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  • CLASSES

    Colony-stimulating Factors

    DEA CLASS

    Rx

    DESCRIPTION

    Granulocyte-macrophage colony-stimulating factor (GM-CSF)
    Used to help increase white blood cell production after bone marrow transplantation (BMT), after BMT failure or engraftment delay, before and after stem-cell transplant, and after induction chemotherapy in older patients with acute myelogenous leukemia
    Also used to treat acute radiation exposure in patients who received myelosuppressive doses of radiation

    COMMON BRAND NAMES

    Leukine

    HOW SUPPLIED

    Leukine Intravenous Inj Pwd F/Sol: 250mcg
    Leukine Intravenous Inj Sol: 1mL, 500mcg
    Leukine Subcutaneous Inj Pwd F/Sol: 250mcg
    Leukine Subcutaneous Inj Sol: 1mL, 500mcg

    DOSAGE & INDICATIONS

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

    150 to 250 mcg/m2/day subcutaneously or IV once daily or 2 to 3 times weekly. Some patients have been treated continuously for up to 6 months. Sargramostim therapy ameliorates the neutropenia due to antiviral agents and other myelosuppressive agents in HIV-infected patients. Although clinical experience with sargramostim in the treatment of opportunistic infections is limited, beneficial effects have been reported in case reports and small studies. The CDC does not routinely recommend this dosage in HIV patients.

    In patients with myelodysplastic syndrome (MDS)†.
    Intravenous dosage
    Adults

    Dosages used range from 150 to 500 mcg/m2/day subcutaneously or IV over 1 to 12 hours. Although data supporting the routine, long-term use of sargramostim is lacking, intermittent administration may be considered in patients with severe neutropenia and recurrent infection.

    Following an autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma, acute lymphoblastic leukemia, or Hodgkin's disease.
    Intravenous dosage
    Adults, Adolescents, and Children 2 years and older

    250 mcg/m2 IV over 2 hours once daily starting 2 to 4 hours after the bone marrow infusion; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy. Start sargramostim when the post-bone marrow infusion absolute neutrophil count (ANC) is less than 500 cells/mm3 and continue until the ANC is greater than 1,500 cells/mm3 for 3 consecutive days. Do not administer sargramostim within 24 hours before or after chemotherapy or radiotherapy. Sargramostim therapy has demonstrated efficacy in shortening the time to neutrophil recovery and in reducing the duration of antibiotic use, infection, and hospitalization.

    Following peripheral blood stem cell (PBSC) transplantation.
    Intravenous dosage
    Adults, Adolescents, and Children 2 years and older

    250 mcg/m2 IV over 24 hours once daily starting immediately after the PBSC infusion and continuing until the absolute neutrophil count is greater than 1,500 cells/mm3 for 3 consecutive days. Do not administer sargramostim within 24 hours before or after chemotherapy or radiotherapy.

    Subcutaneous dosage
    Adults, Adolescents, and Children 2 years and older

    250 mcg/m2 subcutaneously once daily starting immediately after the PBSC infusion and continuing until the absolute neutrophil count is greater than 1,500 cells/mm3 for 3 consecutive days. Do not administer sargramostim within 24 hours before or after chemotherapy or radiotherapy.

    Following engraftment failure or delay after an autologous or allogeneic bone marrow transplantation.
    Intravenous dosage
    Adults, Adolescents, and Children 2 years and older

    250 mcg/m2 IV over 2 hours once daily for 14 days. If neutrophil recovery has not occurred after 7 days off treatment, this dose can be repeated. If neutrophil recovery still has not occurred after 7 days off the second course of treatment, increase the dose to 500 mcg/m2 IV once daily for 14 days. If there is still no improvement after this third course of treatment, it is unlikely that further dose escalation will be beneficial. In patients who develop a grade 3 or 4 adverse reaction, reduce the sargramostim dose by 50% or interrupt therapy until the reaction abates. Interrupt therapy or reduce the sargramostim dose by 50% in patients who develop a white blood cell count greater than 50,000 cells/mm3 or an absolute neutrophil count greater than 20,000 cells/mm3. Discontinue sargramostim if blast cells appear or if disease progression occurs.

    Following an allogeneic bone marrow transplantation from HLA-matched related donors.
    Intravenous dosage
    Adults, Adolescents, and Children 2 years and older

    250 mcg/m2 IV over 2 hours once daily starting 2 to 4 hours after the bone marrow infusion; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy. Start sargramostim when the post-bone marrow infusion absolute neutrophil count (ANC) is less than 500 cells/mm3 and continue until the ANC is greater than 1,500 cells/mm3 for 3 consecutive days. Do not administer sargramostim within 24 hours before or after chemotherapy or radiotherapy. In patients who develop a grade 3 or 4 adverse reaction, reduce the sargramostim dose by 50% or interrupt therapy until the reaction abates. Interrupt therapy or reduce the sargramostim dose by 50% in patients who develop a white blood cell count greater than 50,000 cells/mm3 or an absolute neutrophil count greater than 20,000 cells/mm3. Discontinue sargramostim if blast cells appear or if disease progression occurs. Sargramostim therapy has demonstrated efficacy in shortening the time to neutrophil recovery, reducing the incidence of bacteremia and other culture positive infections, and reducing the duration of hospitalization.

    For peripheral blood stem cell (PBSC) mobilization for collection by leukapheresis.
    Intravenous dosage
    Adults

    250 mcg/m2 IV over 24 hours once daily. Continue therapy at the same dose through the period of PBPC collection. Although the optimal schedule for PBSC collection has not been established, collection of PBSC was usually begun after 5 days and performed daily until protocol specified targets were achieved in clinical trials. Reduce the dose by 50% in patients who develop a white blood cell count greater than 50,000 cells/mm3. Consider other mobilization therapy if an adequate number of PBSC are not collected.

    Subcutaneous dosage
    Adults

    250 mcg/m2 subcutaneously once daily. Continue therapy at the same dose through the period of PBPC collection. Although the optimal schedule for PBSC collection has not been established, collection of PBSC was usually begun after 5 days and performed daily until protocol specified targets were achieved in clinical trials. Reduce the dose by 50% in patients who develop a white blood cell count greater than 50,000 cells/mm3. Consider other mobilization therapy if an adequate number of PBSC are not collected.

    For chemotherapy-induced neutropenia prophylaxis.
    As primary prophylaxis following induction therapy in older patients with acute myelogenous leukemia.
    Intravenous dosage
    Adults 55 years or older

    250 mcg/m2 IV over 4 hours once daily starting approximately on day 11 or starting 4 days after the completion of induction chemotherapy if the day 10 bone marrow is hypoplastic with less than 5% blasts. If a second induction cycle of chemotherapy is given, give 250 mcg/m2 IV over 4 hours once daily starting approximately 4 days after chemotherapy completion if the bone marrow is hypoplastic with less than 5% blasts. Continue sargramostim until the absolute neutrophil count (ANC) is greater than 1,500 cells/mm3 for 3 consecutive days or until a maximum of 42 days. Do not administer sargramostim within 24 hours before or after chemotherapy or radiotherapy. In patients who develop a grade 3 or 4 adverse reaction, reduce the sargramostim dose by 50% or interrupt therapy until the reaction abates. Interrupt therapy or reduce the sargramostim dose by 50% in patients who have an absolute neutrophil count greater than 20,000 cells/mm3. Discontinue sargramostim if leukemic regrowth occurs. Sargramostim therapy has demonstrated efficacy in shortening the time to neutrophil recovery and reducing the incidence of severe and life-threatening infections and infections resulting in death.

    In patients with malignancies other than acute myelogenous leukemia†.
    Intravenous or Subcutaneous dosage
    Adults, Adolescents and Children

    Doses have ranged from 125 to 500 mcg/m2 per day subcutaneously or IV beginning 24 to 72 hours after completion of chemotherapy; the most common dosage is 250 mcg/m2per day subcutaneously. Therapy should be continued for 7 to 14 days, until the absolute neutrophil count (ANC) reaches a clinically adequate neutrophil count. Usually, sargramostim therapy is stopped when the ANC is greater than 1500/mm3 for 3 consecutive days.

    For the treatment of acute radiation exposure, to increase survival, in patients who receive myelosuppressive doses of radiation.
    NOTE: Sargramostim has been designated as an orphan drug by the FDA for the treatment of individuals acutely exposed to myelosuppressive doses of radiation.
    Subcutaneous dosage
    Adults

    7 micrograms/kg subcutaneously once daily in patients weighing greater than 40 kg; administer as soon as possible after suspected or confirmed exposure to radiation doses 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. 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 sargramostim 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 United States government has included sargramostim in the Strategic National Stockpile as a treatment option for hematologic acute radiation syndrome (H-ARS). This decision was based on data from animal studies (mice, canines, rhesus monkeys) and a limited number of human radiation accident victims, which indicated drug efficacy in promoting neutrophil recovery and improving survival following exposure to lethal or sub-lethal doses of radiation. In a majority of the animal studies, treatment resulted in enhanced survival with decreased duration of neutropenia, decreased time for neutrophil recovery, improved neutrophil nadir, and increased WBC counts; however, in one canine study, treatment was not effective in promoting hematopoietic recovery or improving survival. Data in humans is limited, with a total of 21 radiation exposures being treated with sargramostim since the 1986 Chernobyl accident. Although treatment benefits have been observed, determining the drugs role is difficult due to the variable and delayed manner in which sargramostim was administered. Therefore, in order to develop use of sargramostim as a countermeasure against radiological and nuclear threats, the government (with authority from the Project BioShield Act of 2004) has worked with the manufacturer to support additional studies.

    Adolescents and Children

    Dose based on weight as follows: sargramostim 12 micrograms (mcg)/kg subcutaneously once daily in patients weighing less than 15 kg; sargramostim 10 mcg/kg subcutaneously once daily in patients weighing 15 to 40 kg; OR sargramostim 7 mcg/kg subcutaneously once daily in patients weighing greater than 40 kg. Administer as soon as possible after suspected or confirmed exposure to radiation doses 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. 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 sargramostim 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 United States government has included sargramostim in the Strategic National Stockpile as a treatment option for hematologic acute radiation syndrome (H-ARS). This decision was based on data from animal studies (mice, canines, rhesus monkeys) and a limited number of human radiation accident victims, which indicated drug efficacy in promoting neutrophil recovery and improving survival following exposure to lethal or sub-lethal doses of radiation. In a majority of the animal studies, treatment resulted in enhanced survival with decreased duration of neutropenia, decreased time for neutrophil recovery, improved neutrophil nadir, and increased WBC counts; however, in one canine study, treatment was not effective in promoting hematopoietic recovery or improving survival. Data in humans is limited, with a total of 21 radiation exposures being treated with sargramostim since the 1986 Chernobyl accident. Although treatment benefits have been observed, determining the drugs role is difficult due to the variable and delayed manner in which sargramostim was administered. Therefore, in order to develop use of sargramostim as a countermeasure against radiological and nuclear threats, the government (with authority from the Project BioShield Act of 2004) has worked with the manufacturer to support additional studies.

    Infants and Neonates

    12 micrograms/kg subcutaneously once daily in patients weighing less than 15 kg; administer as soon as possible after suspected or confirmed exposure to radiation doses 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. 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 sargramostim 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 United States government has included sargramostim in the Strategic National Stockpile as a treatment option for hematologic acute radiation syndrome (H-ARS). This decision was based on data from animal studies (mice, canines, rhesus monkeys) and a limited number of human radiation accident victims, which indicated drug efficacy in promoting neutrophil recovery and improving survival following exposure to lethal or sub-lethal doses of radiation. In a majority of the animal studies, treatment resulted in enhanced survival with decreased duration of neutropenia, decreased time for neutrophil recovery, improved neutrophil nadir, and increased WBC counts; however, in one canine study, treatment was not effective in promoting hematopoietic recovery or improving survival. Data in humans is limited, with a total of 21 radiation exposures being treated with sargramostim since the 1986 Chernobyl accident. Although treatment benefits have been observed, determining the drugs role is difficult due to the variable and delayed manner in which sargramostim was administered. Therefore, in order to develop use of sargramostim as a countermeasure against radiological and nuclear threats, the government (with authority from the Project BioShield Act of 2004) has worked with the manufacturer to support additional studies.

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

    Sargramostim is usually used in combination with erythropoietin or immunosuppressive therapy (e.g., antithymocyte globulin and cyclosporine) for the treatment of aplastic anemia. Usual doses are 250 to 500 mcg/day or 5 mcg/kg/day subcutaneous for 14 to 90 days, depending upon the treatment regimen.

    For the treatment of malignant melanoma†.
    For the adjuvant treatment of malignant melanoma following surgery for stage III or IV melanoma in patients at high-risk for recurrence†.
    Subcutaneous dosage
    Adults

    The optimal effective dose has not been established. In a phase II trial, sargramostim 125 mcg/m2/day was given subcutaneously for 14 days, alternating with 14 days off therapy following surgery for 1 year or until disease progression. In comparison to matched historical controls, the overall survival of 48 patients treated with sargramostim was significantly increased in all patients (37.5 months vs. 12.2 months).

    For the treatment of unresectable or metastatic malignant melanoma following no more than 1 prior therapy, in combination with ipilimumab†.
    Subcutaneous dosage
    Adults

    250 mcg subcutaneously on days 1 through 14 repeated every 3 weeks for 4 cycles in combination with ipilimumab 10 mg/kg (actual body weight) IV on day 1 repeated every 3 weeks for 4 cycles as induction therapy was evaluated in a randomized, phase IIb study. In patients with stable disease or better, maintenance therapy consisted of sargramostim 250 mcg subcutaneously on days 1 through 14 repeated every 3 weeks (starting on cycle 5) and ipilimumab 10 mg/kg (actual body weight) IV on day 1 repeated every 12 weeks (starting on cycle 8). At a median follow-up of 13.3 months, median overall survival was significantly improved with combination therapy of ipilimumab plus GM-CSF compared to single-agent ipilimumab (17.5 months vs. 12.7 months; p = 0.01).

    For the treatment of neuroblastoma†.
    For the treatment of relapsed or refractory, high-risk neuroblastoma in the bone or bone marrow in patients who have demonstrated a partial response, minor response, or stable disease to prior therapy, in combination with naxitamab†.
    NOTE: Naxitamab is FDA approved in combination with sargramostim for this indication.
    Subcutaneous dosage
    Adults, Adolescents, and Children

    250 mcg/m2 subcutaneously daily for 5 doses starting 5 days prior to the day 1 naxitamab infusion followed by sargramostim 500 mcg/m2 subcutaneously daily on days 1, 2, 3, 4, and 5 repeated each cycle in combination with naxitamab. Administer naxitamab 3 mg/kg (maximum dose of 150 mg) IV on days 1, 3, and 5. Administer sargramostim at least 1 hour prior to the naxitamab infusion on days that both drugs are given. Repeat treatment cycles every 4 weeks until complete response (CR) or partial response (PR). Continue treatment every 4 weeks for 5 additional cycles after CR/PR; subsequent cycles may be repeated every 8 weeks until disease progression. The overall response rate (ORR) was 45% (CR rate, 36%) in pediatric patients (median age, 5 years; range, 3 to 10 years) with refractory or relapsed, high-risk neuroblastoma who received treatment with naxitamab and sargramostim in a multicenter, single-arm trial (n = 22). In another single-arm trial, the ORR was 34% (CR, 26%) in a subpopulation of patients (n = 38; median age, 5 years; range, 2 to 23 years) with relapsed or refractory, high-risk neuroblastoma who received treatment with naxitamab and sargramostim. In these trials, response was assessed by revised International Neuroblastoma Response Criteria.  

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    500 mcg/m2 IV daily or 250 mcg/m2 subcutaneously daily.

    Geriatric

    500 mcg/m2 IV daily or 250 mcg/m2 subcutaneously daily.

    Adolescents

    250 mcg/m2 IV daily.

    Children

    2 years and older: 250 mcg/m2 IV daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Injectable Administration

    Sargramostim is available as a 500-mcg/mL multiple-dose liquid vial and a lyophilized 250-mcg powder vial for single use.
    It may be administered as an intravenous (IV) infusion or a subcutaneous injection; route of administration differs depending on the indication.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Both the liquid formulation and the reconstituted lyophilized powder should be clear and colorless.
     
    Reconstitution of Lyophilized Powder Vial:
    Add 1 mL of Sterile Water for Injection or Bacteriostatic Water for Injection to the 250-mcg lyophilized powder vial for a final concentration of 250 mcg/mL.
    Always use Sterile Water for Injection to reconstitute vials for use in neonates or infant.
    Do not mix together the contents of vials reconstituted with different diluents.
    Storage following reconstitution: store in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F) and use within 6 hours of reconstitution or dilution for IV infusion; do not freeze.
     
    Storage of Liquid Vial: Once the multiple-dose vial is punctured, store in the refrigerator for up to 20 days.

    Intravenous Administration

    Dilution:
    Further dilute the appropriate sargramostim dose in 0.9% Sodium Chloride injection.
    If the final concentration of the admixture is below 10 mcg/mL, add albumin (final concentration of 0.1%) to the admixture before adding the sargramostim to prevent drug adsorption to the drug delivery system. For example, add 1 mL of 5% albumin (human) to 50 mL of 0.9% Sodium Chloride injection.
     
    IV Infusion:
    Administer the diluted admixture IV over 2, 4, or 24 hours; infusion time depends on the indication for use.
    Do NOT use an in-line membrane filter during administration because drug adsorption may occur.
    If compatibility and stability information are unavailable, do NOT mix other drugs with the sargramostim admixture.

    Subcutaneous Administration

    No further dilution of the liquid vial or reconstituted vial is required prior to subcutaneous injection.
    Patient or caregiver may administer after being properly trained on storage, preparation, and administration technique. Follow instructions for use provided by manufacturer.

    STORAGE

    Leukine:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Leukocytosis

    Severe leukocytosis may occur with sargramostim use; leukocytosis is reversible and typically resolves or returns to baseline within 3 to 7 days when sargramostim is discontinued. Obtain a complete blood count panel with differential twice weekly. Based on the clinical condition of the patient, either interrupt therapy or reduce the sargramostim dose by 50% in patients who develop severe leukocytosis.

    Leukemia

    Because sargramostim is a growth factor that simulates normal myeloid precursor cells, it may act as a growth factor for certain types of tumor cells. Therefore, use sargramostim with caution in patients with myeloid malignancies such as myelogenous leukemia. Discontinue sargramostim if disease progression occurs during therapy.

    Edema, heart failure, pericardial effusion, pleural effusion

    Patients with pre-existing pleural effusion, pericardial effusion, fluid retention/edema, pulmonary infiltrates, or congestive heart failure may be at increased risk of developing severe fluid retention; use sargramostim with caution in these patients. Monitor body weight and hydration status during sargramostim therapy. An interruption of therapy or a dose reduction with or without diuretic therapy may lessen or alleviate sargramostim-induced fluid retention.

    Cardiac arrhythmias, cardiac disease

    Patients with a history of cardiac arrhythmias or cardiac disease may be at increased risk of developing serious arrhythmias; use sargramostim with caution in these patients.

    Chemotherapy, radiation therapy

    Do not administer sargramostim within 24 hours before or after chemotherapy or radiation therapy because of the potential sensitivity of rapidly dividing hematopoietic progenitor cells. Concomitant use of sargramostim with chemotherapy or radiation therapy may result in a higher incidence of chemotherapy- or radiation-related adverse events (e.g., severe infection, thrombocytopenia).[61087]

    Benzyl alcohol hypersensitivity, neonates

    Liquid sargramostim solutions and lyophilized sargramostim reconstituted with bacteriostatic water for injection contain benzyl alcohol (11 mg and 9 mg of benzyl alcohol per mL, respectively) and should not be given to patients with benzyl alcohol hypersensitivity or to neonates. Benzyl alcohol may cause fatal 'gasping syndrome' in neonates and low birth weight infants. Consider using lyophilized sargramostim reconstituted with sterile water for injection. If a sargramostim product containing benzyl alcohol is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources.

    Infusion-related reactions, pulmonary disease

    Infusion-related reactions have been reported with sargramostim use, typically following the first dose in a therapy cycle; patients with pre-existing pulmonary disease may be at increased risk of developing a reaction. Infusion reactions usually resolve with symptomatic treatment and do not recur with subsequent doses given in the same therapy cycle. Monitor patients for symptoms of an infusion-related reaction. Reduce the sargramostim rate of infusion by 50% in patients who develop dyspnea or other acute symptoms. Discontinue the sargramostim infusion in patients who have persistent or worsening symptoms despite the rate reduction. In patients who have had an infusion reaction, subsequent sargramostim infusions may be administered following the standard dose schedule with careful monitoring.[61087]

    Pregnancy

    Sargramostim may cause fetal harm when administered to a pregnant woman, based on data from animal studies. Discuss the potential hazard to the fetus if sargramostim is used during pregnancy or if a patient becomes pregnant while taking this drug; additionally, only use the lyophilized sargramostim formulation reconstituted with sterile water for injection in pregnant women. Increased spontaneous abortion was observed in pregnant rabbits who received sargramostim at doses that resulted in drug exposures that were 1.3-times or higher than those observed with the recommended human dose.[61087]

    Breast-feeding

    Endogenous GM-CSF is excreted in breast milk and appears to be inactivated or not absorbed from the gastrointestinal tract. According to the manufacturer, it is not known if sargramostim is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during sargramostim therapy and for at least 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    pericardial effusion / Delayed / 4.0-25.0
    hematemesis / Delayed / 0-13.0
    GI bleeding / Delayed / 0-11.0
    ocular hemorrhage / Delayed / 0-11.0
    pleural effusion / Delayed / 1.0-1.0
    capillary leak syndrome / Early / 0-1.0
    nephrotoxicity / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    antibody formation / Delayed / 1.3-97.7
    hypoalbuminemia / Delayed / 0-36.0
    hypertension / Early / 0-34.0
    hyperbilirubinemia / Delayed / 0-30.0
    hyperglycemia / Delayed / 0-25.0
    bone pain / Delayed / 0-21.0
    bleeding / Early / 0-17.0
    hypercholesterolemia / Delayed / 0-17.0
    chest pain (unspecified) / Early / 0-15.0
    dyspnea / Early / 0-15.0
    hypomagnesemia / Delayed / 0-15.0
    peripheral edema / Delayed / 11.0-11.0
    sinus tachycardia / Rapid / 0-11.0
    dysphagia / Delayed / 0-11.0
    eosinophilia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    erythema / Early / Incidence not known
    hypoxia / Early / Incidence not known
    infusion-related reactions / Rapid / Incidence not known

    Mild

    diarrhea / Early / 81.0-89.0
    fever / Early / 0-81.0
    rash / Early / 44.0-77.0
    nausea / Early / 58.0-70.0
    vomiting / Early / 46.0-70.0
    asthenia / Delayed / 0-66.0
    malaise / Early / 0-57.0
    abdominal pain / Early / 0-38.0
    weight loss / Delayed / 0-37.0
    headache / Early / 0-26.0
    chills / Rapid / 0-25.0
    pruritus / Rapid / 0-23.0
    pharyngitis / Delayed / 0-23.0
    arthralgia / Delayed / 11.0-21.0
    myalgia / Early / 0-18.0
    epistaxis / Delayed / 0-17.0
    anorexia / Delayed / 0-13.0
    anxiety / Delayed / 0-11.0
    insomnia / Early / 0-11.0
    leukocytosis / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    weight gain / Delayed / Incidence not known
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Azelastine; Fluticasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Beclomethasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Betamethasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Budesonide: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Budesonide; Formoterol: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Ciclesonide: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Corticosteroids: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Cortisone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with sargramostim, GM-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and GM-CSF.
    Deflazacort: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Dexamethasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Fludrocortisone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Flunisolide: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Fluticasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Fluticasone; Salmeterol: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Fluticasone; Vilanterol: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Formoterol; Mometasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Hydrocortisone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Lithium: (Major) Avoid the concomitant use of sargramostim and lithium due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Methylprednisolone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Mometasone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Prednisolone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Prednisone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.
    Triamcinolone: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells.

    PREGNANCY AND LACTATION

    Pregnancy

    Sargramostim may cause fetal harm when administered to a pregnant woman, based on data from animal studies. Discuss the potential hazard to the fetus if sargramostim is used during pregnancy or if a patient becomes pregnant while taking this drug; additionally, only use the lyophilized sargramostim formulation reconstituted with sterile water for injection in pregnant women. Increased spontaneous abortion was observed in pregnant rabbits who received sargramostim at doses that resulted in drug exposures that were 1.3-times or higher than those observed with the recommended human dose.[61087]

    Endogenous GM-CSF is excreted in breast milk and appears to be inactivated or not absorbed from the gastrointestinal tract. According to the manufacturer, it is not known if sargramostim is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during sargramostim therapy and for at least 2 weeks after the last dose.

    MECHANISM OF ACTION

    Mechanism of Action: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multilineage growth factor. Sargramostim has the same biologic activity as native GM-CSF. GM-CSF supports the survival, clonal expansion, and differentiation of progenitors in the granulocyte-macrophage pathways as well as megakaryocytic and erythroid progenitor cells. Other growth factors are required to induce complete maturation of megakaryocytic and erythroid cells. GM-CSF is primarily produced by bone marrow stroma and activated B-cells, T-cells, and monocyte/macrophages. The GM-CSF receptor is expressed on granulocytes, erythrocytes, megakaryocytes, macrophage progenitor cells and mature cells including neutrophils, monocytes, macrophages, dendritic cells, plasma cells, certain T-cells, vascular endothelial cells, uterine celss, and myeloid leukemia cells. Synergy with a variety of other hematopoietic growth factors (e.g., interleukin-3, macrophage colony-stimulating factor, c-kit ligand, and erythropoietin) occurs. GM-CSF has multiple actions on mature neutrophils including protection against apoptosis, induction of degranulation, increased production of reactive oxygen species, and enhanced bacteriocidal activity of neutrophils. The half-life of neutrophils is prolonged following administration of GM-CSF. Following exposure to GM-CSF, neutrophil adhesion to vascular endothelium is enhanced, and migration to other sites may be inhibited. When exposed to GM-CSF, macrophages are activated and release secondary cytokines including granulocyte colony-stimulating factor and interferon-alpha. GM-CSF also stimulates dendritic cell formation from lymphoid or myeloid CD34+ progenitor cells and monocytes. Dendritic cells are antigen-presenting cells that stimulate T-cell and lymphocyte responses. Typically, GM-CSF is not detectable in the serum, even during neutropenia or active infection, leading to the theory that GM-CSF is produced locally in tissues as part of the regulation of inflammation and acts to immobilize and prime local neutrophils.
     
    Following administration of exogenous rhuGM-CSF a transient decrease in neutrophil, eosinophil, and monocyte counts is observed, followed by an increase. Chemotactic, antifungal and antiparasitic activities of granulocytes and macrophages are increased with exposure to sargramostim in vitro. Sargramostim increases the cytotoxic activity of monocytes toward certain malignant cell lines and activates polymorphonuclear neutrophils to inhibit the growth of cancer cells. GM-CSF can stimulate the proliferation of leukemias; most require GM-CSF as a growth factor. However, GM-CSF does not cause the initial neoplastic event responsible for the development of leukemia. GM-CSF has been used to recruit leukemic cells into the chemosensitive phases of the cell cycle (i.e., S-phase) and has been shown to increase intracellular phosphorylation of cytarabine.

    PHARMACOKINETICS

    Sargramostim is administered intravenously (IV) or subcutaneously. Following IV administration, the observed volume of distribution was 96.8%. In healthy volunteers, the mean terminal elimination half-life values were 3.84 and 1.4 hours and the mean clearance values were 17.2 and 23 L/hour following sargramostim 500 mcg IV (over 2 hours) and sargramostim as a subcutaneous injection, respectively. Sargramostim appears to be metabolized to small peptides and amino acids.

    Intravenous Route

    The mean Cmax and AUC(0 to inf) values were 16.7 ng/mL and 32 ng X hour/mL, respectively, following IV administration of sargramostim. Steady state values are reached after a single IV dose; there is no accumulation after repeat dosing.

    Subcutaneous Route

    The absolute bioavailability of subcutaneous sargramostim is 75% compared with IV administration. Following a subcutaneous dose of sargramostim 6.5 mcg/kg, the 500-mcg/mL multiple-dose liquid vial and reconstituted 250-mcg powder vial for single use formulations are bioequivalent. In 2 pharmacokinetic (PK) studies in healthy subjects, the mean Cmax values were 3.75 and 3.24 ng/mL and the AUC values were 21.9 and 20.3 ng X hour/mL following a subcutaneous dose of sargramostim 250 mcg/m2. In a population PK model simulation, the mean Cmax and AUC values were 3.03 ng/mL and 21.3 ng X hour/mL, respectively, following a subcutaneous dose of sargramostim 7 mcg/kg. The time to peak concentration (Tmax) is reached between 2.5 and 4 hours following a subcutaneous dose. Steady state values are reached after a single subcutaneous dose; there is no accumulation after repeat dosing.