Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

COLONY STIMULATING FACTORS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors which can stimulate proliferation, differentiation, commitment, and end cell functional activation.

Specific Substances

    A) GRANULOCYTE COLONY-STIMULATING FACTORS (G-CSF)
    1) FILGRASTIM (SYNONYM)FilgrastiiimiFilgrastimumr-metHuG-CSFCAS 121181-53-1
    2) PEGFILGRASTIM (SYNONYM)PegfilgrastiimiPegfilgrastimumPegfilgrastimunCAS 208265-92-3
    3) LENOGRASTIM (SYNONYM)LenograstiimiLenograstimumrG-CSFCAS 135968-09-1
    GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTORS (GM-CSF)
    1) MOLGRAMOSTIM (SYNONYM)rhu GM-CSF
    2) SARGRAMOSTIM (SYNONYM)BI-61.012Sargramostimumrhu GM-CSFCAS 123774-72-1

Available Forms Sources

    A) FORMS
    1) FILGRASTIM
    a) Filgrastim is available as a single dose; each vial contains 300 mcg (1 mL) of filgrastim; dispensed in packs of 10 OR is available as single-dose vials containing 480 mcg (1.6 mL) of filgrastim (300 mcg/mL); dispensed in packs of 10 (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    2) PEGFILGRASTIM
    a) Pegfilgrastim is available as a single dose syringe containing 6 mg (0.6 mL) of pegfilgrastim (Prod Info Neulasta(R) subcutaneous injection, 2011).
    3) SARGRAMOSTIM
    a) Liquid sargramostim is available in vials containing 500 mcg/mL (2.8 x 10(6) international units/mL) and the lyophilized formulation is available in vials containing 250 mcg per vial (1.4 x 10(6) international units/vial) (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    B) USES
    1) Colony stimulating factor agents are used in the treatment and prevention of neutropenia in cancer patients receiving myelosuppressive chemotherapy. They are also used to reduce the period of neutropenia in patients undergoing bone marrow transplantation. In addition, filgrastim and sargramostim are used to mobilize peripheral blood cells for use as an alternative to bone marrow transplantation (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info Neulasta(R) subcutaneous injection, 2011; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Colony stimulating factor agents are used in the treatment and prevention of neutropenia in cancer patients receiving myelosuppressive chemotherapy. They are also used to reduce the period of neutropenia in patients undergoing bone marrow transplantation. In addition, filgrastim and sargramostim are used to mobilize peripheral blood cells for use as an alternative to bone marrow transplantation.
    B) PHARMACOLOGY: Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors which can stimulate proliferation, differentiation, commitment, and end cell functional activation.
    C) TOXICOLOGY: Because colony stimulating factors can increase absolute neutrophil count (ANC) and result in a corresponding increase in WBC, leukocytosis may occur.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, bone pain and influenza-like symptoms are frequently reported with these agents. Other potential events that have been reported include: drug fever, hematologic events (ie, leukocytosis, thrombocytopenia, and anemia), peripheral edema, fluid retention, pulmonary edema (sargramostim), pleural effusion (sargramostim), rash, elevations in serum creatinine and BUN.
    2) SERIOUS: Potentially serious events reported with colony stimulating factors include acute respiratory distress syndrome (ARDS), splenic rupture (rare), and severe sickle cell crisis in patients with a history of sickle cell disease.
    3) SARGRAMOSTIM: A "first-dose" reaction following intravenous therapy has been characterized by tachycardia, respiratory distress, hypoxia, hypotension and syncope. Dyspnea and transient hypotension have also been reported infrequently with filgrastim therapy.
    F) WITH POISONING/EXPOSURE
    1) Data are limited. Clinical events are anticipated to be an extension of adverse events reported with these agents. In a small clinical study, doses of up to 100 mcg/kg/day of sargramostim (16 times the recommended dose) produced dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. Leukocytosis and bone pain were reported following inadvertent self-administration of pegfilgrastim IV 36 mg, instead of the prescribed 6 mg.
    0.2.20) REPRODUCTIVE
    A) Filgrastim, pegfilgrastim, sargramostim, and tbo-filgrastim are classified as FDA pregnancy category C. No data were available to assess the effect of filgrastim, pegfilgrastim, sargramostim, or tbo-filgrastim on human pregnancy, lactation, or fertility. Scientific literature has suggested that filgrastim may cross the placenta in animals and humans. In animal studies, filgrastim and tbo-filgrastim use resulted in an increase in abortions and embryolethality in rabbits. Small amounts of pegfilgrastim crossed the placenta when administered to pregnant rats.

Laboratory Monitoring

    A) Monitor CBC with differential and platelet count following exposure, and continue until WBC normalizes (may remain elevated for up to two weeks).
    B) Monitor renal function and liver enzymes.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Elevations in uric acid levels have occurred with filgrastim therapy; evaluate as needed.
    E) Monitor ECG and consider continuous cardiac monitoring following a significant overdose.
    F) Chest x-ray is indicated if pulmonary toxicity is suspected.
    G) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Assess bone pain and administer analgesics as indicated. Begin with non-narcotics (ie, acetaminophen); narcotics may be required in some patients. Monitor ECG and consider continuous cardiac monitoring following a significant overdose. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat severe hypotension IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    C) DECONTAMINATION
    1) Unlikely to be necessary; these agents are administered parenterally.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or respiratory compromise
    E) ANTIDOTE
    1) None
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and colony stimulating factors are generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected colony stimulating factor overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication.
    J) PHARMACOKINETICS
    1) Peak serum concentrations: Filgrastim: SubQ administration of 3.45 mcg/kg and 11.5 mcg/kg: maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours; Sargramostim: 1 to 3 hrs following SubQ administration. Volume of distribution of filgrastim is 150 mL/kg. Half-lives vary by agent: Filgrastim: 3.5 hrs, Pegfilgrastim: 15 to 80 hrs (SubQ), Sargramostim: 60 min (IV), 162 min (SubQ).
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause leukocytosis or bone pain.

Range Of Toxicity

    A) TOXICITY: Limited data. A maximum dose for these agents has not been established. FILGRASTIM: In studies of patients undergoing bone marrow transplant doses up to 138 mcg/kg/day produced no toxic effects. PEGFILGRASTIM: Single doses of 300 mcg/kg subQ have been tolerated without serious adverse events. SARGRAMOSTIM: Doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) were administered to a limited number of patients via IV infusion for 7 to 18 days and dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills and an increased WBC up to 200,000 cells/mm(3) developed.
    B) THERAPEUTIC DOSE: FILGRASTIM: ADULT: Cancer patients receiving myelosuppressive chemotherapy: Initial dose: 5 mcg/kg/day, as either a single injection by subQ bolus injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or continuous IV infusion; OR Cancer patients receiving bone marrow transplant: Recommended dose following transplant is 10 mcg/kg/day as an IV infusion of 4 or 24 hrs duration, or as a continuous 24-hour subQ infusion. PEDIATRIC: Febrile Neutropenia: Various Conditions: 5 to 10 mcg/kg/day SubQ/IV daily; start at least 24 hours after chemotherapy. PEGFILGRASTIM: Febrile Neutropenia: In patients with non-myeloid malignancies receiving myelosuppressive anticancer therapy: ADULT: Recommended starting dose is 6 mg as a single subQ injection given once per chemotherapy cycle. Do not administer pegfilgrastim during the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. PEDIATRIC:Safety and efficacy have not been established. SARGRAMOSTIM: ADULT: Recommended dose is 250 mcg/m(2)/day administered IV. Duration of infusion can vary, from 2 hours to 24 hours, depending on indication. For mobilization of peripheral blood progenitor cells, it can also be administered subQ once daily. PEDIATRIC: Safety and efficacy have not been established; however, based on some safety data, sargramostim does not exhibit any increase in toxicity in pediatric patients as compared to adults.

Clinical Effects

Summary Of Exposure

    A) USES: Colony stimulating factor agents are used in the treatment and prevention of neutropenia in cancer patients receiving myelosuppressive chemotherapy. They are also used to reduce the period of neutropenia in patients undergoing bone marrow transplantation. In addition, filgrastim and sargramostim are used to mobilize peripheral blood cells for use as an alternative to bone marrow transplantation.
    B) PHARMACOLOGY: Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors which can stimulate proliferation, differentiation, commitment, and end cell functional activation.
    C) TOXICOLOGY: Because colony stimulating factors can increase absolute neutrophil count (ANC) and result in a corresponding increase in WBC, leukocytosis may occur.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, bone pain and influenza-like symptoms are frequently reported with these agents. Other potential events that have been reported include: drug fever, hematologic events (ie, leukocytosis, thrombocytopenia, and anemia), peripheral edema, fluid retention, pulmonary edema (sargramostim), pleural effusion (sargramostim), rash, elevations in serum creatinine and BUN.
    2) SERIOUS: Potentially serious events reported with colony stimulating factors include acute respiratory distress syndrome (ARDS), splenic rupture (rare), and severe sickle cell crisis in patients with a history of sickle cell disease.
    3) SARGRAMOSTIM: A "first-dose" reaction following intravenous therapy has been characterized by tachycardia, respiratory distress, hypoxia, hypotension and syncope. Dyspnea and transient hypotension have also been reported infrequently with filgrastim therapy.
    F) WITH POISONING/EXPOSURE
    1) Data are limited. Clinical events are anticipated to be an extension of adverse events reported with these agents. In a small clinical study, doses of up to 100 mcg/kg/day of sargramostim (16 times the recommended dose) produced dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. Leukocytosis and bone pain were reported following inadvertent self-administration of pegfilgrastim IV 36 mg, instead of the prescribed 6 mg.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever (greater than 38 degrees Celsius) occurred in 8 of 39 cancer patients (21%) receiving intravenous filgrastim to shorten the duration of chemotherapy-induced neutropenia. These patients had no evidence of acute infection. Fever occurred 4 to 8 days following initiation of daily intravenous infusions, which commenced 3 days after intensive chemotherapy. In several patients, fever developed only with filgrastim therapy, and not with chemotherapy alone (Eguchi et al, 1989).
    2) PEGFILGRASTIM: Fever has been reported in some patients (Prod Info Neulasta(TM), 2002; Johnston et al, 2000), although causality was uncertain. With filgrastim, fever has occurred in cancer patients without evidence of infection (Eguchi et al, 1989a).
    3) Fever has occurred with subcutaneous or intravenous lenograstim administration, with an incidence of 2% to 43% (Stoppa et al, 1994; van Hoef et al, 1994; Asano, 1991).
    4) SARGRAMOSTIM: Fever with or without RIGORS has been fairly common with rGM-CSF, and has been dose-limiting. Chills have also been reported frequently (Yee, 1990; Lieschke et al, 1990; Lieschke et al, 1989; Lieschke et al, 1989a; Morstyn et al, 1989; Gianni et al, 1990; Antin et al, 1988; Groopman et al, 1987).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: A 61-year-old healthy peripheral blood progenitor cell donor started on filgrastim and sargramostim developed marginal keratitis with mild iritis 3 days after therapy was begun. Symptoms included bilateral ocular pain, redness of the globes and photosensitivity. Treatment included administration of 1% prednisolone drops and discontinuation of sargramostim. Clinical symptoms improved within 24 hours (Esmaeli et al, 2002).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM: Transient hypotension, which did not require clinical intervention, occurred in 7 of 176 patients receiving filgrastim in phase 3 clinical studies (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    b) SARGRAMOSTIM: A "first-dose" reaction has been reported to occur within 15 to 180 minutes of administration of sargramostim in doses greater than 1 mcg/kg. This reaction is characterized by some or all of the following: hypotension, tachycardia, syncope, fever, rigors, flushing, nausea, vomiting, diaphoresis, back pain, leg spasms, hypoxia, and dyspnea (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Lieschke et al, 1990; Steis et al, 1990). Release of vasodilators may be at least partly responsible for the reaction. This reaction has not been observed with granulocyte colony-stimulating factor (G-CSF; filgrastim) (Morstyn et al, 1989a).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM: Myocardial infarction and dysrhythmias were reported in 11 of 375 cancer patients following filgrastim; the association to filgrastim therapy and the cardiac events observed remains unknown (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) SARGRAMOSTIM
    1) SARGRAMOSTIM: A syndrome characterized by tachycardia, respiratory distress, hypoxia, flushing, hypotension, and syncope may occur following the "first dose" administration of sargramostim (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    2) Dysrhythmias and reversible complete left bundle branch block have been observed rarely during sargramostim administration. It is unclear if these events are related to sargramostim (Gianni et al, 1990; Ganser et al, 1989).
    3) SUPRAVENTRICULAR dysrhythmias have been reported during sargramostim administration. This effect occurs more commonly in patients with a history of cardiac dysrhythmias, but they were reversible after discontinuation (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) SARGRAMOSTIM: Dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills, and an increased WBC up to 200,000 cellls/mm(3) occurred in a limited number of patients, during a phase I uncontrolled clinical trial, who received sargramostim at doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) via IV infusion for 7 to 18 days (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    D) CAPILLARY LEAK SYNDROME
    1) WITH THERAPEUTIC USE
    a) Capillary leak syndrome has been reported infrequently with these agents. Effects may include hypotension, fluid retention, ascites, pericardial and/or pleural effusion, shock, edema, neurologic changes and hepatocellular injury. In most cases, symptoms resolved with the discontinuation of therapy (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Oeda et al, 1994).
    E) PERICARDITIS
    1) WITH THERAPEUTIC USE
    a) SARGRAMOSTIM
    1) Pericarditis, pericardial pain and effusion have been reported with high doses of sargramostim (20 to 64 mcg/kg/day). At doses exceeding 15 mcg/kg/day IV or subQ, pericarditis is a dose-limiting toxic effect (Lieschke et al, 1990; Morstyn et al, 1989; Morstyn et al, 1989a; Lieschke et al, 1989).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported in patients receiving filgrastim (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    b) CASE SERIES: In a retrospective study of 20 patients with chronic myeloid leukemia in chronic phase (CP-CML) with recent allogeneic peripheral blood stem cell transplantation (PBSCT), 2 patients receiving filgrastim 10 mcg/kg/day subcutaneously on post-transplant day 1 developed hypoxemia requiring oxygen and 8 patients developed dyspnea. Filgrastim was discontinued and symptoms rapidly resolved following administration of hydrocortisone and an antihistamine. Adverse reactions to filgrastim were not observed in patients with diagnoses other than CP-CML. Filgrastim treatment in 8 CP-CML patients was uneventful when initiation of therapy was delayed until 5 days post-PBSCT (Khoury et al, 2000).
    c) SARGRAMOSTIM: Dyspnea and respiratory distress along with other symptoms have been observed as "first-dose" reactions to sargramostim. Symptoms usually respond well to treatment and do not recur with subsequent dosing (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) Dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills, and an increased WBC up to 200,000 cellls/mm(3) occurred in a limited number of patients, during a phase I uncontrolled clinical trial, who received sargramostim at doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) via IV infusion for 7 to 18 days (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Acute lung injury (adult respiratory distress syndrome; ARDS) has developed in septic patients receiving filgrastim and is thought to be due to the influx of neutrophils to the site of the infection in the lungs (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012). Induction of ARDS is also possible following pegfilgrastim administration (Prod Info Neulasta(R) subcutaneous injection, 2011) and theoretically possible with other colony stimulating factors.
    b) CASE REPORT: Fatal ARDS occurred in a 59-year-old man receiving concomitant rhGM-CSF and low-dose cytarabine (Verhoef & Boogaerts, 1991).
    C) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) SARGRAMOSTIM: In patients receiving sargramostim 250 mcg/m(2) intravenously over 2 hours, pleural effusion occurred in 1%. Fluid retention has been reversible with the discontinuation of therapy with or without the administration of diuretics (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    D) PULMONARY EDEMA
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema occurred in 4 of 16 patients with refractory urothelial tumors treated with rGM-CSF (E coli derived) in a continuous infusion of 120 to 500 mcg/m(2)/day to reduce the myelotoxicity of chemotherapy. With identical single daily subcutaneous doses, pulmonary edema occurred in 2 of 16 patients (Logothetis et al, 1990).
    E) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) SARGRAMOSTIM: Acute pulmonary embolism has been reported during administration of high doses (64 mcg/kg/day) of intravenous rGM-CSF (mammalian cell derived; Sandoz) (Antman et al, 1988).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may develop with therapeutic use of colony stimulating factors (GM-CSF or G-CSF agents) (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Andre et al, 2007). In two placebo-controlled trials, headache occurred in 16% of patients receiving pegfilgrastim and 7% of patients receiving filgrastim (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info NEULASTA(R) subcutaneous injection, 2006).
    b) In a retrospective study, pegfilgrastim was evaluated in children (over 40 kg) with cancer receiving myelosuppressive chemotherapy and headache was reported in one patient. Of the 126 cases of pegfilgrastim administration, 2 separate doses in one patient produced headache (Andre et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) SARGRAMOSTIM: Dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills, and an increased WBC up to 200,000 cellls/mm(3) occurred in a limited number of patients, during a phase I uncontrolled clinical trial, who received sargramostim at doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) via IV infusion for 7 to 18 days (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    B) LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM
    1) CASE REPORT: Reversible posterior leukoencephalopathy syndrome was temporally related to a 9-day course of filgrastim 300 to 600 micrograms daily in a 45-year-old woman. The syndrome was characterized by acute cortical blindness, seizures, somnolence and disorientation with bilateral parietal and occipital hyperintensities on magnetic resonance imaging (MRI). The patient's condition gradually improved with symptomatic treatment; follow-up MRI revealed significant resolution after 1 week (Leniger et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting and anorexia can develop with these agents during therapeutic use (Smith, 2000; Khoury et al, 2000; Asano, 1991; Gianni et al, 1990; Negrin et al, 1989). GASTROINTESTINAL DISTURBANCES have been dose-limiting with intravenous bolus injections of sargramostim (Rifkin et al, 1988).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may develop with therapeutic use of these agents (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Prod Info Granocyte(R), 1994; Asano, 1991; Gianni et al, 1990; Antin et al, 1988).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevation of bilirubin and hepatic enzymes may occur in patients with preexisting hepatic dysfunction that are treated with filgrastim and sargramostim (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Prod Info NEUPOGEN(R) injection, 2006).
    b) While there have been no reports of severe liver dysfunction, reversible elevations in liver enzymes have occurred with subcutaneous and intravenous GM-CSF (Lieschke et al, 1990; Yee, 1990; Lieschke et al, 1989).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HYPERURICEMIA
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM: Mild to moderate elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase have occurred in 27% to 58% of patients (n=98) receiving blinded therapy with filgrastim. These elevations were transient (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    1) Elevations of serum uric acid have been observed in patients treated with filgrastim, particularly with higher doses (30 to 60 mcg/kg/day) (Gabrilove et al, 1988; Morstyn et al, 1988; Morstyn et al, 1989c). This effect is transient and probably related to an increase in white cell production (Morstyn et al, 1988).
    b) PEGFILGRASTIM: Increases in LDH, uric acid, and alkaline phosphatase have occurred during therapy with pegfilgrastim (less than 20% of patients); these changes were not associated with clinical sequelae (Prod Info Neulasta(TM), 2002; Holmes et al, 2002a). Similar to filgrastim, these changes coincided with increases in neutrophil counts.
    B) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Elevations of serum creatinine have been reported rarely with lenograstim therapy (Gisselbrecht et al, 1994) and were observed in patients with preexisting renal dysfunction while being treated with sargramostim (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) PEGFILGRASTIM: Leukocytosis (white count of greater than 100 x 10(9)/L) has occurred in less than 1% of patients (n=932) with non-myeloid malignancies receiving pegfilgrastim. There were no complications associated with the development of leukocytosis in these patients (Prod Info Neulasta(R) subcutaneous injection, 2011). Modest and transient decreases in platelet counts, without clinical sequelae, have been reported (Johnston et al, 2000; Morstyn et al, 2001a)
    b) Sargramostim can cause increases in white blood cell count (WBC) and/or platelets (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009). Transient cyclic agranulocytosis was associated with intravenous rGM-CSF administration in a 51-year-old woman with chronic granulocytic leukemia (Gluckman et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT/PEGFILGRASTIM: Leukocytosis (64 x 10(3)/mcL with 92% neutrophils) was reported in a 69-year-old man on a chemotherapy regimen for treatment of small cell lung cancer who inadvertently self-administered 36 mg of pegfilgrastim between days 4 and 9 of his fourth chemotherapy cycle instead of the prescribed 6 mg (100 mcg/kg). Further chemotherapy was postponed and the patient underwent observation. Other than complaints of bone pain and a runny nose, the patient remained asymptomatic, laboratory data revealed a gradual decrease in the WBC count, and chemotherapy was resumed, 12 days later, without complications (Kaidar-Person et al, 2011).
    b) SARGRAMOSTIM: Dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills, and an increased WBC up to 200,000 cellls/mm(3) occurred in a limited number of patients, during a phase I uncontrolled clinical trial, who received sargramostim at doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) via IV infusion for 7 to 18 days (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) SARGRAMOSTIM: Transient leukopenia occurs following intravenous and subcutaneous administration of rGM-CSF (Devereux et al, 1987; Morstyn et al, 1989; Lieschke et al, 1989). Leukopenia persists for 4 to 6 hours, with leukocyte counts then increasing to levels higher than baseline.
    b) The transient fall in neutrophils, eosinophils, and monocytes observed with rGM-CSF may be related to stimulation of various cell functions including adhesiveness promoting margination, migration, or aggregation. Sequestration of white cells has occurred within the lungs during leukopenia, and caution is suggested with the use of rGM-CSF in patients with normal neutrophil counts and pulmonary sepsis (Devereux et al, 1987).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Varying degrees of anemia and thrombocytopenia have been associated with lenograstim therapy after bone marrow transplantation and in patients with chemotherapy-induced neutropenia (Anon, 1993; Donadieu et al, 1993; van Hoef et al, 1994). Anemia has also been reported following filgrastim therapy in patients receiving cytotoxic therapy and patients undergoing peripheral blood progenitor cell collection (Prod Info NEUPOGEN(R) injection, 2006; Morstyn et al, 1988).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has developed following therapeutic use of these agents (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    b) FILGRASTIM
    1) Patients undergoing peripheral blood progenitor cell collection receiving filgrastim have reported thrombocytopenia (97%). This event is related to leukapheresis; however, the possibility that filgrastim may contribute to thrombocytopenia cannot be ruled out (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    2) Thrombocytopenia (platelets less than 50,000 per cubic millimeter) was noted in fewer than 6% of patients receiving filgrastim for severe chronic neutropenia conditions. Thrombocytopenia was managed by reducing or discontinuing filgrastim (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    c) LENOGRASTIM
    1) Apheresis-related thrombocytopenia (platelet count less than 100 x 10(9)/liter) occurred in 42% of healthy donors during PBPC mobilization. Platelet counts less than 50 x 10(9)/liter occurred occasionally. There were no related clinical adverse events and platelet counts recovered in all subjects (Prod Info Granocyte(TM)-13, Granocyte(TM)-34, 2000).
    2) Thrombocytopenia (grade I to III) occurred in 27% of cancer patients treated with lenograstim in doses of 1 to 40 mcg/kg/day for 5 days prior to bone marrow harvesting. All cases occurred after completion of treatment (following day 6). Anemia was described in 70% of these patients, also after day 6, but was attributed to the bone marrow harvest procedure (Stoppa et al, 1994). Significant thrombocytopenia (decrease by median of 97 x 10(9)/L) followed administration of lenograstim during a 10-day period prior to chemotherapy in advanced breast cancer patients (van Hoef et al, 1994).
    d) SARGRAMOSTIM
    1) A higher incidence of grade 3/4 thrombocytopenia, grade 3/4 infections, and mortality have occurred when sargramostim was administered concurrently with radiation and chemotherapy (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    2) Bleeding complications (gastrointestinal, central nervous system (CNS) hemorrhage) have been reported occasionally during rGM-CSF therapy. Fatal CNS hemorrhage occurred in 1 patient. However, all patients had thrombocytopenia prior to rGM-CSF, and it is doubtful that bleeding complications were directly related to rGM-CSF; in this trial GM-CSF was mammalian cell-derived (Champlin et al, 1989). Other studies have reported no effect of rGM-CSF on coagulation parameters (Steis et al, 1990; Herrmann et al, 1989).
    3) Thrombocytopenia has been reported in up to 10% of patients treated with rGM-CSF (Lieschke et al, 1989; Ganser et al, 1989).
    4) It is speculated that thrombocytopenia is related to stimulation of the reticuloendothelial system to phagocytose platelets (Lieschke et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Infrequent dermatologic findings reported with filgrastim include erythema nodosum, lichenoid drug reaction, skin rash, pruritus, folliculitis and peripheral edema (Prod Info NEUPOGEN(R) injection, 2006; Prod Info NEULASTA(R) subcutaneous injection, 2006; Prod Info LEUKINE(R) injection, 2006; Viallard et al, 1999; Munoz et al, 1996; Ostlere et al, 1992; Eguchi et al, 1989).
    B) ACUTE FEBRILE NEUTROPHILIC DERMATOSIS
    1) WITH THERAPEUTIC USE
    a) GENERAL: Several cases of Sweet's syndrome have been reported with filgrastim and sargramostim therapy. This syndrome is characterized by rapid onset of erythematous and tender plaques, fever, and leukocytosis.
    b) FILGRASTIM
    1) CASE REPORT: Sweet's syndrome was observed in a 33-year-old man after receiving filgrastim 300 mcg/day. Fevers and painful erythematous skin and oral gingival eruptions developed after 4 days of filgrastim administration. Symptoms resolved with the discontinuation of filgrastim (Arbetter et al, 1999).
    2) CASE REPORT: Sweet's syndrome also developed in another patient with a history of cutaneous vasculitis while receiving filgrastim 3 mcg/kg/day subcutaneously for the treatment of hairy cell leukemia. Discontinuation of filgrastim resulted in gradual improvement over 2 weeks (Glaspy et al, 1988).
    c) CASE REPORT: A 49-year- old man with acute myelogenous leukemia (AML) treated with G-CSF developed Sweet's syndrome with herpes-like lesions. Signs and symptoms rapidly disappeared with corticosteroid treatment while G-CSF administration was continued which may dismiss the etiological role of G-CSF in the development of Sweet's syndrome (van Mook et al, 1999).
    d) SARGRAMOSTIM
    1) CASE REPORT: A 56-year-old man with newly diagnosed AML receiving sargramostim therapy daily, developed symptoms consistent with Sweet's syndrome (ie, fever, violaceous, erythematous, tender plaques, and necrotic bullae). Symptoms improved rapidly with oral prednisone (Kumar et al, 2004).
    2) Leukocytoclastic vasculitis (similar to the "sweet syndrome") developed in a 60-year-old patient after receiving rGM-CSF 3.3 mcg/kg/day for 4 days (Kluin-Nelemans et al, 1989).
    C) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Injection site pain has been reported infrequently with subcutaneous lenograstim use (Prod Info Granocyte(R), 1994). Inflammation and bruising were reported in a small number of patients following subcutaneous infusions of filgrastim (Morstyn et al, 1988a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) One of the most frequent complications of colony stimulating factor agents is mild-to-moderate bone pain during or after intravenous or subcutaneous administration (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info Neulasta(R) subcutaneous injection, 2011; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Lieschke et al, 1990; Lieschke et al, 1989; Yee, 1990; Gabrilove et al, 1988; Morstyn et al, 1989c; Morstyn et al, 1988). The incidence of bone pain has been similar with pegfilgrastim and filgrastim in comparative studies (Vose et al, 2003; Green et al, 2003).
    b) Bone pain is usually mild or moderate in severity, not requiring withdrawal of therapy. Data from the manufacturers indicates that most patients respond to non-narcotic analgesics (ie, acetaminophen, ibuprofen) (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    c) INCIDENCE: Medullary bone pain occurred in 26% of cancer patients (n=465) and was the most common adverse event associated with pegfilgrastim administration from six randomized clinical trials (Crawford, 2003; Lyman, 2005).
    d) In a retrospective study, pegfilgrastim was evaluated in children (over 40 kg) with cancer receiving myelosuppressive chemotherapy and bone pain was the most common event reported. Of the 126 cases of pegfilgrastim administration, 4 (3%) cases of mild to moderate pain developed, which was relieved with acetaminophen (Andre et al, 2007).
    e) During filgrastim phase 2 and 3 trials, bone pain occurred more frequently in patients receiving higher doses (20 to 100 mcg/kg/day) administered IV and less frequently in patients receiving lower doses (3 to 10 mcg/kg/day) administered SubQ (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT/PEGFILGRASTIM: Bone pain was reported in a 69-year-old man on a chemotherapy regimen for treatment of small cell lung cancer who inadvertently self-administered 36 mg of pegfilgrastim between days 4 and 9 of his fourth chemotherapy cycle instead of the prescribed 6 mg (100 mcg/kg) (Kaidar-Person et al, 2011).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgias or myalgias can develop with these agents (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009; Prod Info NEULASTA(R) subcutaneous injection, 2006; Prod Info NEUPOGEN(R) injection, 2006; Johnston et al, 2000; Lieschke et al, 1990; Lieschke et al, 1989; Yee, 1990).
    C) OSTEOPENIA
    1) WITH THERAPEUTIC USE
    a) The chronic administration of G-CSF was associated with the development of severe osteopenia in a 13-year old boy with Kostmann's congenital neutropenia. He was successfully managed with bisphosphonate therapy. This case report suggests that the prolonged administration of G-CSF may contribute to an increase in bone resorption and bone loss (Sekhar et al, 2001).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM: Allergic-type reactions have been reported in less than 1 in 4000 patients treated with filgrastim. Reactions tend to occur within the first 30 minutes after administration and appear to be more frequent in patients receiving intravenous filgrastim. Some reactions occurred on initial exposure (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    b) SARGRAMOSTIM: A similar reaction has been reported within 15 to 180 minutes of administration of sargramostim in doses greater than 1 mcg/kg. Hypoxia has also been documented during these episodes and is associated with transient reductions in circulating neutrophil counts (Lieschke et al, 1990; Steis et al, 1990; Lieschke et al, 1989a).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) FILGRASTIM: Allergic reactions have occurred after single doses or repeated exposure of filgrastim (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012); these reactions should be considered possible with any one of these agents due to the administration of recombinant proteins (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    b) MOLGRAMOSTIM: A patient with myelokatexis (a rare form of chronic hereditary neutropenia) developed hypersensitivity to molgramostim after repeated use. Symptoms included feelings of suffocation, redness and itching of the skin, and pain in the lumbar region which led to the discontinuation of therapy. The patient was able to continue cytokine therapy with filgrastim and lenograstim (Cernelc et al, 2000).
    c) SARGRAMOSTIM: A patient developed palmar itching, urticaria, angioedema, and throat tightness after receiving sargramostim. The patient had received doses for several months with no adverse effects. Several skin tests revealed an immediate wheal and flare reaction. The patient had no adverse effects to subsequent treatment with filgrastim (Engler & Weiss, 1996).

Reproductive

    3.20.1) SUMMARY
    A) Filgrastim, pegfilgrastim, sargramostim, and tbo-filgrastim are classified as FDA pregnancy category C. No data were available to assess the effect of filgrastim, pegfilgrastim, sargramostim, or tbo-filgrastim on human pregnancy, lactation, or fertility. Scientific literature has suggested that filgrastim may cross the placenta in animals and humans. In animal studies, filgrastim and tbo-filgrastim use resulted in an increase in abortions and embryolethality in rabbits. Small amounts of pegfilgrastim crossed the placenta when administered to pregnant rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) FILGRASTIM
    a) RATS: No maternal or fetal malformations were observed in rats administered doses up to 575 mcg/kg/day. However, in a separate study, daily exposures during the perinatal and lactation periods in rate offspring to at least 20 mcg.kg/day led to a delay in external differentiation and growth reduction, and slightly reduced survival rates at 100 mcg/kg/day (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    2) PEGFILGRASTIM
    a) In rat studies, subcutaneous injections of pegfilgrastim up to 1000 mcg/kg/dose administered every other day during the period of organogenesis did not produce embryotoxic or fetotoxic events. However, an increased incidence of wavy ribs was found in rat fetuses at a maternal dose of 1000 mcg/kg every other day (Prod Info NEULASTA(R) subcutaneous injection, 2008).
    b) A low concentration (less than 0.5% of the maternal dose) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats (Prod Info NEULASTA(R) subcutaneous injection, 2008).
    3) SARGRAMOSTIM
    a) At the time of this review, no data were available to assess the effect of this agent on pregnancy in animals or humans . (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).
    4) TBO-FILGRASTIM
    a) RABBITS - SubQ administration of tbo-filgrastim during the period of organogenesis resulted in teratogenic effects, including malformed hind limbs and cleft palate, at a maternally toxic dose in rabbits of 100 mcg/kg/day (50 to 90 times the exposure at the clinical dose of 5 mcg/kg/day based on AUC) (Prod Info GRANIX(TM) subcutaneous injection solution, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Manufacturers have classified filgrastim, pegfilgrastim, sargramostim, and tbo-filgrastim as FDA pregnancy category C (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015; Prod Info LEUKINE(R) subcutaneous, IV injection, 2008; Prod Info NEULASTA(R) subcutaneous injection, 2008; Prod Info GRANIX(TM) subcutaneous injection solution, 2013).
    B) FILGRASTIM
    1) There are no adequate and well-controlled studies of filgrastim use in pregnant women. According to scientific literature, apparent transplacental passage of filgrastim has been demonstrated in pregnant women treated with filgrastim for up to 30 hours before preterm delivery (ie, up to 30 weeks f gestation) (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    C) ANIMAL STUDIES
    1) FILGRASTIM
    a) RATS, RABBITS: Daily exposures in rat offspring during the perinatal and lactation periods to at least 20 mcg.kg/day led to a delay in external differentiation and growth reduction. Survival rates were slightly reduced at 100 mcg/kg/day. Reduced embryofetal survival and increased abortions were observed in rabbits administered 20 mcg/kg/day and 80 mcg/kg/day doses (2 and 10 times the human dose), respectively (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    2) PEGFILGRASTIM
    a) RABBITS - Decreased maternal food consumption, with a decrease in maternal body weight gain and fetal weight gain has been observed in pregnant rabbits given doses of 50 to 1000 mcg/kg/dose. An increase in abortions was found at doses of 200 and 250 mcg/kg/dose; increased post-implantation loss due to resorption occurred at doses of 200 to 1000 mcg/kg/dose, and a decrease in the number of live fetuses were observed at doses of 200 to 1000 mcg/kg/dose when given every other day (Prod Info NEULASTA(R) subcutaneous injection, 2008).
    3) TBO-FILGRASTIM
    a) RABBITS - SubQ administration of tbo-filgrastim during the period of organogenesis was embryotoxic, with increased abortions, post-implantation loss, and decreased mean live litter size and fetal weight, at a maternally toxic dose in rabbits of 100 mcg/kg/day (50 to 90 times the exposure at the clinical dose of 5 mcg/kg/day based on AUC) (Prod Info GRANIX(TM) subcutaneous injection solution, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether FILGRASTIM, PEGFILGRASTIM, SARGRAMOSTIM, or TBO-FILGRASTIM are excreted in human breast milk (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015; Prod Info LEUKINE(R) subcutaneous, IV injection, 2008; Prod Info NEULASTA(R) subcutaneous injection, 2008; Prod Info GRANIX(TM) subcutaneous injection solution, 2013).
    2) FILGRASTIM: It is unknown whether filgrastim is excreted in human milk. Exercise caution when administering filgrastim to a nursing mother since many drugs are excreted in human milk (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FILGRASTIM
    a) No fertility or reproductive effects were noted in male or female rats treated with filgrastim doses up to 500 mcg/kg (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    2) PEGFILGRASTIM
    a) Effects on fertility, reproduction, or sperm were not observed in male or female rats treated with subcutaneous doses of pegfilgrastim up to 1000 mcg/kg administered once weekly (Prod Info NEULASTA(R) subcutaneous injection, 2008).
    3) SARGRAMOSTIM
    a) At the time of this review, no data were available to assess the effect of this agent on animal or human fertility (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).
    4) TBO-FILGRASTIM
    a) Although fertility studies were not conducted with tbo-filgrastim, toxicology studies in rats and monkeys for up to 26 weeks did not find any effects on male or female reproductive organs that would indicate fertility impairment (Prod Info GRANIX(TM) subcutaneous injection solution, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) FILGRASTIM: There are no studies available to determine the carcinogenic potential of filgrastim, filgrastim-sndz, sargramostim, or tbo-filgrastim (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) injection, 2006; Prod Info LEUKINE(R) injection, 2006; Prod Info GRANIX(TM) subcutaneous injection solution, 2013).
    2) PEGFILGRASTIM: There are no long-term studies to determine the carcinogenic potential of pegfilgrastim. However, in a 6-month toxicity study in rats, once weekly injections of up to 1000 mcg/kg (approximately 23-fold higher than the recommended human dose) did not produce any precancerous or cancerous lesions (Prod Info NEULASTA(R) subcutaneous injection, 2006).

Genotoxicity

    A) Filgrastim and filgrastim-sndz did not produce bacterial gene mutations (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) injection, 2006)
    B) Mutagenic studies have not been conducted with pegfilgrastim or sargramostim (Prod Info NEULASTA(R) subcutaneous injection, 2006; Prod Info LEUKINE(R) injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential and platelet count following exposure, and continue until WBC normalizes (may remain elevated for up to two weeks).
    B) Monitor renal function and liver enzymes.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Elevations in uric acid levels have occurred with filgrastim therapy; evaluate as needed.
    E) Monitor ECG and consider continuous cardiac monitoring following a significant overdose.
    F) Chest x-ray is indicated if pulmonary toxicity is suspected.
    G) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor CBC with differential and platelet count following exposure, and continue until WBC normalizes (may remain elevated for up to two weeks).
    B) Monitor renal function and liver enzymes.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Elevations in uric acid levels have occurred with filgrastim therapy; evaluate as needed.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.4) OTHER
    A) OTHER
    1) Assess respiratory function and vital signs following a significant exposure. Alterations in respiratory or cardiovascular function are more likely to occur following an intravenous versus a subcutaneous exposure.
    2) ECG
    a) Monitor ECG and consider continuous cardiac monitoring following a significant overdose.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray is indicated if pulmonary toxicity is suspected.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, and colony stimulating factors are generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor CBC with differential and platelet count following exposure, and continue until WBC normalizes (may remain elevated for up to two weeks).
    B) Monitor renal function and liver enzymes.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Elevations in uric acid levels have occurred with filgrastim therapy; evaluate as needed.
    E) Monitor ECG and consider continuous cardiac monitoring following a significant overdose.
    F) Chest x-ray is indicated if pulmonary toxicity is suspected.
    G) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is unlikely to be necessary because these agents are administered parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. A maximum dose for these agents has not been established. FILGRASTIM: In studies of patients undergoing bone marrow transplant doses up to 138 mcg/kg/day produced no toxic effects. PEGFILGRASTIM: Single doses of 300 mcg/kg subQ have been tolerated without serious adverse events. SARGRAMOSTIM: Doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) were administered to a limited number of patients via IV infusion for 7 to 18 days and dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills and an increased WBC up to 200,000 cells/mm(3) developed.
    B) THERAPEUTIC DOSE: FILGRASTIM: ADULT: Cancer patients receiving myelosuppressive chemotherapy: Initial dose: 5 mcg/kg/day, as either a single injection by subQ bolus injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or continuous IV infusion; OR Cancer patients receiving bone marrow transplant: Recommended dose following transplant is 10 mcg/kg/day as an IV infusion of 4 or 24 hrs duration, or as a continuous 24-hour subQ infusion. PEDIATRIC: Febrile Neutropenia: Various Conditions: 5 to 10 mcg/kg/day SubQ/IV daily; start at least 24 hours after chemotherapy. PEGFILGRASTIM: Febrile Neutropenia: In patients with non-myeloid malignancies receiving myelosuppressive anticancer therapy: ADULT: Recommended starting dose is 6 mg as a single subQ injection given once per chemotherapy cycle. Do not administer pegfilgrastim during the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. PEDIATRIC:Safety and efficacy have not been established. SARGRAMOSTIM: ADULT: Recommended dose is 250 mcg/m(2)/day administered IV. Duration of infusion can vary, from 2 hours to 24 hours, depending on indication. For mobilization of peripheral blood progenitor cells, it can also be administered subQ once daily. PEDIATRIC: Safety and efficacy have not been established; however, based on some safety data, sargramostim does not exhibit any increase in toxicity in pediatric patients as compared to adults.

Therapeutic Dose

    7.2.1) ADULT
    A) FILGRASTIM
    1) CANCER PATIENTS RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY
    a) SUBQ OR IV ROUTE: Initial dose: 5 mcg/kg/day, as either a single injection by subQ bolus injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or continuous IV infusion. Increase doses by 5 mcg/kg for each chemotherapy cycle based on the duration and severity of the ANC nadir (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    2) CANCER PATIENTS RECEIVING BONE MARROW TRANSPLANT
    a) IV ROUTE: Recommended dose following transplant is 10 mcg/kg/day as an IV infusion for no more than 24 hours. Titrate daily dosage against neutrophil response during the period of neutrophil recovery (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    3) PERIPHERAL BLOOD PROGENITOR CELL COLLECTION AND THERAPY
    a) SUBQ ROUTE: Recommended dose to mobilize peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day subQ. Monitor neutrophil counts after 4 days of therapy and discontinue for those patients who develop a WBC count of greater than 100,000/mm(3) (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    4) SEVERE CHRONIC NEUTROPENIA
    a) SUBQ ROUTE: Recommended starting dose is 6 mcg/kg twice daily subQ. For idiopathic or cyclic neutropenia, the recommended dose is 5 mcg/kg as a single daily subQ injection (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    B) LENOGRASTIM
    1) Bone Marrow Transplant: Lenograstim should be initiated the day following transplantation in a dose of 5 micrograms/kilogram/day as a subQ injection or as an IV infusion over 30 minutes (diluted in 100 milliliters normal saline). This is equivalent to 0.64 million International Units (IU)/kg/day, or 150 micrograms (19.2 million IU)/square meter/day. Daily doses should be continued until the expected nadir has passed and the neutrophil count returns to within the normal range, with (if required) a maximum of 28 days consecutive administration. The manufacturer indicates that about 50% of patients will achieve neutrophil recovery by day 14 following transplantation (Prod Info Granocyte(TM)-13, Granocyte(TM)-34, 2000).
    C) PEGFILGRASTIM
    1) ACUTE RADIATION SYNDROME: 6 mg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    2) FEBRILE NEUTROPENIA: In patients with non-myeloid malignancies receiving myelosuppressive anticancer therapy: Recommended starting dose is 6 mg as a single subQ injection given once per chemotherapy cycle. Do not administer pegfilgrastim during the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (Prod Info Neulasta(R) subcutaneous injection, 2011)
    3) MYELOSUPPRESSIVE CHEMOTHERAPY: 6 mg subQ administered once per chemotherapy cycle (Prod Info NEULASTA(R) subcutaneous injection, 2015).
    D) SARGRAMOSTIM
    1) Neutrophil recovery following chemotherapy in acute myelogenous leukemia: The recommended dose is 250 mcg/m(2)/day administered IV over a 4-hour period starting on day 11 or 4 days following the completion of induction chemotherapy (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    2) Mobilization of peripheral blood progenitor cells (PBPC) and post-PBPC transplantation: 250 mcg/m(2)/day either administered subQ once daily or IV over 24 hours (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    3) Myeloid reconstitution after bone marrow transplantation (BMT): 250 mcg/m(2)/day administered as a 2-hour IV infusion (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    4) BMT failure or engraftment delay: 250 mcg/m(2)/day for 14 days as a 2-hour IV infusion. If engraftment has not occurred after 7 days off therapy, the dose may be repeated. If engraftment still has not occurred after another 7 days off therapy, the dose may be increased to 500 mcg/m(2)/day for 14 days (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    E) TBO-FILGRASTIM
    1) Severe neutropenia in patients with non-myeloid malignancies: The recommended dose is 5 mcg/kg/day SUBQ given no earlier than 24 hours after myelosuppressive chemotherapy; continue until neutrophil count passes nadir and has recovered to normal range; do not give within 24 hours prior to chemotherapy (Prod Info GRANIX(TM) subcutaneous injection solution, 2013)
    7.2.2) PEDIATRIC
    A) FILGRASTIM
    1) CANCER PATIENTS RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY
    a) SUBQ OR IV ROUTE: Initial dose: 5 mcg/kg/day, as either a single injection by subQ bolus injection, by short IV infusion (15 to 30 minutes), or by continuous IV infusion. Increase doses by 5 mcg/kg for each chemotherapy cycle based on the duration and severity of the ANC nadir (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    2) CANCER PATIENTS RECEIVING BONE MARROW TRANSPLANT
    a) IV ROUTE: Recommended dose following transplant is 10 mcg/kg/day as an IV infusion for no more than 24 hours. Titrate daily dosage against neutrophil response during the period of neutrophil recovery (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    3) PERIPHERAL BLOOD PROGENITOR CELL COLLECTION AND THERAPY
    a) SUBQ ROUTE: Recommended dose to mobilize peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day subQ. Monitor neutrophil counts after 4 days of therapy and discontinue for those patients who develop a WBC count of greater than 100,000/mm(3) (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    4) SEVERE CHRONIC NEUTROPENIA
    a) SUBQ ROUTE: Recommended starting dose is 6 mcg/kg twice daily subQ. For idiopathic or cyclic neutropenia, the recommended dose is 5 mcg/kg as a single daily subQ injection (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    B) LENOGRASTIM
    1) In children over 2 years of age undergoing bone marrow transplantation, lenograstim should be initiated the day following transplantation in a dose of 5 micrograms/kilogram/day as a subQ injection or as an IV infusion over 30 minutes (diluted in 100 milliliters normal saline). This is equivalent to 0.64 million International Units (IU)/kilogram/day, or 150 micrograms (19.2 million IU)/square meter/day. Daily doses should be continued until the expected nadir has passed and the neutrophil count returns to within the normal range, with (if required) a maximum of 28 days consecutive administration. The manufacturer indicates that about 50% of patients will achieve neutrophil recovery by day 14 following transplantation (Prod Info Granocyte(TM)-13, Granocyte(TM)-34, 2000).
    C) PEGFILGRASTIM
    1) Direct administration is not recommended in patients requiring doses less than 6 mg since the prefilled syringe does not have graduation marks necessary for accurate measurement (Prod Info NEULASTA(R) subcutaneous injection, 2015).
    2) WEIGHING LESS THAN 10 KG: 0.1 mg/kg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    3) WEIGHING 10 TO 20 KG: 1.5 mg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    4) WEIGHING 21 TO 30 KG: 2.5 mg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    5) WEIGHING 31 TO 44 KG: 4 mg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    6) WEIGHING 45 KG OR GREATER:, 6 mg subQ administered 1 week apart for 2 doses. Initiate treatment immediately after suspected or confirmed exposure (Prod Info NEULASTA(R) subcutaneous injection, 2015)
    D) SARGRAMOSTIM
    1) The safety and efficacy of sargramostim in pediatric patients have not been established. Based on some safety data, sargramostim does not exhibit any increase in toxicity in pediatric patients as compared to adults (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).
    E) TBO-FILGRASTIM
    1) The safety and efficacy of tbo-filgrastim in pediatric patients have not been established (Prod Info GRANIX(TM) subcutaneous injection solution, 2013).

Maximum Tolerated Exposure

    A) FILGRASTIM
    1) In studies of patients undergoing bone marrow transplant doses up to 138 mcg/kg/day produced no toxic effects (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012).
    B) PEGFILGRASTIM
    1) Single doses of 300 mcg/kg subQ have been tolerated without serious adverse events (Prod Info Neulasta(R) subcutaneous injection, 2011).
    2) CASE REPORT: Leukocytosis (64 x 10(3)/mcL with 92% neutrophils) was reported in a 69-year-old man on a chemotherapy regimen for treatment of small cell lung cancer who inadvertently self-administered 36 mg of pegfilgrastim between days 4 and 9 of his fourth chemotherapy cycle instead of the prescribed 6 mg (100 mcg/kg). Further chemotherapy was postponed and the patient underwent observation. Other than complaints of bone pain and a runny nose, the patient remained asymptomatic, laboratory data revealed a gradual decrease in the WBC count, and chemotherapy was resumed, 12 days later, without complications (Kaidar-Person et al, 2011).
    3) CASE REPORT: A 59-year-old man with stage III-B peripheral T lymphoma, inadvertently received 1 dose per day for 4 days of pegfilgrastim prophylaxis, starting on Day 1 of his first chemotherapy cycle, instead of a single dose of pegfilgrastim. The patient was observed for 3 days following his last pegfilgrastim dose; he continued to remain stable with no evidence of toxicity and was discharged. His peak ANC, after the fourth dose of pegfilgrastim, was 18 x 10(9)/L (Riu et al, 2012).
    C) SARGRAMOSTIM
    1) Doses up to 100 mcg/kg/day (4000 mcg/m(2)/day or 16 times the recommended dose) were administered to a limited number of patients via IV infusion for 7 to 18 days and dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, chills and an increased WBC up to 200,000 cells/mm(3) developed (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) FILGRASTIM
    a) Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg: maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012)
    2) PEGFILGRASTIM
    a) Peak levels occur in 24 hours in most patients. Serum levels are sustained in most during the neutropenic period post chemotherapy, and begin to decline rapidly after the start of neutrophil recovery, consistent with neutrophil-dependent elimination (Yang et al, 2000; Johnston et al, 2000a). An increase in body weight also appeared to result in higher systemic exposure after receiving a dose normalized for body weight (Prod Info Neulasta(R) subcutaneous injection, 2011).
    b) Pharmacokinetics are nonlinear in cancer patients, and clearance decreased with increases in dose (Prod Info Neulasta(R) subcutaneous injection, 2011).
    3) SARGRAMOSTIM
    a) Peak levels occurred at 1 to 3 hours following subcutaneous injections and remained detectable for up to 6 hours after administration (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) GENERAL
    1) Granulocyte colony-stimulating factor (G-CSF), is one of 5 "classic" hematopoietic growth factors that are involved in the development and functional activation of hematopoietic elements (Klingemann, 1989; Gabrilove, 1989). These glycoproteins are produced naturally in lymphocytes and monocytes, and have been demonstrated to stimulate progenitor cells of different hematopoietic cell lineages to form colonies of recognizable mature blood cells (Cairo, 1989; Yee, 1989; Morstyn et al, 1989a; Morstyn & Burgess, 1988). The 4 other classic colony-stimulating factors are granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim), macrophage colony-stimulating factor (M-CSF), interleukin-3, and erythropoietin (Klingemann, 1989).
    2) In addition to regulating proliferation and release of progenitor cells, colony-stimulating factors also modulate functional activities of mature cells (Cairo, 1989; Morstyn et al, 1989a). There is evidence that colony-stimulating factor may be the major regulator of increased cell production during states of increased demand (Cairo, 1989).
    3) Colony-stimulating factors differ structurally and are named after the hematopoietic lineage on which they preferentially act (Morstyn et al, 1989a; Yee, 1989). Filgrastim specifically promotes proliferation and maturation of neutrophil granulocytes. In contrast, granulocyte-macrophage colony-stimulating factor is a pan-stimulator of all granulocytes, producing multi-lineage effects on neutrophil granulocytes, eosinophil granulocytes, macrophages, and megakaryocytes (in vitro). Granulocyte-macrophage colony-stimulating factor also stimulates the proliferation and activation of monocyte-macrophages, and induces these cells to produce cytokines, including tumor necrosis factor and interleukin-1; this effect is not shared by filgrastim (Gabrilove, 1989; Morstyn et al, 1989a).
    B) INDIVIDUAL AGENTS
    1) GENERAL: Colony-stimulating factors differ structurally and are named after the hematopoietic lineage on which they preferentially act (Morstyn et al, 1989a; Yee, 1989).
    C) FILGRASTIM
    1) Filgrastim binds to hematopoietic cell-surface receptors and stimulates production/maturation of neutrophil precursors; functional activity of neutrophils (eg, phagocytosis, antibody-dependent cytotoxicity) is also enhanced (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Holmes et al, 2002; Morstyn et al, 1989b; Gabrilove, 1989a). Filgrastim is indicated clinically to enhance neutrophil recovery following chemotherapy, and to mobilize peripheral blood progenitor cells (PBPC) to the blood (Molineux et al, 1999).
    D) PEGFILGRASTIM
    1) Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of filgrastim (Prod Info Neulasta(R) subcutaneous injection, 2011; Morstyn et al, 2001; Molineux et al, 1999).
    2) The mechanism of action and clinical applications of pegfilgrastim are the same as those of filgrastim; the primary difference is the longer duration of action of pegfilgrastim (Morstyn et al, 2001; Molineux et al, 1999). Compared to filgrastim, pegfilgrastim exhibits reduced plasma clearance and a longer elimination half-life (up to 80 hours versus 4 hours) (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2012; Prod Info Neulasta(R) subcutaneous injection, 2011; Eguchi et al, 1989b), characteristics imparted by pegylation. The short duration of filgrastim requires daily administration, whereas one injection of pegfilgrastim per cycle of chemotherapy may be adequate (Holmes et al, 2002; Molineux et al, 1999).
    3) "Self-regulation" of pegfilgrastim serum levels as a function of neutrophil counts is observed, related to pegylation; clearance is almost entirely dependent upon neutrophil receptor-mediated clearance (Prod Info Neulasta(R) subcutaneous injection, 2011; Johnston et al, 2000a; Roskos et al, 1998). Serum levels of pegfilgrastim remain elevated during neutropenia induced by chemotherapy, and decline upon recovery of neutrophil counts (Johnston et al, 2000a).
    E) SARGRAMOSTIM
    1) Differing effects have been observed between G-CSF (filgrastim, pegfilgrastim) and GM-CSF (sargramostim) with regard to neutrophil granulocyte migration. G-CSF enhances neutrophil migration, whereas GM-CSF is a potent inhibitor (Gabrilove, 1989b). GM-CSF is not generally observed in serum, and appears to be produced locally in bone marrow or at peripheral sites; GM-CSF may be produced locally during local injury and serve as a weak chemoattractant, inhibiting migration of inflammatory cells away from the site of inflammation. In contrast, G-CSF is present in serum in certain conditions (ie, bacterial sepsis), and during local injury G-CSF may enhance migration of inflammatory cells toward the site of inflammation. This may represent one method where both growth factors work together to augment host defense (Gabrilove, 1989b).

Toxicologic Mechanism

    A) Because colony stimulating factors can increase absolute neutrophil count (ANC) and result in a corresponding increase in WBC, leukocytosis may occur.

Physicochemical

Physical Characteristics

    A) FILGRASTIM is a clear, colorless solution (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2013).
    B) FILGRASTIM-SNDZ is a clear, colorless to slightly yellowish solution (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015).
    C) PEGFILGRASTIM is a clear, colorless solution (Prod Info Neulasta(R) subcutaneous injection, 2011).
    D) TBO-FILGRASTIM is a clear, colorless solution (Prod Info GRANIX(TM) subcutaneous injection solution, 2013).

Ph

    A) PEGFILGRASTIM: 4 (Prod Info Neulasta(R) subcutaneous injection, 2011)
    B) TBO-FILGRASTIM: 4.2 (Prod Info GRANIX(TM) subcutaneous injection solution, 2013)

Molecular Weight

    A) FILGRASTIM: 18,800 daltons (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2013)
    B) FILGRASTIM-SNDZ: 18,800 daltons (Prod Info ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, 2015)
    C) PEGFILGRASTIM: 39 kilodaltons (Prod Info Neulasta(R) subcutaneous injection, 2011)
    D) TBO-FILGRASTIM: 18.8 kilodaltons (Prod Info GRANIX(TM) subcutaneous injection solution, 2013)

References

General Bibliography

    1) Andre N, Kababri ME, Bertrand P, et al: Safety and efficacy of pegfilgrastim in children with cancer receiving myelosuppressive chemotherapy. Anticancer Drugs 2007; 18(3):277-281.
    2) Anon: Haematopoietic growth factors in oncology and haematology. Granulocyte Reports 1993; 1:1-20.
    3) Antin JH, Smith BR, Holmes W, et al: Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome. Blood 1988; 72:705-713.
    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; 319:593-598.
    5) Arbetter KR, Hubbard KW, Markovic SN, et al: Case of granulocyte colony-stimulating factor-induced Sweet's syndrome. Am J Hematol 1999; 61:126-129.
    6) Asano S: Human granulocyte colony-stimulating factor: its basic aspects and clinical applications. Am J Pediatr Hematol Oncol 1991; 13:400-413.
    7) Cairo MS: Review of G-CSF and GM-CSF effects on neonatal neutrophil kinetics. Am J Pediatr Hematol Oncol 1989; 11:238-244.
    8) Cernelc P, Andoljsek D, Mlakar U, et al: Effects of molgramostim, filgrastim and lenograstim in the treatment of myelokathexis. Pflugers Arch 2000; 440(5 Suppl):81-82.
    9) Champlin RE, Nimer SD, Ireland P, et al: Treatment of refractory aplastic anemia with recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989; 73:694-699.
    10) Crawford J: Safety and efficacy of pegfilgrastim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy 2003; 23(8 Pt 2):15-19.
    11) Devereux S, Linch DC, Campos Costa D, et al: Transient leucopenia induced by granulocyte-macrophage colony-stimulating factor (letter). Lancet 1987; 2:1523-1524.
    12) Donadieu J, Bader-Meunier B, Bertrand Y, et al: Recombinant human G-CSF (lenograstim) for infectious complications in glycogen storage disease type Ib. Nouv Rev Fr Hematol 1993; 35:529-534.
    13) Eguchi K, Sasaki S, Tamura T, et al: Dose escalation study of recombinant human granulocyte colony-stimulating factor (KRN8601) in patients with advanced malignancy. Cancer Res 1989; 49:5221-5224.
    14) Eguchi K, Sasaki S, Tamura T, et al: Dose escalation study of recombinant human granulocyte colony-stimulating factor (KRN8601) in patients with advanced malignancy. Cancer Res 1989a; 49:5221-5224.
    15) Eguchi K, Sasaki S, Tamura T, et al: Dose escalation study of recombinant human granulocyte colony-stimulating factor (KRN8601) in patients with advanced malignancy. Cancer Res 1989b; 49:5221-5224.
    16) Engler RJ & Weiss RB: Immediate hypersensitivity to human recombinant granulocyte-macrophage colony-stimulating factor associated with a positive prick skin test reaction. Ann Allergy Asthma Immunol 1996; 76:531-534.
    17) Esmaeli B, Ahmadi MA, Kim S, et al: Marginal keratitis associated with administration of filgrastim and sargramostim in a healthy peripheral blood progenitor cell donor. Cornea 2002; 21(6):621-622.
    18) Falzetti F, Aversa F, Minelli O, et al: Spontaneous rupture of spleen during peripheral blood stem-cell mobilisation in a healthy donor. Lancet 1999; 353(9152):555.
    19) Gabrilove JL, Jakubowksi 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; 82:1454-1461.
    20) Gabrilove JL: Introduction and overview of hematopoietic growth factors. Semin Hematol 1989; 26(suppl 2):1-4.
    21) Gabrilove JL: Introduction and overview of hematopoietic growth factors. Semin Hematol 1989a; 26(suppl 2):1-4.
    22) Gabrilove JL: Introduction and overview of hematopoietic growth factors. Semin Hematol 1989b; 26(suppl 2):1-4.
    23) 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; 73:31-37.
    24) 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; 8:768-778.
    25) Gisselbrecht C, Prentice HG, Bacigalupo A, et al: Placebo-controlled phase III trial of lenograstim in bone-marrow transplantation. Lancet 1994; 343:696-700.
    26) Glaspy JA, Baldwin GC, Robertson PA, et al: Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor. Ann Intern Med 1988; 109:789-795.
    27) Gluckman E, Socie G, Yver A, et al: Transient cyclic neutropenia following GM-CSF in a patient with chronic granulocytic leukemia transplanted with HLA-identical T cell-depleted donor bone marrow. Bone Marrow Transplant 1989; 4:591-592.
    28) Green M, Koelbl H, Baselga J, et al: A randomized, double-blind, phase 3 study evaluating fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003; 14:29-35.
    29) 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; 317:593-598.
    30) 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; 7:159-167.
    31) Holmes FA, O'Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single adminsitration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002; 20:727-731.
    32) Holmes FA, O'Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single adminsitration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002a; 20:727-731.
    33) Johnston E, Crawford J, Blackwell S, et al: Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000; 18(13):2522-2528.
    34) Johnston E, Crawford J, Blackwell S, et al: Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000a; 18(13):2522-2528.
    35) Kaidar-Person O, Moskovitz M, Charas T, et al: Pegfilgrastim overdose: case report and review of the literature. Med Oncol 2011; 28 Suppl 1:S697-S698.
    36) Khoury H, Adkins D, Brown R, et al: Adverse side-effects associated with G-CSF in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2000; 25:1197-1201.
    37) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    38) Klingemann HG: Clinical applications of recombinant human colony-stimulating factors. Can Med Assoc J 1989; 140:137-142.
    39) Kluin-Nelemans JC, Hollander AA, Fibbe WE, et al: Leucocytoclastic vasculitis during GM-CSF therapy. Br J Haematol 1989; 73:419-420.
    40) Kumar G, Bernstein JM, Waibel JS, et al: Sweet's syndrome associated with sargramostim (granulocyte-macrophage colony stimulating factor) treatment. Am J Hematol 2004; 76(3):283-285.
    41) Lane SW, Crawford J, Kenealy M, et al: Safety and efficacy of pegfilgrastim compared to granulocyte colony stimulating factor (G-CSF) supporting a dose-intensive, rapidly cycling anti-metabolite containing chemotherapy regimen (Hyper-CVAD) for lymphoid malignancy. Leuk Lymphoma 2006; 47(9):1813-1817.
    42) Leniger T, Kastrup O, & Diener HC: Reversible posterior leukencephalopathy syndrome induced by granulocyte stimulating factor. J Neurol Neurosurg Psychiatry 2000; 69:280-281.
    43) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    44) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    45) 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 1989a; 74:2634-2643.
    46) Lieschke GJ, Maher D, Cebon J, et al: Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy. Ann Intern Med 1989; 110:357-364.
    47) Lieschke GJ, Maher D, O'Connor M, et al: Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration. Cancer Res 1990; 50:606-614.
    48) 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(8):667-672.
    49) Lyman GH: Pegfilgrastim: a granulocyte colony-stimulating factor with sustained duration of action. Expert Opin Biol Ther 2005; 5(12):1635-1646.
    50) Molineux G, Kinstler O, Briddell B, et al: A new form of filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans. Exp Hematol 1999; 27(12):1724-1734.
    51) Morstyn G & Burgess AW: Hemopoietic growth factors: a review. Cancer Res 1988; 48:5624-5637.
    52) Morstyn G, Campbell L, Souza LM, et al: Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988; 1:667-672.
    53) Morstyn G, Foote MA, Walker T, et al: Filgrastim (r-metHuG-CSF) in the 21st century: SD/01. Acta Haematol 2001; 105(3):151-155.
    54) Morstyn G, Foote MA, Walker T, et al: Filgrastim (r-metHuG-CSF) in the 21st century: SD/01. Acta Haematol 2001a; 105(3):151-155.
    55) 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 1989a; 26(suppl 2):9-13.
    56) Morstyn G, Lieschke GJ, Sheridan W, et al: Pharmacology of the colony-stimulating factors. Trends Pharmacol Sci 1989; 10:154-159.
    57) Morstyn G, Lieschke GL, Sheridan W, et al: Pharmacology of the colony-stimulating factors. TIPS 1989a; 10:154-159.
    58) Morstyn G, Lieschke GL, Sheridan W, et al: Pharmacology of the colony-stimulating factors. TIPS 1989b; 10:154-159.
    59) Morstyn G, Lieschke GL, Sheridan W, et al: Pharmacology of the colony-stimulating factors. TIPS 1989c; 10:154-159.
    60) Morstyn G, Maher D, Layton J, et al: Phase I study of granulocyte colony-stimulating factor in patients receiving melphalan with optimization of timing and duration of G-CSF administration (abstract). Blood 1988a; 72(suppl 1):127A.
    61) Munoz RM, Gomez-Bellver MJ, Navarro Pulido AM, et al: Probable hypersensitivity reaction to filgrastim (letter). Am J Health-Syst Pharm 1996; 53:1607.
    62) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    63) 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; 110:976-984.
    64) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    65) Oeda E, Shinohara K, Kamei S, et al: Capillary leak syndrome likely the result of granulocyte colony-stimulating factor after high-dose chemotherapy. Intern Med 1994; 33:115-119.
    66) Ostlere LS, Harris D, Prentice HG, et al: Widespread folliculitis induced by human granulocyte-colony-stimulating factor therapy. Br J Dermatol 1992; 127:193-194.
    67) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    68) Product Information: GRANIX(TM) subcutaneous injection solution, tbo-filgrastim subcutaneous injection solution. Teva Pharmaceuticals USA, Inc. (per FDA), North Wales, PA, 2013.
    69) Product Information: Granocyte(R), lenograstim. AMRAD Pharmaceuticals Pty Ltd, Victoria, Australia, 1994.
    70) Product Information: Granocyte(TM)-13, Granocyte(TM)-34, lenograstim. Chugai Pharma UK Limited, London, England, 2000.
    71) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    72) Product Information: LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, sargramostim subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution. Genzyme Corporation (per DailyMed), Cambridge, MA, 2009.
    73) Product Information: LEUKINE(R) subcutaneous, IV injection, sargramostim subcutaneous, IV injection. Bayer Healthcare, Seattle, WA, 2008.
    74) Product Information: NEULASTA(R) subcutaneous injection, pegfilgrastim subcutaneous injection. Amgen Inc, Thousand Oaks, CA, 2008.
    75) Product Information: NEULASTA(R) subcutaneous injection, pegfilgrastim subcutaneous injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    76) Product Information: NEULASTA(R) subcutaneous injection, pegfilgrastim subcutaneous injection. Amgen Inc. (per manufacturer), Thousand Oaks, CA, 2015.
    77) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    78) Product Information: NEUPOGEN(R) subcutaneous injection, intravenous injection, filgrastim subcutaneous injection, intravenous injection. Amgen Inc. (per FDA), Thousand Oaks, CA, 2015.
    79) Product Information: NEUPOGEN(R) subcutaneous injection, intravenous injection, filgrastim subcutaneous injection, intravenous injection. Amgen Manufacturing, Limited (per FDA), Thousand Oaks, CA, 2012.
    80) Product Information: NEUPOGEN(R) subcutaneous injection, intravenous injection, filgrastim subcutaneous injection, intravenous injection. Amgen Manufacturing, Limited (per Manufacturer), Thousand Oaks, CA, 2013.
    81) Product Information: Neulasta(R) subcutaneous injection, pegfilgrastim subcutaneous injection. Amgen Inc (per Manufacturer), Thousand Oaks, CA, 2011.
    82) Product Information: Neulasta(TM), pegfilgrastim. Amgen Inc, Thousand Oaks, CA, February 6, 2002, 2002.
    83) Product Information: ZARXIO(TM) subcutaneous injection solution, intravenous injection solution, filgrastim-sndz subcutaneous injection solution, intravenous injection solution. Sandoz Inc. (per FDA), Princeton, NJ, 2015.
    84) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    85) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    86) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    87) Rifkin R, Hersh E, & Salmon S: Continuous intravenous (IV) administration of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) is superior to IV bolus administration: a phase I study (abstract). Proc Am Soc Clin Oncol 1988; 7:165.
    88) Riu G, Estefanell A, Nomdedeu M, et al: Overdose of pegfilgrastim: case report. Int J Clin Pharm 2012; 34(5):690-692.
    89) Roskos LK, Yang B, Schwab G, et al: A cytokinetic model describes the granulopoietic effects of r-metHuG-CSF-SD/01 (SD/01) and the homeostatic regulation of SD/01 clearance in normal volunteers (abstract PIII-81). Clin Pharmacol Ther 1999; 65(2):196.
    90) Roskos LK, Yank B, Schwab G, et al: A cytokinetic model of r-metHuG-CSF-SD/01 (SD/01) mediated granulopoiesis and the "self-regulation" of SD/01 elimination in non-small cell lung cancer (NSCLC) patients (abstract 2085). Blood 1998; 92(10):507.
    91) Sekhar RV, Culbers S, Hoots K, et al: Severe osteopenia in a young boy with Kostmann's Congenital Neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach. Pediatrics 2001; 108(3):1-4.
    92) Smith JW: Tolerability and side-effect profile of rhIL-11. Oncology (Williston Park) 2000; 14(9 Suppl 8):41-47.
    93) Steis RG, VanderMolen LA, Longo DL, et al: Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: a phase Ib trial. J Natl Cancer Inst 1990; 82:697-703.
    94) Stoppa AM, Blaise D, Viens P, et al: Phase I study of in vivo lenograstim (rHuG-CSF) for stem cell collection demonstrates improved neutrophil recovery after autologous bone marrow transplantation. Bone Marrow Transplant 1994; 13:541-547.
    95) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    96) Verhoef G & Boogaerts M: Treatment with granulocyte-macrophage colony stimulating factor and the adult respiratory distress syndrome. Am J Hematol 1991; 36(4):285-287.
    97) Viallard AM, Lavenue A, Balme B, et al: Lichenoid cutaneous drug reaction at injection sites of granulocyte colony-stimulating factor (filgrastim). Dermatology 1999; 198:301-303.
    98) Vose JM, Crump M, Lazarus H, et al: Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003; 21(3):514-519.
    99) Yang B-B, Lum P, Renwick J et al: Pharmacokinetic rationale for a fixed-dose regimen of a sustained-duration form of filgrastim in cancer patients (abstract 4384). Proceedings of ASH, vol. 96, 157b, 2000.
    100) Yee GC: Colony-stimulating factors and tomorrow's pharmacy: why we must be ready. Am J Hosp Pharm 1989; 46(suppl 2):S24-S29.
    101) Yee GC: Focus on GM-CSF and G-CSF: promising biotherapeutics for use in hematology and oncology. Hosp Formul 1990; 25:943-948.
    102) van Hoef MEHM, Baumann I, Lange C, et al: Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer. Ann Oncol 1994; 5:217-224.
    103) van Mook W, Fickers M, van der Kley J, et al: A case of herpes-like sweet's syndrome in acute myelogenous leukemia during treatment with G-CSF. Neth J Med 1999; 55:235-241.