Professional Information

Colony Stimulating Factors (Systemic)

This monograph includes information on the following:

1) Filgrastim
2) Sargramostim ^†

VA CLASSIFICATION
Primary: BL400

Commonly used brand name(s): Leukine²; Neupogen¹.

Other commonly used names for filgrastim are:
Granulocyte colony stimulating factor, recombinant, rG-CSF , recombinant methionyl human granulocyte colony stimulating factor, and r-met HuG-CSF . Other commonly used names for sargramostim are: Granulocyte-macrophage colony stimulating factor, recombinant, recombinant human granulocyte-macrophage colony stimulating factor, rGM-CSF, and rHu GM-CSF .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:

Hematopoietic stimulant—

antineutropenic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Neutropenia, chemotherapy-related (treatment)— Filgrastim (rG-CSF) ^{01} ^{03} ^{04} ^{41} ^{42} ^{44} ^{79} ^{80} ^{92} ^{118} ^{124} ^{125} ^{131} ^{132} ^{144} ^{145} ^{260} ^{261}^{262}and [ sargramostim (rGM-CSF)] ^{03} ^{04} ^{16} ^{80} ^{86} ^{115} ^{120} ^{121} ^{127} ^{138} ^{139} ^{140} ^{141} ^{142} ^{156} ^{173} ^{174} ^{175} ^{176} ^{177} are indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.
—Filgrastim is indicated in adult and [pediatric] cancer patients receiving myelosuppressive chemotherapy^{261}.
—Sargramostim is indicated for decreasing the duration of neutropenia after the completion of acute myelocytic leukemia (AML) induction chemotherapy in older adult patients (55 years of age and older) ^{242} ^{255} ^{256} ^{257}.
—Filgrastim is indicated for decreasing the duration of neutropenia and fever after the completion of AML induction or consolidation chemotherapy in adult patients ^{01}^{261}^{262}.

Note: Caution is recommended in patients with myeloid malignancies such as AML ^{01} ^{08} ^{16} ^{17} ^{22} ^{36} ^{90} ^{97} ^{157} ^{178} ^{179} ^{242} because of the potential of colony stimulating factors to stimulate leukemic blasts ^{07} ^{08} ^{15} ^{60} ^{89} ^{115} ^{125} ^{128} ^{147} ^{148} ^{149} ^{150} ^{151} ^{152} ^{153} ^{154} ^{155} ^{157} ^{178} ^{247}. Filgrastim and sargramostim are not recommended for administration before or with chemotherapy in patients with AML ^{242} ^{254}. Criteria to define patients at increased risk (e.g., those with refractory anemia with excess blasts [RAEB] or refractory anemia with excess blasts in transformation [RAEBT], or cytogenetic abnormality) have been proposed but not established ^{128} ^{157}.
The theoretical risk that use of increased doses of chemotherapy permitted by administration of colony stimulating factors may result in an increase in other hematologic or nonhematologic toxicities not affected by colony stimulating factors ^{01} has not been adequately studied, but caution is recommended ^{167}.

Myeloid engraftment following bone marrow transplantation, promotion of (treatment adjunct)—Filgrastim is indicated for acceleration of myeloid recovery in patients undergoing autologous or allogeneic BMT following myeloablative chemotherapy for non-myeloid malignancies ^{01}^{262}. [Filgrastim] ^{03} ^{41} ^{101} ^{104} ^{107} ^{108} ^{143} ^{158} ^{249} ^{250} ^{251} ^{252} and sargramostim ^{03} ^{15} ^{16} ^{88} ^{98} ^{99} ^{100} ^{101} ^{105} ^{109} ^{110} ^{111} ^{112} ^{113} ^{242} ^{249} ^{250} ^{251} ^{252} are indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphomas, acute lymphoblastic leukemia, and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). Sargramostim is indicated for acceleration of myeloid recovery in patients undergoing [autologous ] or allogeneic BMT following myeloablative chemotherapy for non-myeloid malignancies. [Filgrastim] and sargramostim are indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT following myeloablative chemotherapy for myeloid malignancies ^{01} ^{242} ^{260}.

Myeloid engraftment following bone marrow transplantation, failure or delay of (treatment)—[Filgrastim ]¹ ^{159} and sargramostim ^{15} ^{87} ^{88} ^{93} ^{102} ^{242} are indicated for prolonging survival in patients who have undergone allogeneic or autologous BMT in whom engraftment is delayed or has failed, in the presence or absence of infection.

Note: Filgrastim ^{228} and sargramostim are effective in patients receiving unpurged bone marrow ^{102} or bone marrow purged with monoclonal (e.g., anti-B lymphocyte) antibodies ^{100} ^{102} ^{242}; however, in vitro marrow purging with chemical agents may significantly reduce the number of responsive hematopoietic progenitors and prevent a response ^{87} ^{102} ^{105} ^{113} ^{242}. The bone marrow purging process should preserve more than 1.2 × 10 ⁴ progenitors per kg of body weight ^{242}.
The effect may also be limited in patients who received extensive radiotherapy to hematopoietic sites for treatment of primary disease in the abdomen or chest or who have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics, and antimetabolites) before autologous BMT ^{22} ^{242}.

Peripheral progenitor cell yield, enhancement of (treatment adjunct) —Filgrastim ^{229} ^{230} ^{231} ^{232} ^{233} ^{234} ^{235} ^{236} ^{237} ^{238} ^{261}^{262}and sargramostim ^{57} ^{93} ^{98} ^{101} ^{103} ^{106} ^{107} ^{160} ^{180} ^{181} ^{182} ^{190} ^{191} are indicated as adjuncts to enhance peripheral progenitor cell yield in autologous hematopoietic stem cell transplantation. However, the yield (quantity and quality) of peripheral progenitor cells is dependent on the extent of prior chemotherapy ^{160}.

Myeloid engraftment following hematopoietic stem cell transplantation, promotion of (treatment adjunct)—[Filgrastim] and sargramostim are indicated for acceleration of myeloid recovery in patients who have undergone hematopoietic stem cell transplantation following myeloablative chemotherapy ^{242} ^{259}.

[Myeloid engraftment following hematopoietic stem cell transplantation, failure or delay of (treatment)]—Sargramostim is indicated for prolonging survival in patients who have undergone autologous or allogeneic hematopoietic stem cell transplantation in whom engraftment is delayed or has failed, in the presence or absence of infection ^{146}.

[Neutropenia, AIDS-associated (treatment)]— Filgrastim^{187}^{261}^{262} and sargramostim ^{183} ^{184} ^{185} ^{186} ^{188} ^{189} ^{194} ^{195} ^{196} ^{197} are indicated to treat acquired immunodeficiency syndrome (AIDS) patients with neutropenia caused by the disease itself or infection with opportunistic organisms (such as cytomegalovirus) ^{161} ^{192} ^{197}, or antiretroviral agents (zidovudine, ganciclovir) ^{07} ^{18} ^{161} ^{192} ^{195}.
—The effects of colony stimulating factors on infections, hospitalization, or survival have not been established ^{161}.
—Because there is some evidence that sargramostim (but not filgrastim ^{08}) may increase human immunodeficiency virus (HIV) replication ^{08} ^{161} ^{192} ^{193}, it is recommended that sargramostim be given only in combination with an antiretroviral agent ^{07} ^{08} ^{161} ^{192} ^{193}.
—Ganciclovir is toxic to stem cells. If neutrophil counts decrease despite use of colony stimulating factor, dose reduction or withdrawal of ganciclovir is recommended ^{161}.

[Myelodysplastic syndromes (treatment)]— Filgrastim¹ ^{155} ^{201} ^{204} ^{205} and sargramostim ^{83} ^{84} ^{133} ^{153} ^{154} ^{200} ^{202} ^{203} are indicated to enhance neutrophil function in patients with myelodysplastic syndromes ^{17} ^{36} ^{162} and a history of infection ^{162}.

Note: Caution is necessary because of the risk that colony stimulating factors may precipitate transformation of myelodysplastic syndromes into acute myelocytic leukemia ^{07} ^{08} ^{15} ^{60} ^{89} ^{115} ^{125} ^{128} ^{147} ^{148} ^{149} ^{150} ^{151} ^{152} ^{153} ^{154} ^{155} ^{157} ^{178} ^{247}. Assessment of risk is complicated by the fact that progression to acute leukemia may occur in the natural course of the disease ^{84} ^{247}.
Colony stimulating factors do not have a consistent effect on erythrocytes or platelets in these conditions ^{17} ^{162}.

Neutropenia, severe chronic (treatment)—Filgrastim ^{08} ^{81} ^{82} ^{207} ^{208} ^{210} ^{211} ^{212} ^{214} ^{261}^{262}and [sargramostim] ^{206} ^{209} ^{213} are indicated for treatment of severe chronic neutropenia, including congenital neutropenia (Kostmann's syndrome), idiopathic neutropenia, and cyclic neutropenia ^{07} ^{58} ^{163}.

[Neutropenia, drug-induced (treatment)]—Filgrastim¹ and sargramostim are indicated for treatment of drug-induced neutropenia ^{164} ^{215} ^{216} ^{217} ^{218} ^{219} ^{220}.

Acceptance not established
Use of sargramostim, as a single-agent or in combination therapy, for the treatment of melanoma has not been established.^{263}^{264}^{265}^{266}^{267}^{268}^{269}^{270}^{271}^{272}^{273}^{274}^{275}^{276}^{277}^{278}^{279}^{280}^{281}^{282}^{283}^{284}^{285}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Filgrastim (rG-CSF): Synthetic. A protein chain of 175 amino acids produced by a recombinant DNA process involving genetically engineered Escherichia coli (the human granulocyte colony stimulating factor gene has been inserted into the bacteria) ^{01}. The protein has an amino acid sequence identical to the sequence in naturally occurring human granulocyte colony stimulating factor (G-CSF), predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli ^{01}. In addition, unlike G-CSF isolated from a human cell, filgrastim is non-glycosylated ^{01} ^{30}. Purification is done by conventional means; prior to final purification, filgrastim is allowed to oxidize to its native state and final purity is achieved by sequential passage over a series of chromatography columns; the product is then formulated in an acetate buffer with mannitol and Tween 80 ^{01}.
    Sargramostim (rGM-CSF): Synthetic. The commercially available form is a glycoprotein chain of 127 amino acids, characterized by three primary molecular species, produced by a recombinant DNA process involving a yeast (S. cerevisiae ) expression system ^{242}. The amino acid sequence differs from that of natural human granulocyte-macrophage colony stimulating factor (GM-CSF) by a substitution of leucine at position 23, and the carbohydrate moiety may be different ^{242}. Sargramostim produced in a yeast system is glycosylated; rGM-CSF produced in other systems may not be ^{80} ^{95} ^{98} ^{119} ^{128} ^{129}.

Chemical group—
    Related to naturally occurring colony stimulating factors, which are hormone-like glycoprotein growth factors ^{01} ^{04} ^{78} ^{79} ^{242} also known as cytokines.
Molecular weight—
    Filgrastim: 18,800 daltons ^{01}
    Sargramostim: Contains three primary molecular species with molecular masses of 19,500, 16,800, and 15,500 daltons ^{242}

Mechanism of action/Effect:

In general, endogenous colony stimulating factors act on hematopoietic cells ^{01} ^{38} by binding to specific cell surface receptors ^{01} ^{07} ^{08} ^{11} ^{12} ^{22} ^{23} ^{29} and stimulating proliferation (clonal expansion) ^{01} ^{07} ^{08} ^{10} ^{14} ^{242}, differentiation ^{01} ^{07} ^{08} ^{10} ^{14} ^{242}, and some end-cell functional activation ^{01} ^{03} ^{07} ^{08} ^{10} ^{14} ^{45} ^{48} ^{51} ^{52} ^{53} ^{56}. The recombinant colony stimulating factors have the same biological activity as the endogenous hormones. The actions of these growth factors promote differentiation of myeloid progenitor cells into granulocytes and monocytes ^{05}; other pathways produce erythrocytes and platelets ^{05}.

Filgrastim is a class II hematopoietic growth factor ^{02}. It acts on progenitor cells capable of forming only one differentiated cell type—the neutrophil granulocyte ^{04} ^{05} ^{07} ^{08} ^{09} ^{30} ^{37} ^{79}; it is said to be lineage-specific ^{03} ^{04} ^{08} ^{13}. Sargramostim, a class I hematopoietic growth factor ^{02}, stimulates formation of granulocytes (neutrophils, eosinophils) and macrophages ^{04} ^{05} ^{07} ^{11} ^{13} ^{19} ^{22} ^{24} and is therefore non–lineage specific ^{03} ^{04}.

Administration of colony stimulating factor to patients whose bone marrow has been depleted by myelotoxic agents ^{98} ^{103} or diseases such as acquired immunodeficiency syndrome (AIDS) ^{07} ^{08} ^{161} ^{192} ^{197} results in an increased number of circulating hematopoietic progenitor cells. Filgrastim acts only on mature progenitor cells that are already committed to one pathway, the granulocyte pathway, and therefore increases only neutrophil concentrations ^{03} ^{05} ^{07} ^{11} ^{13} ^{24} ^{35}. Sargramostim acts on progenitor cells at an earlier stage of development and can promote more than one lineage ^{04} ^{08}; it promotes formation of granulocyte, macrophage, and mixed granulocyte-macrophage colonies, resulting in increased concentrations of eosinophils and monocytes as well ^{02} ^{03} ^{13} ^{29} ^{35} ^{91} ^{96} ^{98} ^{115} ^{119}. Neither has a consistent effect on red cell or platelet counts ^{98} ^{101} ^{107} ^{109} ^{124} ^{125}.

Other actions/effects:

Colony stimulating factors may have a proliferative effect on myeloid and erythroid leukemic cells ^{07} ^{08} ^{16} ^{22} ^{33} ^{34} ^{36} ^{39} ^{60} ^{89} ^{115} ^{125} ^{128} ^{147} ^{148} ^{149} ^{150} ^{151} ^{152} ^{153} ^{154} ^{155}. Sargramostim has been reported in some studies to increase replication of human immunodeficiency virus ^{07} ^{08} ^{161} ^{192} ^{193}. Sargramostim has been reported to reduce low-density lipoprotein (LDL) concentrations in blood, with a variable effect on high-density lipoproteins (HDL) ^{27}; it has also been reported to transiently decrease cholesterol concentrations ^{46} ^{119}. Filgrastim has been reported to decrease serum cholesterol with variable changes in triglycerides; these changes return to normal or near baseline within 1 or 2 weeks after it is withdrawn ^{79}.

Absorption:

Filgrastim or sargramostim—Detected in serum within 5 minutes after subcutaneous administration ^{40} ^{165} ^{242}.

Half-life:

Distribution:

Sargramostim—

Intravenous (2-hour infusion)—

12 to 17 minutes ^{242}.

Elimination:

Filgrastim—

Approximately 3.5 hours ^{01}.

Sargramostim—

Intravenous (2-hour infusion)—Approximately 1 hour ^{36} ^{242}.

Subcutaneous—Approximately 3 hours ^{139}.

Onset of action:

Filgrastim—Decrease in circulating neutrophils occurs within the first 5 minutes of intravenous administration ^{36} ^{37}; after 4 hours, counts begin to rise, with an initial peak within 24 hours ^{36} ^{37}.

Sargramostim—Decrease in circulating neutrophils, eosinophils, and monocytes occurs ^{72}, with a nadir at 30 minutes, and rebound to baseline or above by 2 hours ^{28} ^{31} ^{37}. In addition, there is an apparent biphasic response over time ^{36} ^{37}; an initial plateau in leukocyte counts occurs after 3 to 7 days, which is followed by another increase and another plateau ^{37}.

Time to peak concentration:

Filgrastim—After subcutaneous administration: 2 to 8 hours ^{01}.

Sargramostim—After subcutaneous administration: 2 hours ^{40} ^{242}.

Time to peak effect:

Varies according to chemotherapy regimen, underlying disease and prior treatment history, and dose of colony stimulating factor ^{244}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to Escherichia coli–derived proteins may also be hypersensitive to filgrastim (rG-CSF) ^{01}.

Patients hypersensitive to yeast-derived products may also be hypersensitive to sargramostim (rGM-CSF) ^{242}.

Carcinogenicity

Studies have not been done ^{01} ^{242}.

Mutagenicity

Filgrastim did not induce bacterial gene mutations in either the presence or absence of a drug-metabolizing enzyme system ^{01}.

Pregnancy/Reproduction
Fertility—

Filgrastim

No effect has been observed on the fertility of male or female rats or on gestation at doses up to 500 mcg per kg of body weight (mcg/kg) ^{01}.

Sargramostim

Studies in animals have not been done^{242}due to species specificity of the human protein^{166}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done^{01}.

Filgrastim

In pregnant rabbits, adverse effects have been observed at doses of 2 to 10 times the human dose^{01}. Studies in rabbits at doses of 80 mcg/kg per day found increased abortion and embryolethality^{01}. Studies in rabbits at doses of 80 mcg/kg per day during the period of organogenesis found increased fetal resorption, genitourinary bleeding, developmental abnormalities, and decreased body weight, live births, and food consumption; external abnormalities were not observed in the fetuses^{01}^{261}^{262}. Studies in rats at daily intravenous doses up to 575 mcg/kg per day during the period of organogenesis found no associated lethal, teratogenic, or behavioral effects on fetuses^{01}.

FDA Pregnancy Category C^{01}.

Sargramostim

Studies in animals have not been done^{242} due to species specificity of the human protein ^{166}.

FDA Pregnancy Category C^{242}.

Breast-feeding

It is not known whether filgrastim^{01} or sargramostim^{242} is distributed into human breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of colony stimulating factors have not been performed in the pediatric population ^{57}. Trials conducted in infants and children showed no differences in pharmacokinetics compared with results of studies in adults ^{55} ^{95}.

Although filgrastim is not approved by regulatory agencies in the U.S.for use in pediatric patients, there are some limited data available regarding its use in pediatric patients receiving filgrastim for severe chronic neutropenia ^{01} ^{55} ^{58} ^{59} ^{74} ^{81} ^{95}. Pediatric patients 4 months to 17 years of age receiving filgrastim for about 18 months did not experience alterations in growth and development, sexual maturation, or endocrine function ^{01}. Filgrastim was well-tolerated in pediatric patients receiving it for chemotherapy-related neutropenia ^{01}. One of twelve pediatric patients experienced palpable splenomegaly and another experienced musculoskeletal pain ^{01}^{261}^{262}. The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established^{261}^{262}. In Canada, clinical data, in pediatric patients with neutropenia resulting from myelosuppressive chemotherapy, indicate that safety of filgrastim is similar in both adults and children receiving cytotoxic chemotherapy.^{261}

Although sargramostim is not approved by regulatory agencies for use in pediatric patients, there are some limited data available regarding its use in this population ^{242}. Pediatric patients 4 months to 18 years of age have received sargramostim intravenously in doses of 60 to 1000 mcg per square meter of body surface area or subcutaneously in doses of 4 to 1500 mcg per square meter of body surface area ^{242}. Pediatric patients receiving intravenously administered sargramostim 250 mcg per square meter of body surface area experienced side effects similar in type and frequency to those occurring in adult patients ^{242}.

Sargramostim liquid injection contains benzyl alcohol. Administration of excessive amounts of benzyl alcohol to neonates has been associated with neurological and other complications ^{242}.

Geriatrics

Appropriate studies on the relationship of age to the effects of colony stimulating factors have not been performed in the geriatric population. However, studies commonly include older patients ^{86} ^{115}, and geriatrics-specific problems that would limit the usefulness of these medications in the elderly are not expected.

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values

For filgrastim and sargramostim
Blood pressure    (transient decreases occur uncommonly^{01}^{242}; hypotension has been associated with a rare “first-dose reaction” to sargramostim^{94}^{109}^{117}^{129}^{242})

For filgrastim only (in addition to the above)
Alkaline phosphatase, leukocyte (LAP scores) and serum values ^{01} ^{03} ^{08} ^{14} ^{30} ^{43} ^{79} ^{80} ^{118} ^{124} ^{125} ^{143} ^{144} ^{145} and
Lactic dehydrogenase (LDH), serum values ^{01} ^{03} ^{08} ^{14} ^{30} ^{79} ^{80} ^{118} ^{124} ^{143} ^{144} ^{145} and
Uric acid, serum concentrations ^{01} ^{14} ^{30} ^{79} ^{80} ^{118} ^{124} ^{144}    (commonly increased in patients receiving filgrastim; the increases coincide with the rise in neutrophil counts ^{30} ^{80} ^{118} ^{124} ^{144} ^{145}. Concentrations return to normal within 1 or 2 weeks after withdrawal of filgrastim ^{79})

For sargramostim only (in addition to the above)
Albumin, serum    (decreases have been reported during sargramostim therapy ^{75} ^{94} ^{117}; possibly related to capillary leak syndrome ^{117})

Bilirubin, serum concentrations and
Creatinine, serum concentrations and
Hepatic enzymes, serum values    (reportedly increased by sargramostim in some patients with renal or hepatic function impairment ^{08} ^{14} ^{117} ^{242})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist

For filgrastim and sargramostim:
Autoimmune disease, history of, e.g., autoimmune thrombocytopenia ^{36} ^{168} or
Inflammatory conditions, e.g., vaculitis ^{63} ^{64} ^{66} ^{168}    (may be exacerbated ^{94} ^{168})

Cardiovascular disease, pre-existing ^{01} ^{30} ^{242}    (supraventricular arrhythmia has been reported occasionally in patients receiving sargramostim, especially in patients with a history of cardiac arrhythmia ^{242}; myocardial infarction and arrhythmias have been reported with filgrastim ^{01})

» Excessive leukemic myeloid blasts in the bone marrow or peripheral blood (10% or more) ^{115} ^{242}    (growth of leukemic blasts may be stimulated by colony stimulating factors, especially at high doses ^{60} ^{115} ^{128} ^{147} ^{148} ^{149} ^{150} ^{151} ^{152} ^{153} ^{154} ^{155})

» Hypersensitivity to the colony stimulating factor prescribed ^{242}
Sepsis    (theoretical potential of adult respiratory distress syndrome as a result of possible influx of neutrophils at the site of inflammation ^{01})

Caution should be used also in timing of colony stimulating factor administration to patients receiving chemotherapy or radiation therapy ^{01} ^{30} ^{242} ^{244} .
For filgrastim only (in addition to the above):
» Hypersensitivity to Escherichia coli –derived proteins ^{01}
For sargramostim only (in addition to the above):
Congestive heart failure ^{242} or
Fluid retention, pre-existing (including peripheral edema, capillary leak syndrome, pleural and/or pericardial effusion) ^{242} or
Pulmonary infiltrates ^{242}    (sargramostim may aggravate fluid retention ^{242})

Hepatic function impairment ^{242} or
Renal function impairment ^{242}    (elevation of serum creatinine or bilirubin and hepatic enzymes by sargramostim has been reported ^{242}; monitoring of function is recommended at least biweekly during treatment ^{242})

Pulmonary disease, including hypoxia ^{242}    (caution is recommended because sargramostim causes sequestration of granulocytes in the pulmonary circulation ^{242}; dyspnea has been reported ^{242})

» Hypersensitivity to yeast-derived proteins ^{242}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

For filgrastim and sargramostim
Cardiac monitoring    (recommended in patients with pre-existing cardiac conditions ^{01} ^{242})

» Complete blood count (CBC) with differential (including examination for the presence of blast cells) and
Platelet counts    (recommended twice weekly ^{01} ^{242} during treatment to monitor the neutrophil count to assess the hematopoietic response and avoid excessive leukocytosis; recommended prior to chemotherapy; recommended at least 3 times per week after bone marrow transplantation^{262})

Hepatic function and/or
Renal function    (monitoring recommended at least biweekly in patients with hepatic and/or renal function impairment ^{242})

For sargramostim only (in addition to the above)
Body weight and
Hydration status    (recommended during treatment with sargramostim ^{242})

Side/Adverse Effects

Note: There are relatively few side/adverse effects directly associated with colony stimulating factor administration alone. Most side/adverse effects reported are due to the underlying malignancy or cytotoxic therapy ^{01}. Neutropenic effects caused by cytotoxic therapy (fever, infection, mucositis) are decreased in frequency when a colony stimulating factor is used ^{01} ^{03}. Only those side/adverse effects specifically caused by colony stimulating factor are listed below.
Development of antibodies to filgrastim (rG-CSF) has not been detected during treatment in 500 patients for up to almost 2 years ^{01} ^{118} and no blunting or diminishing of response has occurred ^{01}. Neutralizing antibodies have been detected ^{94} in 5 of 165 patients (3%) treated with sargramostim (rGM-CSF) ^{242}; because all 5 had impaired hematopoiesis prior to treatment, assessment of the effect of antibody development on normal hematopoiesis was not possible ^{242}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
For filgrastim
Incidence less frequent

Excessive leukocytosis ^{01} ^{242} —usually asymptomatic

redness or pain at site of subcutaneous injection ^{80} ^{107} ^{116} ^{119} ^{130} ^{242}

Incidence rare

Allergic or anaphylactic reaction ^{76} ^{242} ^{248} ( wheezing)

splenomegaly ^{14} ^{23} ^{30} ^{36} ^{247} —usually asymptomatic

supraventricular arrhythmia, transient ^{01} ^{93} ^{129} ^{242} (rapid or irregular heartbeat)

Sweet's syndrome ^{03} ^{08} ^{30} ^{36} ^{66} ^{69} ^{70} ^{241} ( fever; sores on skin)

vasculitis ^{30} ^{36} (sores on skin)

Note: Splenomegaly has been reported in patients receiving filgrastim for cyclic neutropenia ^{30}. Subclinical splenomegaly occurs in approximately one third of patients and clinical splenomegaly in about 3% of patients receiving chronic treatment with filgrastim ^{01}.
Sweet's syndrome (also known as acute febrile neutrophilic dermatosis) ^{08} ^{241} appears to coincide with the increase in neutrophils ^{03} ^{30}.

For sargramostim
Incidence less frequent

Capillary leak syndrome ^{08} ^{61} ^{88} ^{93} ^{242} , including fluid retention ^{93} ^{95} ^{109} , peripheral edema ^{62} ^{109} ^{242} , or pleural and/or pericardial effusion ^{08} ^{14} ^{23} ^{93} ^{95} ^{102} ^{109} ^{126} ^{141} ^{242} (swelling of feet or lower legs; sudden weight gain ^{62} ^{88} ^{93} ^{99} ^{109}; shortness of breath)

fever ^{03} ^{06} ^{08} ^{29} ^{31} ^{34} ^{47} ^{93} ^{127} ^{141} ^{242}

excessive leukocytosis ^{01} ^{242} —usually asymptomatic

redness or pain at site of subcutaneous injection ^{29} ^{107} ^{116} ^{119} ^{242}

shortness of breath ^{47} ^{242}

Note: Capillary leak syndrome is dose-related ^{93} ^{109} and dose-limiting ^{36} ^{94}; pleural and/or pericardial effusion usually occurs at doses above 32 mcg per kg of body weight per day ^{34} ^{54} ^{88} ^{109}. Fluid retention occurs at usual doses ^{90} ^{242}.
Fever is usually mild ^{06} ^{47} ^{242} and dose-related ^{03}. It occurs in about 50% of patients ^{93} ^{127}. It is not related to leukopenia, but may complicate assessment of fever associated with neutropenia ^{117} ^{127}. Fever resolves on withdrawal of sargramostim ^{127} or administration of antipyretics such as acetaminophen ^{06} ^{242}.
Shortness of breath may be the result of sequestration of granulocytes in the pulmonary circulation ^{242}. An adult respiratory distress syndrome has been reported ^{126}.

Incidence rare

Allergic or anaphylactic reaction ^{76} ^{242} ^{248} ( wheezing)

pericarditis ^{36} ^{80} ^{94} ^{109} ^{253} (chest pain; shortness of breath)

supraventricular arrhythmia, transient ^{01} ^{93} ^{129} ^{242} (rapid or irregular heartbeat)

thrombophlebitis ^{03} ^{29} ^{36} ^{80} ^{94} ^{247} —may occur during continuous infusion into small veins ^{03}

thromboses around tip of venous catheter ^{08} ^{34} ^{93} ^{94} ^{117} ^{126} ^{130} ^{141} ^{247}

vasculitis ^{63} ^{64} ^{65} (sores on skin)

Note: Pericarditis is a dose-limiting effect ^{36} ^{87}.
Development of thromboses is a dose-limiting effect ^{94}.

Those indicating need for medical attention only if they continue or are bothersome
For filgrastim and sargramostim
Incidence more frequent

Arthralgias ^{08} ^{31} ^{93} ^{94} ^{127} ^{130} ^{141} ^{242} or myalgias ^{06} ^{08} ^{47} ^{79} ^{94} ^{95} ^{99} ^{102} ^{108} ^{109} ^{127} ^{242} (pain in joints or muscles)

medullary bone pain ^{01} ^{03} ^{23} ^{31} ^{36} ^{71} ^{79} ^{80} ^{93} ^{94} ^{102} ^{104} ^{108} ^{124} ^{125} ^{126} ^{130} ^{143} ^{144} ^{242} (pain in lower back or pelvis; pain in arms or legs ^{79})

mild to moderate headache ^{06} ^{47} ^{79} ^{93} ^{94} ^{141} ^{242}

skin rash or itching ^{29} ^{36} ^{67} ^{80} ^{90} ^{93} ^{94} ^{95} ^{118} ^{119} ^{127} ^{129} ^{141} ^{144} ^{242}

Note: Arthralgias or myalgias seem to occur when granulocyte counts are returning to normal ^{79}. Pain usually occurs in the lower extremities ^{109}.
Bone pain is usually mild to moderate ^{01} ^{08} ^{30} ^{79} ^{104} ^{118} ^{124} ^{125} ^{126} ^{130} ^{143} ^{144} and is alleviated by analgesics ^{30} ^{79} ^{118}. It occurs in 20 to 50% of patients ^{01} ^{30} ^{79} ^{118} ^{127} and is dose-related ^{01} ^{03} ^{30} ^{94}. It disappears within hours after withdrawal of colony stimulating factor ^{30}, but usually resolves even with continued treatment ^{23} ^{30}. Bone pain is probably secondary to bone marrow expansion ^{03} ^{43}; it occurs over the 1- to 3-day period before myeloid recovery and the rise in peripheral blood neutrophils ^{30} ^{118}. It originates from ^{221} sites containing bone marrow, including the sternum, spine, pelvis, and long bones ^{118}.
Skin rash is usually generalized and mild ^{118}.

For sargramostim only (in addition to the above)
Incidence less frequent or rare

First-dose reaction, with flushing ^{47} ^{94} ^{242} , hypotension ^{79} ^{94} ^{109} ^{117} ^{129} ^{242} , and syncope ^{242} (flushing of face; dizziness or faintness)

weakness ^{31} ^{117} ^{144} ^{242}

Note: The first-dose reaction does not recur with the first dose of each course, although it may occur with the first dose of more than one course ^{222}. The first-dose reaction has been described more consistently with bacterially-derived GM-CSF (molgramostim; not commercially available), and included tachycardia, musculoskeletal pain, and dyspnea ^{32} ^{36} ^{50} ^{80} ^{95} ^{116}.

Overdose
There are no data on massive overdoses of filgrastim or sargramostim. However, sargramostim was administered to four patients at dosages sixteen times the recommended dose for 7 to 18 days in an uncontrolled study ^{242}.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of sargramostim overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic

Chills^{242}

dyspnea^{242} (shortness of breath)

excessive leukocytosis^{242} —usually asymptomatic

fever^{242}

headache^{242}

malaise^{242} (general feeling of bodily discomfort)

nausea^{242}

skin rash^{242}

tachycardia^{242} (rapid heartbeat)

Treatment of overdose

Treatment of sargramostim overdose:
Specific treatment: Sargramostim should be discontinued ^{242}.

Monitoring: Respiratory status and white blood cell counts should be monitored ^{242}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Colony Stimulating Factors (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to the colony stimulating factor prescribed

Pregnancy—Adverse effects with filgrastim found in rabbits

Proper use of this medication

For subcutaneous use
» Compliance with therapy

» Reading patient directions carefully with regard to    • Preparation of the injection
   • Use of disposable syringes
   • Proper administration technique
   • Stability of the injection

» Proper dosing

Missed dose: Checking with physician

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Telling physician right away if signs or symptoms of infection (fever, chills) occur

Possibility of mild bone pain as bone marrow begins to recover; usually relieved by mild analgesics; checking with physician if severe

Side/adverse effects

Signs of potential side effects, especially
For filgrastim—Redness or pain at site of subcutaneous injection, allergic or anaphylactic reaction, arrhythmias, and Sweet's syndrome and other dermatoses

For sargramostim—Fluid retention, peripheral edema, pleural and/or pericardial effusion, fever, redness or pain at site of subcutaneous injection, shortness of breath, allergic or anaphylactic reaction, arrhythmias, pericarditis, and Sweet's syndrome and other dermatoses

General Dosing Information
Patients receiving colony stimulating factor should be under supervision of a physician experienced in cytokine and/or cancer chemotherapy ^{01} ^{242}.

It is recommended that appropriate precautions be taken in the event that an allergic reaction occurs ^{242}. If a serious allergic or anaphylactic reaction occurs, colony stimulating factor should be immediately discontinued and appropriate therapy initiated ^{242}.

It is recommended that colony stimulating factor be discontinued when the absolute neutrophil count (ANC) reaches or exceeds 10,000 per cubic millimeter after the ANC nadir has occurred ^{01}, to avoid excessive leukocytosis ^{244}.

Colony stimulating factor should not be administered within 24 hours before or after administration of the last dose of chemotherapy ^{01} ^{30} ^{242} or within 12 hours before or after radiotherapy ^{242}, because of potential sensitivity of rapidly dividing hematopoietic progenitor cells to cytotoxic chemotherapy or radiologic therapies ^{01} ^{242} ^{244}.

FILGRASTIM

Summary of Differences
Pharmacology/pharmacokinetics: Mechanism of action—Lineage-specific; stimulates production of neutrophil granulocytes.

Laboratory value alterations: Alkaline phosphatase, lactic dehydrogenase, uric acid.

Medical considerations/contraindications: Hypersensitivity to Escherichia coli derived proteins.

Side/adverse effects: Causes splenomegaly with chronic use, Sweet's syndrome; development of antibodies not reported.

Additional Dosing Information
Filgrastim may be administered subcutaneously (by rapid injection ^{118} ^{132} or as a continuous 24-hour infusion ^{98} ^{107} ^{132}) or intravenously (as a short 30-minute ^{124} ^{125} ^{144} or continuous 24-hour ^{145} infusion). Intravenous administration should be by infusion over at least 30 minutes ^{245} ^{246}, because there is a decrease in efficacy when filgrastim is administered by rapid intravenous injection ^{105} ^{107} ^{109} ^{113} ^{246}; in addition, it is preferable not to flush the intravenous line after administration is complete ^{246}.

A variety of dosage schedules are used, depending on the indication and the individual patient, for indications not included in the official labeling. The prescriber may consult the medical literature in choosing a specific dosage.

The chemotherapy-induced nadir usually occurs 2 or 3 days earlier during cycles in which filgrastim is administered ^{244}.

Bone pain usually responds to treatment with non-narcotic analgesics ^{01} ^{80} ^{118}; infrequently, it may be severe enough to require narcotic analgesics ^{01} ^{108}.

Parenteral Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to uses that are not included in U.S. product labeling.

FILGRASTIM INJECTION

Usual adult dose
Neutropenia, chemotherapy-related
Intravenous or subcutaneous, 5 mcg (0.005 mg) per kg of body weight once a day via continuous intravenous (IV) infusion or subcutaneous (SC) infusion or given by short-duration IV infusion (15 to 30 minutes) or SC bolus injection^{261}^{262}, beginning no earlier than twenty-four hours after administration of the last dose of cytotoxic chemotherapy ^{01} ^{30} and not during the period twenty-four hours before the administration of chemotherapy^{261}^{262}. This is continued for up to two weeks, until the absolute neutrophil count (ANC) reaches ten thousand per cubic millimeter following the nadir ^{01} ^{30}; in patients receiving dose-intensified chemotherapy, filgrastim should be continued until two consecutive ANC's of at least ten thousand per cubic millimeter are documented ^{244}. Dosage may be increased, if necessary, in increments of 5 mcg (0.005 mg) per kg of body weight for each chemotherapy cycle ^{01}.

Myeloid engraftment following bone marrow transplantation, promotion of
Intravenous infusion (over four or twenty-four hours) or by continuous subcutaneous infusion (over twenty-four hours), 10 mcg (0.01 mg) per kg of body weight a day for twenty-one days beginning not less than twenty-four hours^{261}^{262} after bone marrow infusion, and not less than twenty-four hours after the last dose of chemotherapy ^{170}^{261}^{262}. When the ANC reaches one thousand per cubic millimeter for three consecutive days, the dose of filgrastim may be lowered to 5 mcg (0.005 mg) per kg of body weight a day. If the ANC exceeds one thousand per cubic millimeter for three more additional days, filgrastim may be discontinued. If the ANC subsequently falls below one thousand per cubic millimeter, filgrastim may be resumed at 5 mcg (0.005 mg) per kg of body weight a day. If ANC decreases to less than one thousand per cubic millimeter at any time while the patient is receiving 5 mcg (0.005 mg) per kg of body weight a day, the dose may be increased to 10 mcg (0.01 mg) per kg of body weight a day ^{01}^{261}^{262}.

[Myeloid engraftment following bone marrow transplantation, failure or delay of (treatment) ]¹
Intravenous or subcutaneous, 5 mcg (0.005 mg) per kg of body weight a day for fourteen days ^{170}; course of therapy may be repeated after seven days if engraftment has not occurred. If engraftment has not occurred within seven days after the second fourteen-day course of therapy, a course of 10 mcg (0.01 mg) per kg of body weight a day for fourteen days may be tried ^{170}.

[Myeloid engraftment following hematopoietic stem cell transplantation, promotion of]
Subcutaneous, continuous or intermittent injection, or intravenous infusion, 5 mcg (0.005 mg) per kg of body weight a day ^{260}.

Peripheral progenitor cell yield, enhancement of
Subcutaneous, continuous or intermittent injection, 10 mcg (0.01 mg) per kg of body weight a day for at least four days prior to the first leukapheresis, and continuing until the last leukapheresis ^{01}.

Note: The optimal schedule of filgrastim administration and leukapheresis has not been established. The administration of filgrastim for six or seven days, with leukapheresis on days five, six, and seven, was found to be effective in clinical trials ^{01}.

[Neutropenia, AIDS-associated ]
Subcutaneously, 1 mcg (0.001 mg) per kg of body weight a day or 300 mcg (0.003 mg) three times per week until a normal neutrophil count is reached and maintained (ANC ³ two thousand per cubic millimeter). Dose adjustments may be needed based on subsequent ANC monitoring.^{261}

Neutropenia, severe chronic

Congenital neutropenia:
Subcutaneous, 6 mcg (0.006 mg) per kg of body weight two times a day ^{01}.

Idiopathic or cyclic neutropenia:
Subcutaneous, 5 mcg (0.005 mg) per kg of body weight a day ^{01}.

Note: The dose should be adjusted based on the clinical condition of the patient and the ANC. In some clinical trials, the target ANC was fifteen hundred per cubic millimeter ^{01}.

Note: The calculated dose may be rounded off, within reason, to the nearest vial size (300 or 480 mcg) to reduce wastage ^{240}.

Usual adult prescribing limits
Not defined. Patients have received doses as high as 115 mcg (0.115 mg) per kg of body weight a day without toxic effects ^{244}.

Usual pediatric dose
[Neutropenia, chemotherapy-related ]
Subcutaneous, 5 mcg per kg of body weight once a day^{261}.

Strength(s) usually available
U.S.—

300 mcg (0.3 mg) per mL (300 mcg per 1-mL vial or 480 mcg per 1.6-mL vial) (Rx) [Neupogen (acetate 0.59 mg per mL) ( mannitol 50 mg per mL) ( 0.004% of Tween 80) (sodium 0.035 mg per mL)]

Canada—

300 mcg (0.3 mg) per mL (300 mcg per 1-mL vial or 480 mcg per 1.6-mL vial) (Rx) [Neupogen (acetate 0.59 mg per mL) ( 0.004% of Tween 80) (sodium 0.035 mg per mL)]

Note: The specific activity is 1 ± 0.6 × 10 ⁸ Units per mg as measured by a cell mitogenesis assay ^{01}.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) ^{01}, unless otherwise specified by manufacturer. Protect from freezing ^{01}. Avoid shaking ^{01}.

Preparation of dosage form:
Filgrastim injection may be diluted for administration by intravenous infusion in 5% dextrose injection to produce a concentration greater than or equal to 15 mcg of filgrastim per mL ^{169}, but not recommended for a final dilution concentration less than 5 mcg of filgrastim per mL^{262}. If the final concentration is to be between 5 and 15 mcg per mL, addition of human albumin to the dextrose injection before addition of filgrastim injection is necessary to prevent adsorption to the components of the drug delivery system. The concentration of human albumin in the final solution should be 0.2% (2 mg per mL) ^{169}^{262}; this can be achieved with 2 mL of 5% human albumin in 50 mL of 5% dextrose injection.

Stability:
Filgrastim injection contains no preservative ^{01}. Before use, filgrastim injection may be allowed to reach room temperature for a maximum of 6 hours ^{01}; after that period of time, the vial should be discarded ^{01}.

Incompatibilities:
Filgrastim injection is not compatible with sodium chloride–containing solutions^{01}, as product may precipitate^{262}.

Auxiliary labeling:
• Do not shake.

SARGRAMOSTIM

Summary of Differences
Pharmacology/pharmacokinetics: Mechanism of action—Non–lineage specific; stimulates production of granulocytes, macrophages, and eosinophils.

Laboratory value alterations: Serum albumin, bilirubin, serum creatinine, hepatic enzymes.

Medical considerations/contraindications: Congestive heart failure, hepatic or renal function impairment, pulmonary disease.

Patient monitoring: Body weight, hydration status.

Side/adverse effects: Causes capillary leak syndrome and fluid retention, fever, shortness of breath, pericarditis, thrombophlebitis, thromboses, first-dose reaction, and weakness.

Additional Dosing Information
Sargramostim is administered as an intravenous infusion ^{15} ^{242} via a central venous line ^{29} ^{99} ^{102} ^{127} ^{141} ^{247}. An in-line membrane filter should not be used ^{242}. Sargramostim also may be administered subcutaneously ^{40} ^{95} ^{96} ^{116} ^{119} ^{123} ^{129} ^{130} ^{142} ^{143} ^{144} ^{171} ^{223} ^{224} ^{225} ^{226} ^{227}.

A variety of dosage schedules are used, depending on the indication and the individual patient, for indications not included in the official labeling. The prescriber may consult the medical literature in choosing a specific dosage.

Systemic adverse effects (bone pain, fever, asthenia, etc.) are usually prevented or reversed by administration of analgesics and antipyretics such as acetaminophen ^{06} ^{08} ^{242}.

Fluid retention is reversible on withdrawal or dose reduction, with or without diuretic treatment ^{242}.

If dyspnea occurs during sargramostim administration, the rate of administration should be reduced by half ^{242}. The standard dosing schedule may be used, with careful monitoring, for subsequent infusions ^{242}. If dyspnea persists following infusion rate reduction, the infusion should be discontinued ^{242}.

If the absolute neutrophil count (ANC) exceeds 20,000 or the platelet count exceeds 500,000, sargramostim treatment should be discontinued or the dose reduced by half ^{242}. Excessive blood counts usually return to normal or baseline levels within 3 to 7 days following withdrawal of sargramostim ^{242}.

If progression of the underlying neoplastic disease (non-Hodgkin's lymphoma, acute lymphocytic leukemia, Hodgkin's disease) occurs during sargramostim therapy, it is recommended that sargramostim be discontinued ^{242}.

If blast cells appear, it is recommended that sargramostim be discontinued ^{242}.

Parenteral Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to uses that are not included in U.S. product labeling.

SARGRAMOSTIM FOR INJECTION

Usual adult dose
Myeloid engraftment following bone marrow transplantation, promotion of
Intravenous infusion (over two hours) ^{242} or subcutaneous ^{171}, 250 mcg (0.25 mg) per square meter of body surface area a day for twenty-one days beginning two to four hours after allogeneic or autologous bone marrow infusion, and not less than twenty-four hours after the last dose of chemotherapy or radiotherapy and continued until an absolute neutrophil count (ANC) of fifteen hundred per cubic millimeter is achieved and maintained for three consecutive days ^{100} ^{242}.

Myeloid engraftment following hematopoietic stem cell transplantation, promotion of
Intravenous infusion (continuous) or subcutaneous, 250 mcg (0.25 mg) per square meter of body surface area a day through the period of peripheral blood progenitor cell (PBPC) collection, then immediately following infusion of progenitor cells and continued until an ANC of fifteen hundred per cubic millimeter is achieved and maintained for three consecutive days ^{242}.

Myeloid engraftment following bone marrow transplantation, failure or delay of
Intravenous infusion (over two hours) ^{242} or subcutaneous ^{171}, 250 mcg (0.25 mg) per square meter of body surface area a day for fourteen days ^{102} ^{146} ^{242}; course of therapy may be repeated after seven days if engraftment has not occurred ^{242}. If engraftment has not occurred within seven days after the second fourteen-day course of therapy, a course of 500 mcg (0.5 mg) per square meter of body surface area a day for fourteen days may be tried ^{242}.

Neutropenia, chemotherapy-related, in older adult patients (55 years of age and older) with acute myelocytic leukemia (AML)
Intravenous infusion (over four hours) or subcutaneous, 250 mcg (0.25 mg) per square meter of body surface area a day beginning approximately on day eleven (or four days after completion of induction chemotherapy) if the bone marrow is hypoplastic with fewer than five percent blasts on day ten ^{242}.

[Neutropenia, chemotherapy-related ]
Intravenous infusion (over two hours) or subcutaneous, 250 mcg (0.25 mg) per square meter of body surface area a day ^{172} beginning no earlier than twenty-four hours after administration of the last dose of cytotoxic chemotherapy. This is continued for up to two weeks ^{172}, until the ANC reaches ten thousand per cubic millimeter following the nadir; in patients receiving dose-intensified chemotherapy, sargramostim should be continued until two consecutive ANC's of at least ten thousand per cubic millimeter are documented. Dosage may be increased, if necessary, in an increment of 250 mcg (0.25 mg) per square meter of body surface area, up to 500 mcg (0.5 mg) per square meter of body surface area ^{172}.

Peripheral progenitor cell yield, enhancement of
Intravenous infusion (continuous) or subcutaneous, 250 mcg (0.25 mg) per square meter of body surface area a day through the period of peripheral blood progenitor cell (PBPC) collection, then immediately following infusion of progenitor cells and continued until an ANC of fifteen hundred per cubic millimeter is achieved and maintained for three consecutive days ^{242}.

Note: The calculated dose may be rounded off, within reason, to the nearest vial size (250 or 500 mcg) to reduce wastage ^{240}.

Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—

250 mcg (0.25 mg) (Rx) [Leukine (lyophilized) (mannitol 40 mg) (sucrose 10 mg) (tromethamine 1.2 mg)]

500 mcg (0.5 mg) (Rx) [Leukine (lyophilized) (mannitol 40 mg) (sucrose 10 mg) (tromethamine 1.2 mg)]

Canada—
Not commercially available.

Note: The specific activity is approximately 5 × 10 ⁷ colony forming units per mg in a normal human bone marrow colony formation assay ^{242}.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) ^{242}, unless otherwise specified by manufacturer. Protect reconstituted solution from freezing ^{242}. Avoid shaking solution ^{242}.

Preparation of dosage form:
Lyophilized sargramostim for injection is reconstituted by adding 1 mL of sterile water for injection (without preservative) to the vial containing 250 or 500 mcg, producing a clear, colorless solution containing 250 or 500 mcg of sargramostim per mL, respectively ^{242}. To avoid foaming during dissolution, the diluent should be directed at the side of the vial and the contents swirled gently; excessive or vigorous agitation should be avoided; the vial should not be shaken ^{242}.

The reconstituted solution is diluted further for administration by intravenous infusion with 0.9% sodium chloride injection ^{100} ^{242}. If the final concentration of sargramostim is to be less than 10 mcg per mL, addition of human albumin to the saline before addition of sargramostim solution is necessary to prevent adsorption to the components of the drug delivery system ^{242}. The concentration of human albumin in the final solution should be 0.1% (1 mg per mL); this can be achieved with 1 mL of 5% human albumin in 50 mL of 0.9% sodium chloride injection ^{100} ^{242}.

Stability:
Because lyophilized sargramostim contains no antibacterial preservative, solutions reconstituted with sterile water for injection (without preservative) should be used within 6 hours and any unused portion should be discarded ^{242}. Lyophilized sargramostim reconstituted with bacteriostatic water for injection may be stored for 20 days between 2 and 8 °C (36 and 46 °F) ^{242}.

Auxiliary labeling:
• Do not shake.

SARGRAMOSTIM INJECTION

Usual adult dose
See Sargramostim for Injection .

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—

500 mcg (0.5 mg) per mL (Rx) [Leukine (benzyl alcohol 1.1% ) (mannitol 40 mg) (sucrose 10 mg) (tromethamine 1.2 mg)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) ^{242}, unless otherwise specified by manufacturer. Protect reconstituted solution from freezing ^{242}.

Preparation of dosage form:
Sargramostim injection for administration by intravenous infusion is diluted with 0.9% sodium chloride injection ^{100} ^{242}. The solution should not be shaken ^{242}. If the final concentration of sargramostim is to be less than 10 mcg per mL, it is necessary to add human albumin to the saline before addition of sargramostim solution in order to prevent adsorption of sargramostim onto the components of the drug delivery system ^{242}. The concentration of human albumin in the final solution should be 0.1% (1 mg per mL); this can be achieved with 1 mL of 5% human albumin in 50 mL of 0.9% sodium chloride injection ^{100} ^{242}.

Stability:
After the vial has been entered, undiluted sargramostim injection may be stored for 20 days between 2 and 8 °C (36 and 46 °F) ^{242}. Unopened vials of sargramostim injection are stable for 14 days when stored at 30 °C (86 °F) ^{255}. After dilution with 0.9% sodium chloride injection in polyvinyl chloride bags to final concentrations of sargramostim of 2.5 mcg per mL (mcg/mL), 8 mcg/mL, or 12 mcg/mL, sargramostim injection may be stored for 48 hours between 2 and 8 °C (36 and 46 °F) or 25 °C (77 °F) ^{255}.

Auxiliary labeling:
• Do not shake.

Revised: 07/23/2001

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Hold.

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Vellenga E, Halie MR. Effects of colony-stimulating factors on myeloid leukemia cells. In: Mertelsmann R, Herrmann F, editors. Hematopoietic growth factors in clinical applications. New York: Marcel Dekker; 1990. p. 363-79.

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Groopman JE. Status of colony-stimulating factors in cancer and AIDS. Semin Oncol 1990 Feb; 17(1 Suppl 1): 31-7.

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Furman WL, Crist WM. Potential uses of recombinant human granulocyte-macrophage colony-stimulating factor in children. Am J Pediatr Hematol Oncol 1991; 13: 388-99.

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Quesenberry PJ. Treatment of marrow stem-cell disorder with granulocyte colony-stimulating factor [editorial]. N Engl J Med 1989; 320: 1343-5.

Sheridan WP. The role of colony-stimulating factors in bone marrow transplantation. Cancer Invest 1991; 9: 221-8.

Lazarus HM, Andersen J, Chen MG et al: Recombinant granylocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group trial. Blood 1991; 78: 830-7.

Nemunaitis J, Rabinowe SN, Singer JW et al: Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med 1991; 324: 1773-8.

Peters WP. Use of cytokines during prolonged neutropenia associated with autologous bone marrow transplantation. Rev Infect Dis 1991; 13: 993-6.

Nemunaitis J, Singer JW, Buckner CD et al: Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation. Blood 1990; 76: 245-53.

Haas R, Ho AD, Bredthauer W et al: Successful autologous transplantation of blood stem cells mobilized with recombinant human granulocyte-macrophage colony-stimulating factor. Exp Hematol 1990; 18: 94-8.

Kitayama H, Ishikawa J, Yamagami T et al: Granulocyte colony-stimulating factor in allogeneic bone marrow transplantation. Jpn J Clin Oncol 1989; 19: 367-72.

Blazar BR, Kersey JH, McGlave PB et al: In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73: 849-57.

Gianni AM, Bregni M, Stern AC et al: Granulocyte-macrophage colony-stimulating factor to harvest circulating haemopoietic stem cells for autotransplantation. Lancet 1989; 2: 580-4.

Sheridan WP, Wolf M, Lusk J et al: Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 1989; 2: 891-5.

Taylor KM, Jagannath S, Spitzer G et al: Recombinant human granulocyte colony-stimulating factor hastens granulocyte recovery after high-dose chemotherapy and autologous bone marrow transplantation in Hodgkin's disease. J Clin Oncol 1989; 17: 1791-9.

Brandt SJ, Peters WP, Atwater S et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 1988; 318: 869-76.

Sauter C. Granulocyte-macrophage colony-stimulating factor and marrow transplantation (letter). N Engl J Med 1988; 319: 870.

Peters WP, Brandt SJ. Granulocyte-macrophage colony-stimulating factor and marrow transplantation (letter)—Reply. N Engl J Med 1988; 319: 870-1.

Appelbaum FR, Nemunaitis J. Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) following autologous marrow transplantation in man. Behring Inst Mitt 1988; 83: 145-8.

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Hogan KR, Peters MD. Granulocyte-macrophage colony-stimulating factor in neutropenia. DICP 1991; 25: 32-5.

Buchner T, Hiddemann W, Koenigsmann M et al: Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78: 1190-7.

Rusthoven J, Levin L, Eisenhauer E et al: Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor. J Natl Cancer Inst 1991; 83: 1748-53.

Hoekman K, Wagstaff J, van Groeningen CJ et al: Effects of recombinant human granulocyte-macrophage colony-stimulating factor on myelosuppression induced by multiple cycles of high-dose chemotherapy in patients with advanced breast cancer. J Natl Cancer Inst 1991; 83: 1546-53.

Crawford J, Ozer H, Stoller R et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325: 164-70.

De Vries EGE, Biesma B, Willemse PHB et al: A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma. Cancer Res 1991; 51: 116-22.

Lichtman S, Ratain M, Budman DR et al: Phase I trial of recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) plus high dose cyclophosphamide (Cyc) in solid tumors [abstract 256]. Proc Am Soc Clin Oncol 1990; 9: 66.

Vadhan-Raj S, Broxmeyer HE, Hittelman WN et al: Abrogating chemotherapy (CT)-induced myelosuppression by GM-CSF: optimizing the schedule [abstract 1241]. Proc Am Soc Clin Oncol 1991; 10: 349.

Steward WP, Verweij J, Somers R et al: High dose chemotherapy (CT) with two schedules of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in the treatment of advanced adult soft tissue sarcomas (STS) [abstract 1240]. Proc Am Soc Clin Oncol 1991; 10: 349.

Herrmann F, Schulz G, Wieser M et al: Effect of granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy. Am J Med 1990; 88: 619-24.

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Ohno R, Tomonaga M, Kobayashi T et al: Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med 1990; 323: 871-7.

Ho AD, Del Valle F, Engelhard M et al: Mitoxantrone/high-dose ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study. Cancer 1990; 66: 423-30.

Gianni AM, Bregni M, Siena S et al: Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma. J Clin Oncol 1990; 8: 768-78.

Estey EH, Dixon D, Kantarjian HM et al: Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75: 1766-9.

Logothetis CJ, Dexeus FH, Sella A et al: Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor. J Natl Cancer Inst 1990; 82: 667-72.

Jost LM, Picher G, Stahel RA. Placebo controlled phase I/II study of subcutaneous GM-CSF in patients with germ cell tumors undergoing chemotherapy. Ann Oncol 1990; 1: 439-42.

Neidhart J, Mangalik A, Kohler W et al: Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation. J Clin Oncol 1989; 7: 1685-92.

Morstyn G, Campbell L, Lieschke G et al: Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy. J Clin Oncol 1989; 7: 1554-62.

Vadhan-Raj S, Broxmeyer HE, Spitzer G et al: Stimulation of nonclonal hematopoiesis and suppression of the neoplastic clone after treatment with recombinant human granulocyte-macrophage colony-stimulating factor in a patient with therapy-related myelodysplastic syndrome. Blood 1989; 74: 1491-8.

Salmon SE, Liu R. Effects of granulocyte-macrophage colony-stimulating factor on in vitro growth of human solid tumors. J Clin Oncol 1989; 7: 1346-50.

Shepherd FA, Goss PE, Rusthoven J et al: Phase I trial for granulocyte-macrophage colony-stimulating factor with high-dose cisplatin and etoposide for treatment of small-cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. J Natl Cancer Inst 1992; 84: 59-60.

Bar MH, Aronson FR. Recombinant human GM-CSF in myelosuppression of chemotherapy (continued) (letter). N Engl J Med 1989; 320: 939-40.

Antman KH, Elias AM, Cannistra SA et al: Recombinant human GM-CSF in myelosuppression of chemotherapy (continued) (letter)—Reply. N Engl J Med 1989; 320: 940.

Pollak MN. Recombinant GM-CSF in myelosuppression of chemotherapy (letter). N Engl J Med 1989; 320: 253.

Brennan LV. Recombinant GM-CSF in myelosuppression of chemotherapy (letter). N Engl J Med 1989; 320: 253.

Antman K, Elias S, Cannistra SA et al: Recombinant GM-CSF in myelosuppression of chemotherapy (letter)—Reply. N Engl J Med 1989; 320: 253-4.

Antman KS, Griffin JD, Elias A et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 1988; 319: 593-8.

Herrmann F, Wieser M, Schulz G et al: Single daily subcutaneous administration of rHuGM-CSF ameliorates hematopoietic toxicity of chemotherapy in outpatients [abstract 120]. Blood 1988; 72: 40.

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Vose JM, Bierman PJ, Kessinger A et al: The use of recombinant human granulocyte-macrophage colony-stimulating factor for the treatment of delayed engraftment following high dose therapy and autologous hematopoietic stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant 1991; 7: 139-43.

Griffin JD, Young D, Herrmann F et al: Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia. Blood 1986; 67: 1448-53.

Hoang T, Nara N, Wong G et al: Effects of recombinant GM-CSF on the blast cells of acute myeloblastic leukemia. Blood 1986; 68: 313-6.

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Delwel R, Dorssers L, Touw I et al: Human recombinant multilineage colony stimulating factor (interleukin-3): stimulator of acute myelocytic leukemia progenitor cells in vitro. Blood 1987; 70: 333-6.

Begley CG, Metcalf D, Nicola NA et al: Primary human myeloid leukemia cells: comparative responsiveness to proliferative stimulation by GM-CSF or G-CSF and membrane expression of CSF receptors. Leukemia 1987; 1: 1-8.

Gavosto F et al: Granulocyte-macrophage colony-stimulating factor and myelodysplastic syndromes (letter). N Engl J Med 1988; 319: 51.

Ganser A, Volkers B, Greher J et al: Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes—a phase I/II trial. Blood 1989; 73: 31-7.

Thompson JA, Lee DJ, Kidd P et al: Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. J Clin Oncol 1989; 7: 629-37.

Negrin RS, Haeuber DH, Nagler A et al: Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood 1990; 76: 36-43.

Responses to panel question #1, 3/92.

Responses to panel question #2a and 2b, 3/92.

Responses to panel question #3, 3/92.

Responses to panel question #4, 3/92.

Responses to panel question #5, 3/92.

Responses to panel question #6a (1) and (2), 3/92.

Responses to panel question #6a (3), 3/92.

Responses to panel question #6a (7) and #7a (1) and (2), 3/92.

Responses to panel question #7a (3), 3/92.

Reviewer comment, panel round 3/92.

Reviewer comment, panel round 3/92.

Responses to panel question #10, 3/92.

Responses to panel question #11, 3/92.

Reviewer comment, panel round 3/92.

Responses to panel question #12, 3/92.

Responses to panel question #13, 3/92.

Responses to panel question #14, 3/92.

Anderson H, Gurney H, Thatcher N et al: Recombinant human GM-CSF in small cell lung cancer: a phase I/II study. Cancer Res 1991; 121: 155-61.

Ardizzoni A, Sertoli MR, Corcione A et al: Accelerated chemotherapy with or without GM-CSF for small cell lung cancer: a non-randomized study. Eur J Cancer 1990; 26: 937-41.

Barlogie B, Jagannath S, Dixon D et al: High dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma. Blood 1990; 4: 677-80.

Bregni M, Siena S, Ravagnani F et al: High dose cyclophosphamide in patients with operable breast cancer: recombinant GM-CSF ameliorates drug-induced leukopenia and thrombocytopenia. Haematologica 1990; 75 Suppl 1: 95-8.

Kantarjian H, Estey E, O'Brien S et al: Intensive chemotherapy with mitoxantrone and high dose cytosine arabinoside followed by GM-CSF in the treatment of patients with ALL. Blood 1992; 4: 876-81.

Cannistra SA, Di Carlo J, Groshek P et al: Simultaneous administration of granulocyte-macrophage colony-stimulating factor and cytosine arabinoside for the treatment of relapsed acute myeloid leukemia. Leukemia 1991; 5: 230-8.

Bettelheim P, Valent P, Andreeff M et al: Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia. Blood 1991; 77: 700-11.

Ho AD, Haas R, Korbling M et al: Utilization of recombinant human GM-CSF to enhance peripheral progenitor cell yield for autologous transplantation. Bone Marrow Transplant 1991; 7 Suppl 1: 13-7.

Socinski MA, Cannistra SA, Elias A et al: Granulocyte-macrophage stimulating factor expands the circulating hemopoietic progenitor cell compartment in man. Lancet 1988; 1: 1194-8.

Siena S, Bregni M, Brando B et al: Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989; 74: 1905-16.

Groopman JE, Mitsuyasu RT, DeLeo MJ et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med 1987; 317: 593-8.

Baldwin GC, Gasson JC, Quan SG et al: Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci U S A 1988; 85: 2763-6.

Groopman JE. Granulocyte-macrophage colony-stimulating factor in human immunodeficiency virus disease [review]. Semin Hematol 1990; 27(3 Suppl 3): 8-14.

Pluda JM, Yarchoan R, Smith PD et al: Subcutaneous recombinant granuloycte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection. Blood 1990; 76: 463-72.

Miles SA, Mitsuyasu RT, Moreno J et al: Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. Blood 1991; 77: 2109-17.

Scadden DT, Bering HA, Levine JD et al: Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma. J Clin Oncol 1991; 9: 802-8.

Kaplan LD, Kahn JO, Crowe S et al: Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial. J Clin Oncol 1991; 9: 929-40.

Advani R, Chao N, Horning S et al: GM-CSF as an adjunct to autologous hematopoietic stem cell transplantation for lymphoma. Ann Intern Med 1992; 116: 183-89.

Bregni M, Siena S, Magni M et al: Circulating hematopoietic progenitors mobilized by cancer chemotherapy and by GM-CSF in the treatment of high-grade non-Hodgkin's lymphoma. Leukemia 1991; 5: 123-7.

Yarchoan R, Pluda JM, Perno C et al: Anti-retroviral therapy of human immunodeficiency virus infection: current strategies and challenges for the future. Blood 1991; 78: 859-84.

Pluda JM, Mitsuya H, Yarchoan R. Hematologic effects of AIDS therapies. Hematol Oncol Clin North Am 1991; 5: 229-48.

Davey R, Davey V, Metcalf J et al: A phase I/II trial of zidovudine, interferon-alpha, and GM-CSF in the treatment of HIV Type 1 infection. J Infect Dis 1991; 164: 43-52.

Mitsuyasu R. Hematopoietic growth factors in the treatment of patients with HIV infection. Biotherapy 1990; 2: 173-81.

Levine JD. Allan J, Tessitore J et al: GM-CSF ameliorates zidovudine-induced neutropenia in patients with acquired AIDS/AIDS-related complex. Blood 1991; 12: 3148-54.

Hardy WD. Combined ganciclovir and recombinant GM-CSF in the treatment of cytomegalovirus retinitis in AIDS patients. J Acquir Immune Defic Syndr 1991; 4: 522-8.

Kurzrock R, Talpaz M, Gomez JA et al: Differential dose-related haematological effects of GM-CSF in pancytopenia: evidence supporting the advantage of low- over high-dose administration in selected patients. Br J Haematol 1991; 78: 352-8.

Verhoef G, Boogaerts M. In vivo administration of granulocyte-macrophage colony stimulating factor enhances neutrophil function in patients with myelodysplastic syndromes. Br J Haematol 1991; 79: 177-84.

Vadhan-Raj S, Keating M, LeMaistre A et al: Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 1987; 317: 1545-52.

Negrin RS, Haeuber DH, Nagler A et al: Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor. A phase I-II trial. Ann Intern Med 1989; 110: 976-84.

Herrmann F, Lindemann A, Klein H et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome with excess blasts. Leukemia 1989; 3: 335-8.

Estey EH, Kurzrock R, Talpaz M et al: Effects of low doses of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes. Br J Haematol 1991; 77: 291-5.

Yoshida Y, Hirashima K, Asano S et al: A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes. Br J Haematol 1991; 78: 378-84.

Nagler A, Greenberg PL. Granulocyte-monocyte and granulocyte-colony stimulating factors in myelodysplastic syndromes. Leuk Lymphoma 1991; 5: 219-30.

Ganser A, Ottmann OG, Erdmann H et al: The effect of recombinant human granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity in chronic severe neutropenia. Ann Intern Med 1989; 111: 887-92.

Weston B, Axtell RA, Todd RF et al: Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis. J Pediatr 1991; 118: 229-34.

Bonilla MA, Gillio AP, Ruggeiro M et al: Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med 1989; 320: 1574-80.

Welte K, Zeidler C, Reiter A et al: Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 1990; 75: 1056-63.

Tsunogake S, Nagashima S, Maekawa R et al: Myeloid progenitor cell growth characteristics and effect of G-CSF in a patient with congenital cyclic neutropenia. Int J Hematol 1991; 54: 251-6.

Jakubowski AA, Souza L, Kelly F et al: Effects of human granulocyte colony-stimulating factor in a patient with idiopathic neutropenia. N Engl J Med 1989; 320: 38-42.

Sonoda Y, Yashige H, Fujii H et al: Treatment of idiopathic neutropenia in the elderly with recombinant human granulocyte colony-stimulating factor. Acta Haematol 1991; 85: 146-52.

Kurzrock P, Talpz M, Gutterman J. Treatment of cyclic neutropenia with very low doses of GM-CSF. Am J Med 1991; 91: 317-8.

Boxer LA, Hutchinson R, Emerson S. Recombinant human granulocyte-colony-stimulating factor in the treatment of patients with neutropenia. Clin Immunol Immunopathol 1992 Jan; 62: S39-S46.

Delannoy A, Gehenot M. Colony-stimulating factor and drug-induced agranulocytosis (letter). Ann Intern Med 1989; 110: 942-3.

Muroi K, Ito M, Sasaki R et al: Treatment of drug-induced agranulocytosis with granulocyte-colony stimulating factor (letter). Lancet 1989; 2: 55.

Heinrich B, Gross M, Goebel FD et al: Methimazole-induced agranulocytosis and granulocyte-colony stimulating factor (letter). Ann Intern Med 1989; 111: 621-2.

Palmblad J, Jonson B, Kanerud L. Treatment of drug-induced agranulocytosis with recombinant GM-CSF. J Intern Med 1990; 228: 537-9.

Nand S, Bayer R, Prinz RA et al: Granulocyte-macrophage colony stimulating factor for the treatment of drug induced agranulocytosis. Am J Hematol 1991; 37: 267-9.

Gerl A, Gerhartz H, Wilmanns W. GM-CSF for agranulocytosis (letter). J Intern Med 1991; 230: 89-91.

Panelist comment, 3/92.

Manufacturer comment, 3/92.

Aglietta M, Monzeglio C, Placibello W et al: GM-CSF: Intravenous versus subcutaneous treatment. Leukemia 1990; 4: 523.

Cebon J, Dempsey P, Fox R et al: Pharmacokinetics of human granulocyte-macrophage colony-stimulating factor using a sensitive immunoassay. Blood 1988; 72: 1340-7.

Rifkin RM, Hersh EM, Hultquist KN et al: Subcutaneous (SC) recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates myelopoiesis in patients (PTS) with bone marrow failure. Proc Am Soc Clin Oncol, San Francisco: 1989; 178 [Abstract].

Schwinghammer TL, Shadduck RK, Waheed A et al: Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) after intravenous infusion and subcutaneous injection. Pharmacotherapy 1991; 11: 105 [Abstract 60].

Sulecki M, Rosenfeld CS, Evans C et al: Comparison of intravenous versus subcutaneous recombinant human granulocyte macrophage colony-stimulating factor in myelodysplasia (MDS): a phase I crossover study. Blood 1989; 74 Suppl 1:155a [Abstract 576].

Responses to panel question #3b, 5/92. Information in the Note also applies to filgrastim.

Responses to panel question #4, 5/92.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 61.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 143.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 322.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 337.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 1075.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 1237.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 1326.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 1332.

Proceedings ASCO meeting, San Diego, May 17-19, 1992, abstract no. 1405.

Manufacturer comment, 5/92.

Panel comment, 5/92.

Park JW, Mehrota B, Barnett B et al: The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med 1992 Jun 15; 116(12 Pt 1): 996-8.

Leukine package insert (Immunex—US), Rev 2/98, Rec 4/99.

Hold.

Personal communication from AMGEN, 2/28/91, to Melissa Furio, Bryn Mawr Hospital, Bryn Mawr, PA; same as communication to Sandra Boyer, USP DID, 2/22/91.

Personal communication from AMGEN, 9/10/91, to Melissa Furio, Bryn Mawr Hospital, Bryn Mawr, PA.

Drug Product Problem Reporting Program correspondence, 10/2/91.

Shriner DA. Colony-stimulating factors: clinical trials in humans. Highlights on Antineoplastic Drugs 1990 Feb/Mar; 6-7, 11-4.

Brown SL, Hill E. Subcutaneous granulocyte colony-stimulating factor and acute anaphylaxis (letter)—Reply. N Engl J Med 1991; 325: 587.

Masaoka T, Takaku F, Kato S et al: Recombinant human granulocyte colony-stimulating factor in allogeneic bone marrow transplantation. Exp Hematol 1989; 17: 1047-50.

Peters WP, Kurtzberg J, Atwater S et al: Comparative effects of rHuG-CSF and rHuGM-CSF on hematopoietic reconstitution and granulocyte function following high dose chemotherapy and autologous bone marrow transplantation (ABMT) [abstract]. Blood 1988; 72: 130a.

Taylor K, Spitzer G, Jagannath S et al: Phase II study of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in Hodgkin's disease after high-dose chemotherapy with ABMT [abstract]. Blood 1988; 72: 135a.

Kodo H, Tajika K, Takahashi S et al: Acceleration of neutrophilic granulocyte recovery after bone marrow transplantation by administration of recombinant human granulocyte colony-stimulating factor. Lancet 1988; 2: 38-9.

Steward WP, Scarffe JH, Dirix LY et al: Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer. Br J Cancer 1990; 61: 749-54.

American Society of Clinical Oncology. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1996; 14: 1957-60.

Personal communication, Kim M. Murray, PharmD, Professional Services Manager, Immunex Corporation, 9/4/97.

Rowe J, Anderson J, Mazza J et al: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: A study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86: 457-62.

Stone R, Berg D, George S et al: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 1995; 332: 1671-7.

Dombret H, Chastang C, Fenaux P et al: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N Engl J Med 1995; 332: 1678-83.

Klumpp T, Mangan K, Goldberg S et al: Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: a prospective, randomized trial. J Clin Oncol 1995; 15: 949-54.

Neupogen package insert (Amgen—Canada), Rev 2/96, Rec 8/97.

Product Information: Neupogen®, filgrastim. Amgen Canada, Mississauga, Ontario, Canada, (PI revised 12/1998) reviewed 3/2001.

Product Information: Neupogen®, filgrastim. Amgen, Thousand Oaks, California, (PI revised 6/2000) reviewed 3/2001.

Vaughan MM, Moore J, Riches PG et al: GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma [In Process Citation]. Ann Oncol 2000; 11(9): 1183-1189.

Mastrangelo MJ, Maguire HC & Lattime EC: Intralesional vaccinia/GM-CSF recombinant virus in the treatment of metastatic melanoma. Adv Exp Med Biol 2000; 465: 391-400.

Keilholz U, Scheibenbogen CM, Hoffman U et al: Therapeutic vs. adjuvant peptide vaccination: comparison of two phase I/II trials in melanoma patients. Proc Am Soc Clin Oncol 2000; 19: 556a [Abst 2191].

de Gast GC, Klumpen HJ, Vyth-Dreese FA et al: Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage-colony stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma. Clin Cancer Res 2000; 6(4): 1267-1272.

Lawson D & Kirkwood JM: Granulocyte macrophage-colony stimulating factor: another cytokine with adjuvant therapeutic benefit in melanoma? J Clin Oncol 2000; 18(8): 1603-1605.

Spitler LE, Grossbard ML, Ernstoff MS et al: Adjuvant therapy of stage III and IV malignant melanoma using granulocyte macrophage-colony stimulating factor. Clin Oncol 2000; 18(8): 1614-1621.

Tretter CPG, Schwaab T, Heaney JA et al: Induction of T-cell precursor frequency in patients with high-risk renal cell carcinoma (RCC) and melanoma treated with autologous tumor vaccine and GM-CSF. Proc Am Soc Clin Oncol 2000; 19: 469a [Abst 1841].

Scheibenbogen C, Schmittel A, Keilholz U et al: Phase II trial of vaccination with tyrosinase peptides and GM-CSF inpatients with metastatic melanoma. J Immunotherapy 2000; 23(2): 275-281.

Urba WJ, Smith JW, Kurt RA et al: Immune effects of escalating doses of granulocyte macrophage-colony stimulating factor (GM-CSF) added to a fixed low-dose interleukin-2 (IL-2) regimen: a randomized phase I trial in patients with metastatic melanoma and renal cell carcinoma. Proc Am Soc Clin Oncol 2000; 19: 457a [Abst 1794].

Gajewski TF & Flickinger SR: A phase II study of outpatient chemoimmunotherapy using cisplatin and DTIC followed by GM-CSF and IFN-a2b in patients (Pts) with metastatic melanoma. Proc Am Soc Clin Oncol 2000; 19: 576a [Abst 2271].

Gibbs P, O'Day S, Richards J et al: A multicenter phase II study of modified biochemotherapy (BCT) for stage IV melanoma, incorporating temozolomide, decrescendo interleukin-2 (IL-2), and GM-CSF. Proc Am Soc Clin Oncol 2000; 19: 572a [Abst 2255].

Nasi ML, Lieberman P, Busam KJ et al: Intradermal injection of GM-CSF in patients with metastatic melanoma recruits dendritic cells. Cytokines 1999; 5: 139-144.

Mastrangelo MJ, Maguire HC, McCue P et al: Intratumoral (IT) recombinant GM-CSF encoding vaccinia virus as gene therapy in patients (Pts) with melanoma. Proc Am Soc Clin Oncol 1999; 18: 431a [Abst 1660].

Leong SP, Enders-Zohr P, Zhou YM et al: Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma. J Immunotherapy 1999; 22(2): 166-174.

Chang JWC, Vaquerano JE, Cadbury P et al: Active specific immunotherapy with autologous tumor vaccine plus recombinant Granylocyte Macrophage-Colony Stimulating Factor (GM-CSF) with and without interferon alfa-2B mediates tumor regression in stage IV melanoma patients. Proc Am Soc Clin Oncol 1999; 440a: [Abst 1697].

Ravaud A, Delaunay M, Chevreau C et al: GM-CSF vs. GM-CSF + DTIC in first-line chemotherapy for metastatic melanoma (MM): randomized phase II trials. Proc Am Soc Clin Oncol 1999; 18: 530a [Abst 2046].

de Gast GC, Klümpen HJ, Vyth-Dreese FA et al: Phase I trial of combined immunotherapy with subcutaneous GM-CSF, low-dose IL-2, and IFNa in progressive metastatic melanoma or renal cell carcinoma. Proc Am Soc Clin Oncol 1999; 18: 446a [Abst 1720].

Vaughan MM, Moore J, Riches PG, et al. Phase I/II trial of biochemotherapy: cisplatin, DTIC, interleukin-2 (IL-2), and interferon-alfa (IFN) in combination with GM-CSF in malignant melanoma. Proc Am Soc Clin Oncol 1998; 507a [Abst 1955].

Daponte A, Presutti F, Comella P et al: Cisplatin (CDDP), dacarbazine (DTIC), fotemustine (FM), and interferon-a2B (IFN-a2B) in advanced melanoma. A phase II study of Italian Melanoma Study Group (IMSG). Proc Am Soc Clin Oncol 1998; 17: 509a [Abst 1961].

Schachter J, Rakowsky E, Sulkes A et al: A sequential four-drug chemotherapy and biotherapy with interferon alpha and GM-CSF--an innovative protocol for the treatment of metastatic melanoma. Cancer Biother Radiopharm. 1998 Jun; 13(3): 155-164.

Jäger E, Ringhoffer M, Dienes HP et al: Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 1996; 67: 54-62.

Si Z, Hersey P & Coates AS: Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. Melanoma Res 1996; 6(3): 247-255.

Reviewers' consensus on the use of sargramostim for the treatment of melanoma, 7/10/01.

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