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

References

Neupogen package insert (Amgen—US), Rev 4/98, Rec 6/98.

Cairo MS. Hematopoietic growth factors: a new frontier in immunotherapy. J Pediatr 1991; 118: S1-S3.

Mertelsmann R. Hematopoietins: biology, pathophysiology, and potential as therapeutic agents. Ann Oncol 1991; 2: 251-63.

Kanz L, Lindemann A, Oster W et al: Hemopoietins in clinical oncology. Am J Clin Oncol 1991; 14 Suppl 1: S27-S33.

DiJulio J. Hematopoiesis: an overview. Oncol Nurs Forum 1991; 18(2 Suppl): 3-6.

Balmer CM. Clinical use of biologic response modifiers in cancer treatment: an overview. Part II. Colony-stimulating factors and interleukin-2. DICP 1991; 25: 490-8.

Golde DW. Overview of myeloid growth factors. Semin Hematol 1990; 27(3 Suppl 3): 1-7.

Groopman JE, Molina J, Scadden DT. Hematopoietic growth factors. Biology and clinical applications. N Engl J Med 1989; 321: 1449-59.

Gabrilove JL. Introduction and overview of hematopoietic growth factors. Semin Hematol 1989; 26(2 Suppl 2): 1-4.

Glaspy JA, Golde DW. Clinical applications of the myeloid growth factors. Semin Hematol 1989; 26(2 Suppl 2): 14-7.

Morstyn G, Burgess AW. Hemopoietic growth factors: a review. Cancer Res 1988; 48: 5624-37.

Nienhuis AW. Hematopoietic growth factors. Biologic complexity and clinical practice [editorial]. N Engl J Med 1988 ; 318: 916-8.

Deisseroth A, Wallerstein R. Use of hematopoietic growth factors. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. Philadelphia: JB Lippincott Co; 1989. p. 2060-4.

Anon. Granulocyte colony-stimulating factors. Med Lett Drugs Ther 1991 Jun 28; 33: 61-3.

Nemunaitis J, Singer JW. The use of recombinant human granulocyte-macrophage colony stimulating factor in autologous bone marrow transplantation. Am J Clin Oncol 1991; 14 Suppl 1: S15-S18.

Schulz G, Frisch J, Greifenberg B et al: New therapeutic modalities for the clinical use of rhGM-CSF in patients with malignancies. Am J Clin Oncol 1991; 14 Suppl 1: S19-S26.

Ganser A, Seipelt G, Hoetzer D. The role of GM-CSF, G-CSF, interleukin-3, and erythropoietin in myelodysplastic syndromes. Am J Clin Oncol 1991; 14 Suppl 1: S34-S39.

Scadden DT, Bering HA, Levine JD et al: GM-CSF as an alternative to dose modification of the combination zidovudine and interferon-alpha in the treatment of AIDS-associated Kaposi's sarcoma. Am J Clin Oncol 1991; 14 Suppl 1: S40-S44.

Haeuber D. Future strategies in the control of myelosuppression: the use of colony-stimulating factors. Oncol Nurs Forum 1991; 18(2 Suppl): 16-21.

Hold.

Hold.

Metcalf D. The colony stimulating factors. Discovery, development, and clinical applications. Cancer 1990; 65: 2185-95.

Wakefield PE, James WD, Samlaska CP et al: Colony-stimulating factors. J Am Acad Dermatol 1990; 23(5 Part 1): 903-12.

Griffin JD (consultant). Colony-stimulating factors: a review. New York: Triclinica Communications Inc; 1990. p.1-31.

Hold.

Hold.

Nimer SD, Champlin RE, Golde DW. Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor. JAMA 1988; 260: 3297-300.

Peters WP. The effect of recombinant human colony-stimulating factors on hematopoietic reconstitution following autologous bone marrow transplantation. Semin Hematol 1989; 26(2 Suppl 2): 18-23.

Weisbart RH (moderator), Gasson JC, Golde DW (discussants). Colony-stimulating factors and host defense. Ann Intern Med 1989; 110: 297-303.

Hollingshead LM, Goa KL. Recombinant granulocyte colony-stimulating factor (rG-CSF). A review of its pharmacological properties and prospective role in neutropenic conditions. Drugs 1991; 42: 300-30.

Burdach S. The granulocyte/macrophage-colony stimulating factor (GM-CSF): basic science and clinical application. Klin Padiatr 1991; 203: 302-10.

Morstyn G, Lieschke GJ, Sheridan W et al: Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor. Semin Hematol 1989; 26(2 Suppl 2): 9-13.

Sakamoto KM, Golde DW, Gasson JC. The biology and clinical applications of granulocyte-macrophage colony-stimulating factor. J Pediatr 1991; 118: S17-S20.

Ruef C, Coleman DL. Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Infect Dis 1990; 12: 41-62.

Mazur EM, Cohen JL. Basic concepts of hematopoiesis and the hematopoietic growth factors. Clin Pharmacol Ther 1989; 46: 250-6.

Metcalf D, Morstyn G. Colony-stimulating factors: general biology. In: DeVita VT, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer. New York: JB Lippincott 1991; p. 417-44.

Gabrilove J. Colony-stimulating factors: clinical status. In: DeVita VT, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer. New York: JB Lippincott 1991; p. 445-53.

Cannistra SA, Griffin JD. Regulation of the production and function of granulocytes and monocytes. Semin Hematol 1988; 25: 173-88.

Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 1986; 67: 257-67.

Shadduck RK, Waheed A, Evans C et al: Serum and urinary levels of recombinant human granulocyte-macrophage colony-stimulating factor: assessment after intravenous infusion and subcutaneous injection [abstract # 201]. Exp Hematol 1990; 18: 601.

Takaku F. Clinical use of G-CSF [abstract # 202]. Exp Hematol 1990; 18: 601.

Muller MR, Schmid L, Lehner R et al: High dose chemotherapy combined with recombinant human granulocyte-macrophage colony stimulating factors: effects on granulocyte counts and myeloid progenitor cells [abstract # 204]. Exp Hematol 1990: 18: 601.

Gabrilove J, Jakubowski A, Fain K et al: Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium. J Clin Invest 1988; 82: 1454-61.

Gabrilove J, Jakubowski A, Scher H et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 1988; 318: 1414-22.

Wing EJ, Magee DM, Whiteside TL et al: Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients. Blood 1989; 73: 643-6.

Stoudemire JB, Garnick MB. Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels. Blood 1991; 77: 750-5.

Herrmann F, Schulz G, Lindemann A et al: Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor. J Clin Oncol 1989; 7: 159-67.

Toner GC, Jakubowski AA, Crown JPL. Colony-stimulating factors and neutrophil migration (letter). Ann Intern Med 1989; 110: 846-7.

Motoyoshi K, Takaku F. Serum cholesterol-lowering activity of human monocytic colony-stimulating factor (letter). Lancet 1989; 2: 326-7.

Lieschke GJ, Cebon J, Morstyn G. Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989; 74: 2634-43.

Paul CC, Baumann MA. Modulation of spontaneous outgrowth of Epstein-Barr virus immortalized B-cell clones by granulocyte-macrophage colony-stimulating factor and interleukin-3. Blood 1990; 75: 54-8.

Aglietta M, Monzeglio C, Apra F et al: In vivo priming of human normal neutrophils by granulocyte-macrophage colony stimulating factor: effect on the production of platelet activating factor. Br J Haematol 1990; 75: 333-9.

Smith PD, Lamerson CL, Banks SM et al: Granulocyte-macrophage colony-stimulating factor augments human monocyte fungicidal activity for Candida albicans. J Infect Dis 1990; 161: 999-1005.

Gutterman J, Vadhan-Raj S, Logothetis C et al: Effects of granulocyte-macrophage colony-stimulating factor in iatrogenic myelosuppression, bone marrow failure, and regulation of host defense. Semin Hematol 1990; 27(3 Suppl 3): 15-24.

Furman WL, Fairclough DL, Huhn RD et al: Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy. J Clin Oncol 1991; 9: 1022-8.


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