 consecutive days; resume therapy at 5 mcg/kg/day if the ANC decreases to less than 1,000 cells/mm3 after drug discontinuation. If the ANC decreases to less than 1,000 cells/mm3 when a patient is receiving 5 mcg/kg/day, increase the dose to 10 mcg/kg/day. The American Society of Clinical Oncology clinical guidelines recommend colony-stimulating factors following an autologous peripheral blood stem-cell transplant.

    For peripheral blood stem cell (PBSC) mobilization prior to and during leukapheresis in cancer patients undergoing an autologous PBSC collection and therapy.
    Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults

    10 mcg/kg/day administered as a subcutaneous injection. Start at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis procedure. Although the optimal duration of administration and leukapheresis schedule have not been determined, a safe and effective schedule involved administration of filgrastim for 6 to 7 days, with leukapheresis on days 5, 6, and 7. Discontinue filgrastim if the white blood cell count is increased to greater than 100,000 cells/mm3.

    For the treatment of acute radiation exposure, to increase survival, in patients who receive myelosuppressive doses of radiation.
    Filgrastim has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults, Adolescents, Children, and Infants 7 months and older

    10 mcg/kg/day as a subcutaneous injection. Start filgrastim therapy as soon as possible after a patient received or is suspected of receiving a radiation dose greater than 2 gray (Gy). Use information from public health authorities, biodosimetry (if available), or clinical findings (e.g., time to onset of vomiting or lymphocyte depletion kinetics) to estimate a patient’s level of radiation exposure. Advise patients that efficacy for this indication was based on animal data in monkeys. Obtain a complete blood cell count panel prior to starting filgrastim (if access to laboratory testing is readily available) and then every 3 days during filgrastim therapy. Discontinue therapy when the absolute neutrophil count (ANC) is greater than 1,000 cells/mm3 for 3 consecutive days or the ANC is greater than 10,000 cells/mm3 after a radiation-induced nadir. The 60-day mortality rate was significantly decreased in non-human primates who received filgrastim compared with placebo (21% vs. 59%; p = 0.023) starting 1 day after acute myelosuppressive radiation exposure in a randomized, blinded, placebo-controlled study; this study was halted at an interim analysis. For ethical reasons, filgrastim could not be studied in human subjects with acute radiation exposure. Therefore, filgrastim 10 mcg/kg (n = 24) or placebo of 5% dextrose in water (n = 22) was administered as a once daily subcutaneous injection in rhesus macaques exposed to total body irradiation (TBI) of 7.4 +/- 0.15 Gy delivered at 0.8 +/- 0.03 Gy/minute. The TBI represented a dose that would be lethal in 50% of animals by 60 days of follow-up (LD 50/60). Treatment was stopped when the ANC was at least 1,000 cells/mm3 for 3 consecutive days, the ANC was at least 10,000 cells/mm3 for more than 2 consecutive days within study days 1 to 5, or the ANC was at least 10,000 cells/mm3 any time after study day 5. All animal subjects received supportive care including IV fluids, antibiotics, and blood transfusions. The timing of filgrastim administration appears important. The 60-day mortality rate was not significantly decreased in rhesus macaques who received filgrastim 10 mcg/kg compared with placebo of 5% dextrose in water (47.5% vs. 50%) as a daily subcutaneous injection starting 48 hours after exposure to TBI at approximately the LD 50/60 in a randomized, blinded, placebo-controlled study (n = 80); this study was stopped for futility at an interim analysis.

    For the treatment of aplastic anemia†.
    Subcutaneous dosage
    Adults, Adolescents, and Children

    In combination with immunosuppressive regimens (e.g., antithymocyte globulin and cyclosporine), filgrastim doses range from 300 to 480 mcg/day (5 mcg/kg/day) subcutaneously for 14 to 90 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: Maximum daily dosage is indication dependent.

    Adults

    IV, 30 mcg/kg/day; Subcutaneous, 24 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

    Geriatric

    IV, 30 mcg/kg/day; Subcutaneous, 24 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

    Adolescents

    Subcutaneous, 15 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

    Children

    Subcutaneous, 15 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

    Infants

    7 months or older: Subcutaneous, 12 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No filgrastim dosage adjustment in necessary in patients with hepatic impairment.

    Renal Impairment

    No filgrastim dosage adjustment in necessary in patients with renal impairment.

    ADMINISTRATION

    Injectable Administration

    Filgrastim may be administered as a subcutaneous injection, a short intravenous (IV) infusion, or as a continuous IV infusion.
    Do not administer filgrastim between 24 hours before and 24 hours after chemotherapy.
    Do not shake filgrastim vials or prefilled syringes; do not re-enter the vial or save unused drug for later administration.
    Store vials or prefilled syringes in the refrigerator between 36 to 46 degrees Fahrenheit (2 to 8 degrees Celsius) in the carton to protect from light.
    Avoid freezing filgrastim products. If frozen, thaw in the refrigerator; throw away if the product has been frozen more than once.
    Prior to use, allow filgrastim vials or prefilled syringes to reach room temperature for at least 30 minutes; discard any vial or prefilled syringe exposed to room temperature for more than 24 hours.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Only single-dose vials may be used to prepare IV infusion solutions; do not re-enter the vial or save unused drug for later administration.
    Dilution is recommended prior to use.
     
    Dilution:
    After calculating/selecting the appropriate dose, dilute the filgrastim vial (concentration of 300 mcg/mL) in 5% Dextrose Injection, USP to a final concentration of 5 mcg/mL or higher. Do NOT dilute with Normal Saline; the product may precipitate.
    Use a glass bottle, a polyvinyl chloride (PCV) or polyolefin IV bag, or a polypropylene syringe as a container for the diluted solution.
    To protect the absorption of filgrastim to the plastic container in diluted solutions at concentrations of 5 to 15 mcg/mL, add albumin to a final concentration of 2 mg/mL.
    Storage following dilution: filgrastim diluted solutions may be stored at room temperature for up to 24 hours; the total storage time includes the infusion time.
     
    Intravenous infusion:
    Administer the diluted IV infusion over 15 to 30 minutes or as a continuous IV infusion given over up to 24 hours.

    Subcutaneous Administration

    Single-dose filgrastim vials (Neupogen) or filgrastim prefilled-syringes (Neupogen or Zarxio) may be used for subcutaneous injections.
    Patient or caregiver may administer after being properly trained on storage, preparation, and administration technique. Follow instructions for use provided by manufacturer.
    No dilution is necessary.
    Subcutaneous Injection Using Prefilled Syringe:
    Do not activate the needle guard prior to injection; pull the needle cover straight off.
    The Zarxio prefilled syringe is not designed to administer doses less than 0.3 mL (180 mcg).
    Inject filgrastim in a recommended injection site (i.e., the outer area of the upper arm, the abdomen excluding the 2-inch area around the navel, the front of the middle thigh, and the upper outer areas of the buttocks).
    Do not recap the needle; slide the needle guard over the needle until the needle is completely covered and the needle guard clicks into place.
     
    Subcutaneous Injection Using Single-Use Vials:
    Withdraw the contents of the vial into a syringe.
    Inject filgrastim in a recommended injection site (i.e., the outer area of the upper arm, the abdomen excluding the 2-inch area around the navel, the front of the middle thigh, and the upper outer areas of the buttocks).

    STORAGE

    Neupogen:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard product if stored above 77 degrees F for more than 24 hours
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Prior to use, product may be allowed to reach room temperature for a maximum of 24 hours
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Refrigerated product should reach room temperature before administration
    - Store in original container
    Zarxio:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard product if stored above 77 degrees F for more than 24 hours
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Prior to use, product may be allowed to reach room temperature for a maximum of 24 hours
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Refrigerated product should reach room temperature before administration
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    E. coli protein hypersensitivity

    Filgrastim is contraindicated for use in patients with a history of serious allergic reactions to granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim or any other component of the product (e.g., E. coli protein hypersensitivity). Serious allergic reactions (e.g., anaphylaxis) have been reported with filgrastim use. Most reactions occurred with the first dose and some reactions recurred days after treatment with anti-allergy medications. Permanently discontinue filgrastim in patients who experience a serious allergic reaction.

    Radiation therapy

    In general, avoid the use of hematopoietic colony-stimulating factors (CSFs), such as filgrastim, in patients receiving concomitant chemotherapy and radiation therapy, particularly in patients receiving mediastinum radiation. In patients receiving radiation therapy alone, consider the use of CSFs if prolonged delays due to neutropenia are expected.

    Hypersplenism

    Splenic rupture has been reported with filgrastim therapy; some cases were fatal. Evaluate patients who have left upper abdominal or shoulder pain for evidence of hypersplenism (splenomegaly) or splenic rupture.

    Respiratory distress syndrome

    Acute respiratory distress syndrome (ARDS) has been reported with filgrastim therapy. Evaluate patients who have signs (e.g., lung infiltrates) or who develop symptoms (e.g., fever, respiratory distress) of ARDS. Discontinue filgrastim if a patient is diagnosed with ARDS.

    Sickle cell disease

    Use filgrastim with caution in patients with sickle cell disease or sickle cell trait because sickle cell crises have been reported in this patient population; some cases were fatal. Monitor patients with sickle cell disease for signs and symptoms of sickle cell crises such as pain or difficulty breathing.

    Leukocytosis, thrombocytopenia

    Filgrastim stimulates the production of hematopoietic stem cells and leukocytosis (white blood cell (WBC) count >= 100,000 cells/mm3) has been reported. Thrombocytopenia has also occurred with filgrastim use. When filgrastim is used following myelosuppressive chemotherapy, obtain a complete blood count (CBC) panel including differential and platelets at least twice weekly during therapy; discontinue filgrastim if the absolute neutrophil count (ANC) is greater than 10,000 cells/mm3 (after the chemotherapy-induced ANC nadir occurs). The ANC usually decreases by 50% within 1 to 2 days after filgrastim is discontinued, then neutrophil counts return to pretreatment levels in 1 to 7 days. When filgrastim is used for peripheral blood progenitor cell mobilization, obtain a CBC panel 4 days after starting therapy; discontinue filgrastim if the WBC count is greater than 100,000 cells/mm3. When filgrastim is used following a bone marrow transplantation, obtain a CBC panel including differential frequently and titrate the daily filgrastim dose based on the ANC. In patients with severe chronic neutropenia, monitor the CBC with differential during the initial 4 weeks of therapy and during the 2 weeks following dosage adjustments. Begin monthly monitoring throughout the first year of therapy when the patient is clinically stable; thereafter, monitoring may be less frequent if the neutrophil count remains stable.

    Leukemia

    Filgrastim stimulates the production of hematopoietic stem cells, primarily neutrophils, and it may act as a growth factor for myeloid cells in myeloid malignancies. Therefore, filgrastim is not indicated for use in patients with chronic myelogenous leukemia or myelodysplastic syndrome (MDS). Patients with congenital neutropenia had an increased risk of developing MDS and acute myelogenous leukemia in postmarketing surveillance of filgrastim. Because the risk of developing a myeloid malignancy is increased in patients with abnormal cytogenetics or MDS, perform a risk/benefit analysis in patients with congenital neutropenia who develop abnormal cytogenetics or myelodysplasia. Additionally, increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

    Latex hypersensitivity

    The needle cap on the single-use prefilled filgrastim syringe contains dry natural rubber. Health care workers or patients with a latex hypersensitivity should not handle or administer this product. Patients with a latex hypersensitivity should receive this product with caution.

    Vasculitis

    Moderate to severe cutaneous vasculitis has been reported in patients who have received filgrastim; most cases occurred in patients with severe chronic neutropenia who received long-term filgrastim therapy. Interrupt therapy in patients who develop cutaneous vasculitis; consider restarting filgrastim at a reduced dosage after the symptoms resolve if the neutrophil count drops.

    Pulmonary bleeding

    Pulmonary bleeding/alveolar hemorrhage requiring hospitalization has been reported in healthy subjects who received filgrastim for peripheral blood progenitor cell mobilization and collection; use of filgrastim in this population is not a FDA-approved indication. Hemoptysis resolved when filgrastim was discontinued.

    Obstetric delivery

    Transplacental filgrastim passage has been reported in pregnant women when filgrastim was administered up to 30 hours prior to preterm obstetric delivery (30 weeks gestation or less).

    Pregnancy

    Filgrastim is classified as FDA pregnancy risk category C. No adequate or well controlled human studies have been conducted; no fetal malformations were observed in rabbit and rat studies. Advise females of reproductive potential to use filgrastim only if the potential benefit justifies the potential risk to the fetus.

    Breast-feeding

    Caution is advised by the manufacturer when administering filgrastim to a woman who is breast-feeding her infant. Of note, recombinant filgrastim is poorly secreted into breast milk, and filgrastim is not orally absorbed by neonates. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    splenic rupture / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    sickle-cell crisis / Delayed / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    azotemia / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 5.0-38.0
    bone pain / Delayed / 5.0-30.0
    chest pain (unspecified) / Early / 5.0-13.0
    dyspnea / Early / 13.0-13.0
    antibody formation / Delayed / 3.0-3.0
    hypertension / Early / 5.0
    anemia / Delayed / 5.0
    splenomegaly / Delayed / 5.0
    erythema / Early / 2.0
    constipation / Delayed / 2.0
    peripheral edema / Delayed / 5.0
    osteoporosis / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    edema / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known

    Mild

    fever / Early / 16.0-48.0
    nausea / Early / 43.0-43.0
    back pain / Delayed / 2.0-15.0
    dizziness / Early / 14.0-14.0
    cough / Delayed / 14.0-14.0
    rash (unspecified) / Early / 5.0-14.0
    headache / Early / 10.0-10.0
    arthralgia / Delayed / 5.0-9.0
    leukocytosis / Delayed / 2.0-2.0
    muscle cramps / Delayed / 5.0
    musculoskeletal pain / Early / 5.0
    hypoesthesia / Delayed / 5.0
    epistaxis / Delayed / 2.0
    maculopapular rash / Early / 2.0
    alopecia / Delayed / 5.0
    vomiting / Early / 5.0
    anorexia / Delayed / 5.0
    diarrhea / Early / 2.0
    malaise / Early / 5.0
    fatigue / Early / 20.0
    asthenia / Delayed / 5.0
    infection / Delayed / 5.0
    insomnia / Early / 5.0

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Alemtuzumab: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Alpha interferons: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Altretamine: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Antimetabolites: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Bevacizumab: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Bexarotene: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Chlorambucil: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim, is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Cladribine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Clofarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with filgrastim, G-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF.
    Denileukin Diftitox: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Docetaxel: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Estramustine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fludarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Ibritumomab Tiuxetan: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Ifosfamide: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, and filgrastim induces the proliferation of neutrophil-progenitor cells, filgrastim, G-CSF and tbo-filgrastim should not be used in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Lithium: (Moderate) Lithium prompts the release of neutrophils and should be used with caution during filgrastim therapy. White blood cell counts above 100,000 cells/mm3 represent a medical emergency because of the risk of serious adverse effects such as brain infarction, respiratory failure, intracranial hemorrhage, retinal hemorrhage, myocardial infarction, and acute limb ischemia. Patients receiving lithium and filgrastim or pegfilgrastim should have more frequent monitoring of WBC counts.
    Lomustine, CCNU: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Mercaptopurine, 6-MP: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Methotrexate: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Natural Antineoplastics: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Nelarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Paclitaxel: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Pentostatin: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Topotecan: (Major) Do not initiate colony stimulating factors until 24 hours after completion of topotecan treatment; concomitant administration may prolong the duration of neutropenia. This may also apply to sargramostim, GM-CSF.
    Tositumomab: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tretinoin, ATRA: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Filgrastim is classified as FDA pregnancy risk category C. No adequate or well controlled human studies have been conducted; no fetal malformations were observed in rabbit and rat studies. Advise females of reproductive potential to use filgrastim only if the potential benefit justifies the potential risk to the fetus.

    Caution is advised by the manufacturer when administering filgrastim to a woman who is breast-feeding her infant. Of note, recombinant filgrastim is poorly secreted into breast milk, and filgrastim is not orally absorbed by neonates. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein involved in the regulation and production of neutrophils in response to host defense needs. Filgrastim has the same biologic activity as native G-CSF. The production of G-CSF can be induced by exposure to bacterial cell wall proteins, endotoxin, or proinflammatory cytokines (e.g., interleukin (IL)-1, IL-17, interferon gamma, or tumor necrosis factor). Cells responsible for the production of G-CSF include monocytes and macrophages, endothelial cells, fibroblasts, and bone marrow stromal cells. Normally, G-CSF plasma levels are low or undetectable, but in response to bacterial stimuli, the levels are rapidly and markedly elevated. G-CSF acts on a specific receptor located on hematopoietic progenitor cells and mature neutrophils. G-CSF is also important for the survival of multilineage hematopoietic stem cells, but it cannot sustain their proliferation or differentiation.
     
    Administration of exogenous G-CSF results in increased total neutrophil counts, including mature, banded, and precursor neutrophils, without increasing the number of basophils, eosinophils, or monocytes. The rise in neutrophils is due to increased production by the bone marrow and not increased survival of neutrophils. Morphological changes in neutrophils, including densely staining secondary cytoplasmic granules and Dohle bodies, have been observed following administration of exogenous G-CSF. The morphological changes are similar to those seen in neutrophils during infection and are consistent with changes seen in functionally "primed" neutrophils. G-CSF activates polymorphic neutrophils (PMNs) by mobilizing secretory vesicles and inducing the release of granules, which enhance bacterial cytotoxicity. G-CSF also affects selected neutrophil functions including enhanced phagocytic ability, priming of cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some functions associated with cell surface antigens. Exogenous G-CSF increases the number of circulating hematopoietic progenitor cells in a dose-dependent manner. Hematopoietic stem and progenitor cell mobilization is thought to be related to the ability of G-CSF to downregulate endothelial intercellular adhesion molecule 1 (ICAM-1), and upregulate vascular cell adhesion molecule-1.

    PHARMACOKINETICS

    Filgrastim is administered intravenously (IV) or subcutaneously. In both healthy subjects and cancer patients, the volume of distribution averaged 150 mL/kg, the elimination half-life was about 3.5 hours, and the clearance was about 0.5 to 0.7 mL/min/kg following IV filgrastim administration. The half-life of filgrastim is similar following IV (231 minutes) or subcutaneous (210 minutes) administration. Additionally, single IV doses or daily IV doses resulted in comparable half-life values. Filgrastim is cleared by the kidney. Clearance is nonlinear and is dependent on drug concentration and neutrophil count. High filgrastim concentrations result in saturated granulocyte colony-stimulating factor receptors and neutropenia leads to decreased clearance. A dose-dependent increase in circulating neutrophil counts occurred following filgrastim administration (dose range, 1 to 70 mcg/kg/day) in patients with nonmyeloid malignancies in phase I studies. This dose-dependent neutrophil increase occurred with IV (1 to 70 mcg/kg twice daily), subcutaneous (1 to 3 mcg/kg once daily), or continuous subcutaneous infusion (3 to 11 mcg/kg/day) administration. In most cases, the neutrophil count returned to baseline within 4 days of stopping filgrastim.

    Intravenous Route

    The steady state concentration was achieved and there was no evidence of drug accumulation when filgrastim 20 mcg/kg/day was given as a continuous 24-hour IV infusion over 11 to 20 days.

    Subcutaneous Route

    The absolute bioavailability of filgrastim is 60% to 70% following subcutaneous administration. The Cmax was 4 and 49 nanograms/mL following subcutaneous filgrastim doses of 3.45 mcg/kg and 11.5 mcg/kg, respectively. The Tmax ranged from 2 to 8 hours.