Sargramostim

You should not use this medication if you are allergic to sargramostim or to yeast. Sargramostim should not be used within 24 hours before or after you receive chemotherapy or radiation.

To make sure you can safely use sargramostim, tell your doctor if you have any of these other conditions:

• fluid retention;
• a buildup of fluid around your lungs (also called pleural effusion);
• bone marrow cancer;
• heart disease, high blood pressure; congestive heart failure;
• epilepsy or other seizure disorder;
• liver or kidney disease; or
• asthma, chronic obstructive pulmonary disease (COPD), or other breathing problems.

Using sargramostim may increase your risk of developing other cancers. Ask your doctor about your individual risk.

FDA pregnancy category C. It is not known whether sargramostim will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether sargramostim passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Sargramostim is part of the drug class:

• Colony stimulating factors

Drug Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of sargramostim, such as lithium and corticosteroids, should be used with caution.

If you take too much sargramostim, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Since sargramostim is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Biosynthetic hematopoietic agent that affects the proliferation and differentiation of a variety of hematopoietic progenitor cells; a yeast-derived (Saccharomyces cerevisiae) recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF).1 5 131 132

Contraindications

• Excessive (i.e., ≥10%) leukemic myeloid blasts in the bone marrow or peripheral blood.1 5

• Known hypersensitivity to sargramostim, any ingredient in the formulation, or yeast-derived products.1

• Concomitant use of chemotherapy or radiation therapy.1

Warnings/Precautions

Warnings

Possible edema, capillary leak syndrome, and pleural and/or pericardial effusion.1 5 8 Possible precipitation or aggravation of fluid retention, especially in patients with preexisting pleural and pericardial effusions.1

Monitor body weight and hydration status during therapy.201

Use with caution in patients with preexisting fluid retention, pulmonary infiltrates, or CHF.1 5

Possible sequestration of granulocytes in the pulmonary circulation; dyspnea reported occasionally.1

Use with caution in patients with preexisting lung disease and/or hypoxia.1 5

Give special attention to respiratory symptoms that develop during or immediately following administration.1 If dyspnea develops during administration, decrease the IV infusion rate by 50%;1 5 administer oxygen to provide symptomatic relief if necessary.5 106 108 If respiratory symptoms worsen despite reduction in the infusion rate, discontinue the infusion.1 Subsequent doses may be administered according to the usual dosage schedule with careful monitoring.1

Possible transient, reversible supraventricular arrhythmia.1

Use with caution in patients with preexisting cardiac disease.1

Increased incidence of syncope with or without hypotension reported with edetate disodium (EDTA)-containing sargramostim injection (formulation no longer commercially available in the US).232 233 234 (See Preparations.) A similar increase in such adverse effects not observed with commercially available sargramostim lyophilized powder for injection (without EDTA).232 233 234

Sensitivity Reactions

Serious allergic or anaphylactic reactions reported rarely.1

Discontinue sargramostim and initiate appropriate therapy if such reactions occur.1

General Precautions

Syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia reported following the first dose of sargramostim in each treatment cycle.1 Manifestations usually resolve with symptomatic treatment and generally do not recur with subsequent doses in the same treatment cycle.1

If a first-dose reaction occurs, provide symptomatic treatment (e.g., oxygen, IV fluids, acetaminophen or NSAIA).106 108

Safety and efficacy of concomitant radiation therapy or myelosuppressive antineoplastic agents not established.1 Do not administer sargramostim within 24 hours of radiation therapy or a dose of a myelosuppressive antineoplastic agent.1 (See Interactions.)

Patients who previously received extensive radiation therapy or were exposed to multiple myelotoxic agents (e.g., alkylating agents, anthracycline antibiotics, antimetabolites) may have a limited response to sargramostim therapy following autologous BMT.1 93 122

Is effective in accelerating myeloid recovery following BMT when the marrow is purged by anti-B lymphocyte monoclonal antibodies.1 Patients receiving chemically purged marrow may not respond to sargramostim if the chemical agents cause a clinically important decrease in the number of responsive hematopoietic progenitors;1 if the purging process preserves a sufficient number of progenitors (>1.2 × 104 per kg), sargramostim may provide a beneficial effect on myeloid engraftment.1

Possible rapid rise in leukocyte count.1 134 Marked leukocytosis (leukocyte count ≥100,000/mm3) reported occasionally.47 Various effects on platelet counts reported in patients receiving biosynthetic GM-CSFs.5 11 24 29 36 94 108 109 122 129

Monitor CBC and platelet counts twice weekly during therapy to avoid potential complications of excessive leukocytosis and/or thrombocytosis.1 5 95 Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm3 or if the platelet count is >500,000/mm3.1

The possibility that sargramostim could act as a growth factor for any tumor type, particularly myeloid malignancies, has not been excluded.1 54 72

Caution recommended in patients with any malignancy with myeloid characteristics.1 43 44 45 47 49 51 88 96 129 215 216 Discontinue therapy if disease progression is detected in patients with non-Hodgkin’s lymphoma, ALL, or Hodgkin’s disease.1

Has been used in patients with MDS† or AML without evidence of increased relapse rates;1 43 44 45 47 48 49 52 54 91 96 129 220 however, regrowth of leukemic cells and an increase in leukemic blasts have occurred in a few patients with AML who were receiving the drug.54

When used for mobilization of hematopoietic progenitor cells, possible release of tumor cells from the marrow and subsequent collection in the leukapheresis product; effect of reinfusion of tumor cells not well studied and limited data available to date are inconclusive.1

Perform CBC and platelet counts prior to initiation of therapy and routinely (e.g., twice weekly) during therapy.1 5 95

Development of anti-GM-CSF antibodies reported occasionally in patients receiving sargramostim.1 100 212 Consider the possibility that formation of anti-GM-CSF antibodies during sargramostim therapy theoretically could result in drug-induced neutropenia, neutralization of endogenous GM-CSF activity, or decreased effectiveness of sargramostim.1 87 100

Specific Populations

Category C.1

Not known whether sargramostim is distributed into milk; use only if clearly needed.1 193

Safety and efficacy not established.1 5 30 42 59 However, no unusual adverse effects reported during use in children 4 months to 18 years of age (at daily dosages of 60–1000 mcg/m2 IV or 4–1500 mcg/m2 sub-Q).1 5 30 42 59 Some evidence that children may tolerate higher dosages of biosynthetic GM-CSF compared with adults in the treatment of chemotherapy-induced neutropenia†.5 30 82

Avoid administration of solutions containing benzyl alcohol (sargramostim injection, sargramostim powder reconstituted with bacteriostatic water for injection) in neonates.1 Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates.224 225 226 227 228

Experience in patients ≥65 years of age limited to those with AML.1 Analysis of general trends in safety and efficacy demonstrate a response in geriatric patients similar to that in younger adults.76 1 The possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Possible increased concentrations of serum bilirubin and hepatic enzymes.1 21 44

Monitor hepatic function every other week during therapy in patients with hepatic impairment.1 206

Possible increased Scr.1 21 44

Monitor renal function every other week during therapy in patients with renal impairment.1 206

Common Adverse Effects

Fever, asthenia, chills, headache, nausea, diarrhea, myalgia, bone pain.1 5 47 55 73 87 112 134 172

Absorption

Bioavailability

Peak serum concentrations are attained during or immediately after completion of an IV infusion.1

Rapidly absorbed following sub-Q injection,1 67 104 with peak serum concentrations generally attained within 1–4 hours.1 67 104

Duration

In patients with sargramostim-associated leukocytosis or thrombocytosis, excessive blood cell counts usually return to normal or baseline levels within 2–10 days following interruption of therapy.1 11 43 44 47 87 91 94 121 129

Distribution

Extent

Murine GM-CSF is distributed into various tissues including liver, spleen, and kidney in mice.102

Not known whether sargramostim distributes into CSF193 or milk or crosses the placenta in humans.1 193

Elimination

Metabolism

Not known whether sargramostim is metabolized.193

Elimination Route

Elimination route not known.193

Half-life

Terminal elimination half-life is approximately 60 minutes following IV infusion over 2 hours.1

Following sub-Q administration, terminal elimination half-life is approximately 162 minutes.1

• Exerts the pharmacologic effects usually produced by endogenous human GM-CSF.1 5 11 85 86 95 132

• Influences leucopoiesis;1 5 85 95 affects the proliferation and differentiation of a variety of hematopoietic progenitor cells,1 5 131 132 principally in the granulocyte-macrophage lineage.1 11 78 83 84 85 86 87 90 91 132

• Acts directly on various progenitor target cells5 98 150 203 by binding to GM-CSF-specific receptors on their cell surfaces.1 5 78 83 84 87 88 91 105 140 141 142

• Induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways.1 11 78 83 84 85 86 87 90 91 132 150 151 Also stimulates the proliferation of eosinophils, megakaryocytes, erythroid progenitors, and mast-cell precursors.1 11 46 83 84 85 87 90 132 150

• Alters the kinetics of myeloid progenitor cells within the bone marrow.5 82 94 198 203 204 Causes rapid entry of cells into the cell cycle and decreases the cell cycle time.5 82 94 198 203 204

• Produces a dose-dependent11 32 78 84 87 91 122 and biphasic increase in the leukocyte count.24 93 122

• Enhances certain functions of normal mature neutrophils, eosinophils, basophils, and macrophages78 79 83 85 119 150 (e.g., oxidative metabolism of neutrophils, phagocytosis, eosinophil cytotoxicity, antibody-dependent cellular cytotoxicity, chemotaxis, and hydrogen peroxide production).5 11 24 40 41 78 79 83 85 98 119 150

• Initiates proliferation in erythroid and megakaryocytic lineages;85 94 122 however, other factors are necessary for production of mature cells in these lineages.85 94 122 Variable effects on platelet counts have been reported.5 11 24 29 36 94 108 109 122 129

• Leukocyte differentials usually demonstrate a shift to the left (toward progenitor cells) during therapy;24 87 93 94 myelocytes, promyelocytes, and myeloblasts may be present on the differential.24 87 93 94 Absolute lymphocyte and basophil counts generally are unaffected.5 94 108 122

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sargramostim injection containing EDTA was withdrawn from the US market as of January 2008 because of reports of increased adverse effects associated with its use.232 233 Any remaining stock of EDTA-containing sargramostim injection should not be used but should be returned to the manufacturer.233 Commercially available sargramostim injection has been reformulated without EDTA.232

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Do not get sargramostim at the same time or within 24 hours before or after chemo or radiation treatment. Talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may cause a very bad and sometimes deadly problem called capillary leak syndrome (CLS). CLS may lead to low blood pressure and harm to the body. It may also lead to a heartbeat that is not normal, chest pain or pressure, heart attack, lung or breathing problems, bleeding or lower blood flow in the stomach or bowel, kidney problems, swelling, or feeling confused. Talk with the doctor.
• Do not give this medicine to a newborn. It has benzyl alcohol.
• Low blood pressure, a fast heartbeat, flushing, and passing out may rarely happen with the first dose.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using sargramostim while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• Store in a refrigerator. Do not freeze.
• After mixing, be sure you know how long the product is good for and how to store it. Ask your doctor or pharmacist if you are not sure.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(sar GRAM oh stim)

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Leukine: 500 mcg/mL (1 mL [DSC]) [contains benzyl alcohol]

Solution Reconstituted, Intravenous [preservative free]:

Leukine: 250 mcg (1 ea [DSC])

Leukine: 250 mcg (1 ea) [contains benzyl alcohol]

>10%:

Cardiovascular: Hypertension (34%), edema (13% to 25%), pericardial effusion (4% to 25%), chest pain (15%), peripheral edema (11%), tachycardia (11%)

Central nervous system: Malaise (57%), headache (26%), chills (25%), anxiety (11%), insomnia (11%)

Dermatologic: Skin rash (44% to 77%), pruritus (23%)

Endocrine & metabolic: Weight loss (37%), hyperglycemia (25%), hypercholesterolemia (17%), hypomagnesemia (15%)

Gastrointestinal: Diarrhea (81% to 89%), nausea (58% to 70%), vomiting (46% to 70%), abdominal pain (38%), anorexia (13%), hematemesis (13%), dysphagia (11%), gastrointestinal hemorrhage (11%)

Genitourinary: Urinary tract infection (14%)

Hepatic: Hyperbilirubinemia (30%)

Neuromuscular & skeletal: Weakness (66%), ostealgia (21%), arthralgia (11% to 21%), myalgia (18%)

Ophthalmic: Retinal hemorrhage (11%)

Renal: Increased blood urea nitrogen (23%), increased serum creatinine (15%)

Respiratory: Pharyngitis (23%), epistaxis (17%), dyspnea (15%)

Miscellaneous: Fever (81%)

1% to 10%:

Immunologic: Antibody development (2%)

Respiratory: Pleural effusion (1%)

<1% (Limited to important or life-threatening): Anaphylaxis, capillary leak syndrome, cardiac arrhythmia, dizziness, eosinophilia, flushing, hypotension, hypoxia, injection site reaction, leukocytosis, liver function impairment (transient), pain, prolonged prothrombin time, respiratory distress, supraventricular cardiac arrhythmia, syncope, thrombocythemia, thrombosis

Concerns related to adverse effects:

• First-dose effect: A “first-dose effect”, characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia, may occur (rarely) with the first dose of a cycle and resolve with appropriate symptomatic treatment; symptoms do not usually occur with subsequent doses within that cycle.

• Fluid retention: Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported; fluid retention has been shown to be reversible with dosage reduction or discontinuation of sargramostim with or without concomitant use of diuretics. Use with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure; may exacerbate fluid retention.

• Hematologic effects: If there is a rapid increase in blood counts (ANC >20,000/mm3 or platelets >500,000/mm3), decrease the dose by 50% or discontinue therapy. Excessive blood counts should fall to normal within 3 to 7 days after the discontinuation of therapy. Monitor CBC with differential twice weekly during treatment.

• Hypersensitivity: Serious allergic and anaphylactic reactions have been reported; discontinue immediately and initiate appropriate therapy if a serious allergic or anaphylactic reaction occurs.

• Immunogenicity: Treatment with sargramostim may induce neutralizing anti-drug antibodies. Antibody formation may be related to duration of sargramostim exposure; use sargramostim for the shortest duration necessary.

• Pulmonary symptoms: Sequestration of granulocytes in pulmonary circulation and dyspnea have been reported; monitor respiratory symptoms during and following IV infusion. Decrease infusion rate by 50% if dyspnea occurs; discontinue the infusion if dyspnea persists despite reduction in the rate of administration. Subsequent doses may be administered at the standard rate with careful monitoring. Use with caution in patients with hypoxia or pre-existing pulmonary disease.

Disease-related concerns:

• Cardiac disease: Use with caution in patients with pre-existing cardiac disease. Reversible transient supraventricular arrhythmias have been reported, especially in patients with a history of arrhythmias.

• Hepatic impairment: Use with caution in patients with hepatic impairment; hyperbilirubinemia and elevated transaminases have been observed in this patient population. Monitor hepatic function at least every other week in patients with history of hepatic dysfunction.

• Renal impairment: Use with caution in patients with renal impairment; serum creatinine elevations have been observed in this patient population. Monitor renal function at least every other week in patients with history of renal dysfunction.

Concurrent drug therapy issues:

• Cytotoxic chemotherapy/radiotherapy: Simultaneous administration, or administration 24 hours preceding/following cytotoxic chemotherapy or radiotherapy is contraindicated due to the sensitivity of rapidly dividing hematopoietic progenitor cells.

Special populations:

• Elderly patients: The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update recommend that prophylactic colony-stimulating factors be used in patients ≥65 years with diffuse aggressive lymphoma treated with curative chemotherapy (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), especially if patients have comorbid conditions (Smith 2015).

• Pediatric patients: Colony-stimulating factor (CSF) use in pediatric patients is typically directed by clinical pediatric protocols. The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update states that CSFs may be reasonable as primary prophylaxis in pediatric patients when chemotherapy regimens with a high likelihood of febrile neutropenia are employed. Likewise, secondary CSF prophylaxis should be limited to high-risk patients. In pediatric cancers in which dose-intense chemotherapy (with a survival benefit) is used, CSFs should be given to facilitate chemotherapy administration. CSFs should not be used in the pediatric population for non-relapsed acute lymphoblastic or myeloid leukemia when no infection is present (Smith 2015).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: CSFs should not be routinely used in the treatment of established neutropenic fever. Colony-stimulating factors may be considered in cancer patients with febrile neutropenia who are at high risk for infection-associated complications or who have prognostic factors indicative of a poor clinical outcome (eg, prolonged and severe neutropenia, age >65 years, hypotension, pneumonia, sepsis syndrome, presence of invasive fungal infection, uncontrolled primary disease, hospitalization at the time of fever development) (Freifeld 2011, Smith 2006). CSFs should not be routinely used for patients with neutropenia who are afebrile. Dose-dense regimens that require CSFs should only be used within the context of a clinical trial or if supported by convincing evidence (Smith 2015).

• Efficacy: Limited response to sargramostim may be seen in patients who have received bone marrow purged by chemical agents which do not preserve an adequate number of responsive hematopoietic progenitors (eg, <1.2 x 104/kg progenitors). In patients receiving autologous bone marrow transplant, response to sargramostim may be limited if extensive radiotherapy to the abdomen or chest or multiple myelotoxic agents were administered prior to transplant.

• Peripheral blood progenitor cell mobilization: Limited in vitro data suggest that when using sargramostim to mobilize peripheral blood progenitor cells, tumor cells may be released and reinfused into patients in the leukapheresis product; the effect of tumor cell reinfusion has not been well studied.

• Tumor growth factor: May potentially act as a growth factor for any tumor type, particularly myeloid malignancies; caution should be exercised when using in any malignancy with myeloid characteristics. Discontinue use if disease progression occurs during treatment.

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

• Patient may experience headache, anxiety, nausea, vomiting, abdominal pain, bone pain, joint pain, muscle pain, loss of strength and energy, diarrhea, pharyngitis, or weight loss. Have patient report immediately to prescriber signs of capillary leak syndrome (abnormal heartbeat; angina; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; urinary retention or change in amount of urine passed; or hematuria); tachycardia; abnormal heartbeat; shortness of breath; excessive weight gain; swelling of arms or legs; severe dizziness; passing out; flushing; chills; vomiting blood; black, tarry, or bloody stools; or angina (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

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

Data not available.