Description of Sargramostim (Leukine)

Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). It works by promoting proliferation and differentiation of hematopoietic progenitor cells. Sargramostim is used as primary prophylaxis following induction therapy in older patients with acute myelogenous leukemia; for peripheral blood stem cell (PBSC) mobilization for collection by leukapheresis; following an autologous bone marrow transplantation (BMT) in patients with non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, and Hodgkin’s disease; following an allogeneic BMT from an HLA-matched related donor; and following engraftment failure or delay after an autologous or allogeneic BMT.

Sargramostim is also indicated for use to treat acute radiation exposure to improve survival in patients who received myelosuppressive doses of radiation; efficacy for this indication was based on data from animal studies in monkeys and from data in patients who experienced severe neutropenia following an autologous or allogeneic BMT or after myelosuppressive chemotherapy in patients with AML.

Mechanism of Action of Sargramostim (Leukine)

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 of Sargramostim (Leukine)

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.

Route-Specific Pharmacokinetics

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.

Generic Name

• Sargramostim

• Leukine

• Colony Stimulating Factor
• Hematopoietic

• Acute myeloid leukemia – Neutrophil recovery, Following induction chemotherapy: Adult: yes (55 years or older)
• Allogeneic bone marrow transplantation, Myeloid reconstitution: Adult
• Allogeneic bone marrow transplantation, Myeloid reconstitution: Pediatric: yes (2 years or older)
• Autologous bone marrow transplant, Myeloid reconstitution: Adult
• Autologous bone marrow transplant, Myeloid reconstitution: Pediatric: yes (2 years or older)
• Autologous peripheral blood stem cell transplant, Following myeloablative chemotherapy: Adult
• Autologous peripheral blood stem cell transplant, Following myeloablative chemotherapy: Pediatric: yes (2 years or older)
• Bone marrow transplant, Delay or failure of myeloid engraftment: Adult
• Bone marrow transplant, Delay or failure of myeloid engraftment: Pediatric: yes (2 years or older)
• Hematopoietic subsyndrome of acute radiation syndrome: Adult
• Hematopoietic subsyndrome of acute radiation syndrome: Pediatric
• Mobilization, Of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis: Adult

• Cardiovascular: Chest pain (Allogeneic bone marrow transplant, 15% ), Hypertension (Allogeneic bone marrow transplant, 34% ), Peripheral edema (Autologous peripheral blood progenitor cell and bone marrow transplantation, 11% )
• Dermatologic: Pruritus (allogeneic bone marrow transplant, 23% ), Rash (autologous bone marrow transplant, 44% ), Skin reaction – finding (acute myelogenous leukemia, 77% )
• Endocrine metabolic: Hypercholesterolemia (allogeneic bone marrow transplant, 17% ), Hypomagnesemia (allogeneic bone marrow transplant, 15% ), Metabolic disease (acute myelogenous leukemia, 58% ), Weight loss (acute myelogenous leukemia, 37% )
• Gastrointestinal: Abdominal pain (allogeneic bone marrow transplant, 38% ), Diarrhea (allogeneic bone marrow transplant, 81%; autologous bone marrow transplant, 89% ), Dysphagia (allogeneic bone marrow transplant, 11% ), Gastrointestinal hemorrhage (allogeneic bone marrow transplant, 11% ), Hematemesis (allogeneic bone marrow transplant, 13% ), Nausea (allogeneic bone marrow transplant, 70%; acute myelogenous leukemia, 58% ), Vomiting (allogeneic bone marrow transplant, 70%; acute myelogenous leukemia, 46% )
• Hepatic: Increased bilirubin level (allogeneic bone marrow transplant, 30% )
• Musculoskeletal: Arthralgia (allogeneic bone marrow transplant, 11%; bone marrow transplant graft failure, 21%), Bone pain (allogeneic bone marrow transplant, 21% ), Myalgia (bone marrow transplant graft failure, 18% )
• Neurologic: Asthenia (autologous bone marrow transplant, 66% )
• Ophthalmic: Intraocular hemorrhage (allogeneic bone marrow transplant, 11% )
• Psychiatric: Anxiety (allogeneic bone marrow transplant, 11% )
• Renal: Serum blood urea nitrogen raised (allogeneic bone marrow transplant, 23% )
• Respiratory: Pharyngitis (allogeneic bone marrow transplant, 23% )
• Other: Fever (acute myelogenous leukemia, 81%), Malaise (autologous bone marrow transplant, 57% ), Rigor (allogeneic bone marrow transplant, 25% )

Serious Effects

• Cardiovascular: Capillary leak syndrome (Less than 1% ), Pericardial effusion (Autologous peripheral blood progenitor cell and bone marrow transplantation, 4%; graft failure, 25% ), Supraventricular arrhythmia
• Endocrine metabolic: Metabolic acidosis
• Immunologic: Hypersensitivity reaction
• Neurologic: Central nervous system depression, Cerebral hemorrhage
• Renal: Renal failure
• Respiratory: Gasping for breath, Pleural effusion (Autologous peripheral blood progenitor cell and bone marrow transplantation, 1% )

• Reconstitute the vial of lyophilized powder with 1 mL Sterile Water for Injection (without preservatives) or Bacteriostatic Water for Injection (with 0.9% benzyl alcohol); do not shake
• Reconstituted solution is a clear, colorless, single-dose solution
• Reconstitution with Sterile Water for Injection (preservative free): Use within 24 hours after reconstitution if stored at 2 to 8 degrees C; do not freeze
• Reconstitution with Bacteriostatic Water for Injection (contains 0.9% benzyl alcohol): Use within 20 days after reconstitution if stored at 2 to 8 degrees C; do not freeze
• Do not mix contents of vials if reconstituted with different diluents
• Reconstitution with Bacteriostatic Water for Injection: Contains benzyl alcohol; avoid use in neonates and low birth weight infants; if use is required, consider all metabolic sources of benzyl alcohol, including sargramostim (9 mg/mL)
• Discard any unused portions
• Do not administer simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy
• Intravenous: Dilute further with NS only; if the final concentration is less than 10 mcg/mL, add Albumin (Human) to a final concentration of 0.1% (1 mL 5% Albumin (Human) per 1 mL NS) to prevent adsorption to the drug delivery system
• Intravenous: Use solution immediately after dilution with NS
• Intravenous: Do not use an in-line membrane filter for IV infusion
• Intravenous: Do not add any other medication to the infusion solution

• Leukine: Injection Powder for Solution: 250 MCG

• Important Note: Orphan drug designation: Treatment of neutropenia associated with bone marrow transplant, for the treatment of graft failure and delay of engraftment, and for the promotion of early engraftment
• Important Note: Orphan drug designation: To reduce neutropenia and leukopenia and decrease the incidence of death due to infection in patients with acute myelogenous leukemia
• Important Note: Orphan drug designation: Treatment of individuals acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome)
• Important Note: Orphan drug designation: Treatment of pulmonary alveolar proteinosis (PAP)
• Important Note: Orphan drug designation: Treatment of Stage IIb-IV melanoma
• Acute myeloid leukemia – Neutrophil recovery, Following induction chemotherapy: 250 mcg/m(2)/day IV over 4 hours beginning on or about day 11 or 4 days following the completion of induction chemotherapy if the day 10 bone marrow is hypoplastic (less than 5% blasts). Continue sargramostim until the absolute neutrophil count is greater than 1500 cells/mm(3) for 3 consecutive days or for a maximum of 42 days. If a second cycle of induction chemotherapy is required, administer sargramostim approximately 4 days following the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Discontinue if leukemic regrowth occurs .
• Allogeneic bone marrow transplantation, Myeloid reconstitution: 250 mcg/m(2)/day IV over 2 hours; begin 2 to 4 hours after bone marrow infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy, within 24 hours before chemotherapy or radiotherapy, or until the post marrow infusion ANC is less than 500 cells/mm(3) .
• Autologous bone marrow transplant, Myeloid reconstitution: 250 mcg/m(2)/day IV over 2 hours; begin 2 to 4 hours after bone marrow infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy, within 24 hours before chemotherapy or radiotherapy, or until the post marrow infusion ANC is less than 500 cells/mm(3) .
• Autologous peripheral blood stem cell transplant, Following myeloablative chemotherapy: 250 mg/m(2)/day IV over 24 hours or subQ once daily; begin immediately following peripheral blood progenitor cell infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer within 24 hours before or after chemotherapy or radiotherapy
• Bone marrow transplant, Delay or failure of myeloid engraftment: 250 mcg/m(2)/day IV over 2 hours for 14 days; may repeat after 7 days off therapy if neutrophil recovery has not occurred; after an additional 7 days, may administer a third course of 500 mcg/m(2)/day for 14 days. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. Discontinue if blast cells appear or disease progression occurs
• Hematopoietic subsyndrome of acute radiation syndrome: Prior to initiation, obtain baseline CBC with differential and serial CBCs approximately every third day; estimate absorbed radiation dose; do not delay administration if CBC not available .
• Hematopoietic subsyndrome of acute radiation syndrome: (Greater than 40 kg) 7 mcg/kg subQ once daily as soon as possible following suspected or confirmed radiation exposure greater than 2 gray (Gy); continue therapy until ANC is greater than 1000/mm(3) for 3 consecutive CBCs or exceeds 10,000/mm(3) after radiation-induced nadir
• Mobilization, Of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis: 250 mcg/m(2)/day IV over 24 hours or subQ once daily; continue through the peripheral blood progenitor cell collection period; collection usually began by day 5 in studies; consider other mobilization therapy if an adequate number of progenitor cells are not collected
• Pulmonary alveolar proteinosis: 125 mcg inhaled twice daily on days 1 through 7 and none on days 8 through 14 for 12 two-week cycles (off-label dosage)
• Pulmonary alveolar proteinosis: 250 mcg inhaled twice daily every other week; diluted with 2 ml bronchosaline and administered using a Pari LC Plus nebulizer set with an interrupter valve; MAX 500 mcg inhaled twice daily every other week was used if no response to the initial dose after at least 12 weeks of treatment (off-label dosage)

• Important Note: Orphan drug designation: Treatment of neutropenia associated with bone marrow transplant, for the treatment of graft failure and delay of engraftment, and for the promotion of early engraftment
• Important Note: Orphan drug designation: To reduce neutropenia and leukopenia and decrease the incidence of death due to infection in patients with acute myelogenous leukemia
• Important Note: Orphan drug designation: Treatment of individuals acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome)
• Important Note: Orphan drug designation: Treatment of pulmonary alveolar proteinosis (PAP)
• Important Note: Orphan drug designation: Treatment of Stage IIb-IV melanoma
• Allogeneic bone marrow transplantation, Myeloid reconstitution: 250 mcg/m(2)/day IV over 2 hours; begin 2 to 4 hours after bone marrow infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy, within 24 hours before chemotherapy or radiotherapy, or until the post marrow infusion ANC is less than 500 cells/mm(3) .
• Autologous bone marrow transplant, Myeloid reconstitution: 250 mcg/m(2)/day IV over 2 hours; begin 2 to 4 hours after bone marrow infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer sooner than 24 hours after the last dose of chemotherapy or radiotherapy, within 24 hours before chemotherapy or radiotherapy, or until the post marrow infusion ANC is less than 500 cells/mm(3) .
• Autologous peripheral blood stem cell transplant, Following myeloablative chemotherapy: (2 years or older) 250 mg/m(2)/day IV over 24 hours or subQ once daily; begin immediately following peripheral blood progenitor cell infusion and continue until the ANC is greater than 1500 cells/mm(3) for 3 consecutive days; do not administer within 24 hours before or after chemotherapy or radiotherapy
• Bone marrow transplant, Delay or failure of myeloid engraftment: (2 years or older) 250 mcg/m(2)/day IV over 2 hours for 14 days; may repeat after 7 days off therapy if neutrophil recovery has not occurred; after an additional 7 days, may administer a third course of 500 mcg/m(2)/day for 14 days. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. Discontinue if blast cells appear or disease progression occurs
• Hematopoietic subsyndrome of acute radiation syndrome: Prior to initiation, obtain baseline CBC with differential and serial CBCs approximately every third day; estimate absorbed radiation dose; do not delay administration if CBC not available
• Hematopoietic subsyndrome of acute radiation syndrome: (Greater than 40 kg) 7 mcg/kg subQ once daily as soon as possible following suspected or confirmed radiation exposure greater than 2 gray (Gy); continue therapy until ANC is greater than 1000/mm(3) for 3 consecutive CBCs or exceeds 10,000/mm(3) after radiation-induced nadir
• Hematopoietic subsyndrome of acute radiation syndrome: (15 to 40 kg) 10 mcg/kg subQ once daily as soon as possible following suspected or confirmed radiation exposure greater than 2 gray (Gy); continue therapy until ANC is greater than 1000/mm(3) for 3 consecutive CBCs or exceeds 10,000/mm(3) after radiation-induced nadir
• Hematopoietic subsyndrome of acute radiation syndrome: (Less than 15 kg) 12 mcg/kg subQ once daily as soon as possible following suspected or confirmed radiation exposure greater than 2 gray (Gy); continue therapy until ANC is greater than 1000/mm(3) for 3 consecutive CBCs or exceeds 10,000/mm(3) after radiation-induced nadir

• Bioavailability, subQ: 75%
• Tmax, inhalation: 2 hours
• Tmax, subQ: 2.5 to 4 hours