      Document 0161
 DOCN  DRG0161
 UNIQUE IDENTIFIER        DRG-0086
 NAME OF SUBSTANCE        Filgrastim [USAN 1996]
 REGISTRY NUMBER          121181-53-1
 STANDARD CHEMICAL NAME   N-L-Methionyl-colony-stimulating factor
                          (human clone 1034) [USAN 1996]
 SYNONYMS                 G-CSF [PDR 1995]
 SYNONYMS                 Neupogen [PDR 1995]
 SYNONYMS                 Recombinant methionyl granulocyte colony
                          stimulating factor [PDR 1995]
 SYNONYMS                 r-metHug-C-SF [FDA 61A]
 SYNONYMS                 r-metHuG-CSF [USAN 1996]
 SYNONYMS                 Granulocyte colony stimulating factor [USP DI
                          1995]
 PROTOCOL ID NUMBERS      NCI 91 C-01
 PROTOCOL ID NUMBERS      FDA 061A
 PROTOCOL ID NUMBERS      NIAID ACTG 149
 PROTOCOL ID NUMBERS      NIAID ACTG 286
 SECONDARY SOURCE ID      GCSF-8808-109 [FDA 61A]
 PHARMACOLOGICAL ACTION   Colony stimulating factors are glycoproteins
                          which act on hematopoietic cells by binding
                          to specific cell surface receptors and
                          stimulating proliferation, differentiation
                          commitment, and some end-cell functional
                          activation. Endogenous G-CSF is a lineage
                          specific colony stimulating factor with
                          selectivity for the neutrophil lineage. G-CSF
                          is not species specific and has been shown to
                          primarily affect neutrophil progenitor
                          proliferation, differentiation, and selected
                          end-cell functional activation (including
                          enhanced phagocytic ability, priming of the
                          cellular metabolism associated with
                          respiratory burst, antibody dependent
                          killing, and the increased expression of some
                          functions associated with cell surface
                          antigens). In Phase I studies involving 96
                          patients with various non-myeloid
                          malignancies, G-CSF administration resulted
                          in a dose-dependent increase in circulating
                          neutrophil counts over the dose range of 1-70
                          mcg/kg/day. Absorption and clearance of the
                          drug follows first-order pharmacokinetic
                          modeling without apparent concentration
                          dependence. A positive linear correlation
                          occurred between the parenteral dose and both
                          the serum concentration and area under the
                          concentration time curves. Subcutaneous
                          administration of 3.45 mcg/kg and 11.5 mcg/kg
                          resulted in maximum serum concentrations and
                          4 and 49 ng/mL, respectively, within 2 to 8
                          hours. The volume of distribution averaged
                          150 mL/kg in both normal subjects and cancer
                          patients. The elimination half-life in both
                          normal subjects and cancer patients was
                          approximately 3.5 hours. Clearance rates of
                          the drug were approximately 0.5-0.7
                          mL/min/kg. [PDR 1995]
 DISEASES STUDIED/TREATED Used to correct or minimize HIV associated
                          neutropenia and/or drug induced neutropenia
                          [AHFS Drug Information 1995] [HHS Press
                          Release]
 DISEASES STUDIED/TREATED In AIDS patients receiving zidovudine (ZDV)
                          therapy, filgrastim, either alone or with
                          epoetin alfa, has been used to decrease
                          hematologic toxicity of ZDV [AHFS Drug
                          Information 1995] [HHS Press Release]
 DISEASES STUDIED/TREATED Similarly, filgrastim, has been evaluated in
                          hematologic toxicity of ganciclovir,
                          co-trimoxazole, sulfadoxine and pyrimethamine
                          [AHFS Drug Information 1995] [HHS Press
                          Release]
 DISEASES STUDIED/TREATED FDA approved 2/21/91 for neutropenia due to
                          chemotherapy for cancers including lymphomas
                          and Kaposis's sarcoma. [AHFS Drug Information
                          1995] [HHS Press Release]
 CLASSIFICATION CODE      Immunomodulator [PDR 1995]
 CLASSIFICATION CODE      Hematopoietic stimulant [USAN 1996]
 CLASSIFICATION CODE      Antineutropenic [USAN 1996]
 OTHER MAJOR USES         Used to decrease the incidence of infection,
                          as manifested by febrile neutropenia, in
                          patients with non-myeloid malignancies
                          receiving myelosuppressive anti-cancer drugs
                          associated with a significant incidence of
                          severe neutropenia with fever. Used in cancer
                          patients receiving bone marrow transplants.
                          [PDR 1995] [AHFS Drug Information 1995]
 SUBSTANCE INTERACTIONS   The safety and efficacy of concomitant doses
                          of filgrastim and myelosuppressive
                          antineoplastic agents has not been
                          established. Because filgrastim stimulates
                          the proliferation of neutrophil precursors
                          and because many antineoplastic agents target
                          rapidly proliferating cells, filgrastim
                          should not be administered within 24 hours
                          before or after a dose of one of these
                          agents. Because transient decreases in
                          platelet counts have been reported in some
                          patients receiving filgrastim the drug should
                          be used with caution in patients receiving
                          other agents decreasing platelet counts.
                          Drugs which could possibly potentiate the
                          myeloproliferative effect of filgrastim,
                          e.g., lithium, should be used with caution.
                          [AHFS Drug Information 1995]
 ADVERSE EFFECTS          Medullary bone pain is the most common side
                          effect. This side effect can be controlled in
                          most patients with non-narcotic analgesics.
                          This effect was seen less in patients who
                          received the drug subcutaneously rather than
                          intravenously. Spontaneously reversible
                          elevations in uric acid, lactate
                          dehydrogenase, and alkaline phosphatase
                          occurred in 27% to 58% of 98 patients. These
                          increases were generally mild to moderate.
                          Splenomegaly has occasionally been reported
                          in patients receiving chronic filgrastim,
                          principally in those with congenital or
                          cyclic neutropenia. Transient decreases in
                          blood pressure have also been reported. Rare
                          occurrences of hematuria/proteinuria and
                          osteoporosis have also been reported. [AHFS
                          Drug Information 1995]
 CONTRAINDICATIONS        Contraindicated in the presence of previous
                          hypersensitivity to myeloid growth factors;
                          leukemic or preleukemic conditions; hairy
                          cell leukemia because of possible increased
                          incidence of Sweet Syndrome gout because
                          elevations in uric acid levels may occur;
                          psoriasis because exacerbation has been
                          reported; however, some investigators feel
                          there are no absolute contraindications to
                          G-CSF. [TIPS 1989, 10] [Ann Intern Med 1989,
                          110] [N Engl J Med 1989, 320]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Endogenous form: One of
                          several hematopoietic growth factors secreted
                          by T lymphocytes, monocytes, macrophages and
                          other tissues which stimulate myeloid cell
                          growth and differentiation [Blood Cells 1987;
                          13] [USAN 1996]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Recombinant form: a single
                          chain, 175 amino acid polypeptide,
                          nonglycosylated, expressed by E. coli [Blood
                          Cells 1987; 13] [USAN 1996] [Science 1987;
                          263]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C845H1339N223O243S9 [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 18,800 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   STABILITY: Filgrastim may aggregate if
                          frozen. Solutions should not be shaken in
                          order to avoid frothing or bubble formation
                          [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: The injection is stable over a pH
                          range of 3.8-4.2. To avoid adsorption to
                          infusion containers or equipment albumin
                          human should be added to the admixtures [AHFS
                          Drug Information 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vials containing 300 mcg
                          filgrastim per 1 ml. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous and
                          subcutaneous. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store at 2 to 8 C prior to use; do
                          not refreeze. [PDR 1995]
 MANUFACTURERS            Amgen
 REFERENCES               McLeish S, Decoster G, Rich W. Clinical trial
                          and post-marketing safety profile of
                          Filgrastim in oncology patients (Neupogen)
                          (Meeting abstract). Proc Annu Meet Am Soc
                          Clin Oncol. 1994;13:A543.
 REFERENCES               Oksenhendler E, Dubreull ML, Gerard L,
                          Barateau V, Levy U, Deforges L, Ferchal F,
                          Clauvel JP. Intensive chemotherapy and G-CSF
                          in HIV-associated non-Hogkin's lymphoma. Int
                          Conf AIDS. 1994 Aug 7-12;10(1):18 (abstract
                          no. 044B).
 REFERENCES               Balbiano R, Degioanni M, Valle M, Crivelli P,
                          Bordino C, Mastinu A, Biglino A. Prevention
                          of severe neutropenia in AIDS patients with
                          intermittent, low-dose G-CSF (filgrastim).
                          Int Conf AIDS. 1994 Aug 7-12;10(1):223
                          (abstract no. PB0323).
 REFERENCES               Miguelez M, Laynez P, Linarez M, Romero F,
                          Rosquete J, Antolin J. Use of granulocyte
                          colony stimulating factor (G-CSF) in patients
                          with HIV infections. Int Conf AIDS. 1994 Aug
                          7-12;10(1):225 (abstract no. PB0329).
 REFERENCES               De Longis P, Ghirga P, Bove G, Giannini V,
                          Paglia MG. Weekly low dose of G-CSF treatment
                          in patients with AIDS and iatrogenic
                          neutropenia. Int Conf AIDS. 1993 Jun
                          6-11;9(1):500 (abstract no. PO-B29-2190).
 REFERENCES               Malamud S, Perentesis V. G-CSF vs GM-CSF in
                          hospitalized neutropenic patients: a
                          randomized trial. Proc Annu Meet Am Soc Clin
                          Oncol. 1993;12:A1550.
 REFERENCES               Sandor P, Bogner JR, Held M, Spathling S,
                          Rolinski B, Goebel FD. Use of G-CSF in the
                          management of chemotherapy-induced
                          neutropenia in patients with advanced-stage
                          Kaposi-sarcoma. Int Conf AIDS. 1993 Jun
                          6-11;9(1):450 (abstract no. PO-B21-1890).
 REFERENCES               Hermans P, Franchioly P, Thioux C, Gray S,
                          Vannerom H, Clumeck N. Granulocyte-colony
                          stimulating factor (G-CSF [filgrastim]) for
                          treatment of neutropenia in patients with
                          AIDS. Int Conf AIDS. 1993 Jun 6-11;9(1):65
                          (abstract no. WS-B22-3).
 REFERENCES               Katz A, Levy GC. The role of G-CSF in
                          zidovudine-induced leukopenia and
                          granulocytopenia (G) in AIDS patients (pts):
                          results of a pilot study (Meeting Abstract).
                          Proc Annu Meet Am Soc Clin Oncol.
                          1993;12:A20.
 REFERENCES               Tirelli U, Errante D, Tavio M, Polizzi P,
                          Bernardi D, Talamini R. Treatment of
                          HIV-related non-Hodgkin's lymphoma (NHL) with
                          chemotherapy (CT) and granulocyte-colony
                          stimulating factor (G-CSF), reduction of
                          toxicity and of days of hospitalization with
                          concomitant overall reduction of the cost.
                          Int Conf AIDS. 1993 Jun 6-11;9(1):59
                          (abstract no. WS-B16-2).
 ENTRY MONTH              9007
 LAST REVISION DATE       951107
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
