Filgrastim

NEUPOGEN is a leukocyte growth factor indicated to Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever ( 1.1 ) Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) ( 1.2 ) Reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT) ( 1.3 ) Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis ( 1.4 ) Reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia ( 1.5 ) Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) ( 1.6 )

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy NEUPOGEN is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever [see Clinical Studies (14.1) ] .

1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy NEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) [see Clinical Studies (14.2) ] .

1.3 Patients with Cancer Undergoing Bone Marrow Transplantation NEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies (14.3) ] .

1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy NEUPOGEN is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4) ] .

1.5 Patients with Severe Chronic Neutropenia NEUPOGEN is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia [see Clinical Studies (14.5) ] .

1.6 Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) NEUPOGEN is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.6) ] .

NEUPOGEN is a clear, colorless, preservative-free solution available as: Vial: Injection: 300 mcg/mL in a single-dose vial Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial Prefilled Syringe: Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe Vial Injection: 300 mcg/mL in a single-dose vial ( 3 ) Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial ( 3 ) Prefilled Syringe Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe ( 3 ) Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe ( 3 )

NEUPOGEN is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim [see Warnings and Precautions (5.3) ] . Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim. ( 4 )

Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. ( 5.1 ) Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NEUPOGEN in patients with ARDS. ( 5.2 ) Serious allergic reactions, including anaphylaxis: Permanently discontinue NEUPOGEN in patients with serious allergic reactions. ( 5.3 ) Fatal sickle cell crises: Discontinue NEUPOGEN if sickle cell crisis occurs. ( 5.4 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NEUPOGEN if causality is likely. ( 5.5 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using NEUPOGEN in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.8 ) Thrombocytopenia: Monitor platelet counts. ( 5.9 ) Large and Medium Vessel Arteritis: Discontinue NEUPOGEN if arteritis is suspected. ( 5.15 )

5.1 Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of NEUPOGEN. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NEUPOGEN in patients with ARDS.

5.3 Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving NEUPOGEN. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving NEUPOGEN can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NEUPOGEN in patients with serious allergic reactions. NEUPOGEN is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim.

5.4 Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NEUPOGEN if sickle cell crisis occurs.

5.5 Glomerulonephritis Glomerulonephritis has occurred in patients receiving NEUPOGEN. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose-reduction or discontinuation of NEUPOGEN. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of NEUPOGEN.

5.6 Alveolar Hemorrhage and Hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in NEUPOGEN-treated healthy donors undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of NEUPOGEN. The use of NEUPOGEN for PBPC mobilization in healthy donors is not an approved indication.

5.7 Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including NEUPOGEN, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.8 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) Patients with Severe Chronic Neutropenia Confirm the diagnosis of SCN before initiating NEUPOGEN therapy. MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with NEUPOGEN for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of NEUPOGEN on the development of abnormal cytogenetics and the effect of continued NEUPOGEN administration in patients with abnormal cytogenetics or MDS are unknown. Monitor patients for signs and symptoms of MDS/AML in these settings. If a patient with SCN develops abnormal cytogenetics or myelodysplasia, the risks and benefits of continuing NEUPOGEN should be carefully considered. Patients with Breast and Lung Cancer MDS and AML have been associated with the use of NEUPOGEN in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.9 Thrombocytopenia Thrombocytopenia has been reported in patients receiving NEUPOGEN. Monitor platelet counts.

5.10 Leukocytosis Patients with Cancer Receiving Myelosuppressive Chemotherapy White blood cell counts of 100,000/mm 3 or greater were observed in approximately 2% of patients receiving NEUPOGEN at dosages above 5 mcg/kg/day. In patients with cancer receiving NEUPOGEN as an adjunct to myelosuppressive chemotherapy, to avoid the potential risks of excessive leukocytosis, it is recommended that NEUPOGEN therapy be discontinued if the ANC surpasses 10,000/mm 3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of NEUPOGEN that increase the ANC beyond 10,000/mm 3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy, discontinuation of NEUPOGEN therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to pretreatment levels in 1 to 7 days. Peripheral Blood Progenitor Cell Collection and Therapy During the period of administration of NEUPOGEN for PBPC mobilization in patients with cancer, discontinue NEUPOGEN if the leukocyte count rises to > 100,000/mm 3 .

5.11 Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with NEUPOGEN. In most cases, the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term NEUPOGEN therapy. Hold NEUPOGEN therapy in patients with cutaneous vasculitis. NEUPOGEN may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

5.12 Potential Effect on Malignant Cells NEUPOGEN is a growth factor that primarily stimulates neutrophils. The granulocyte colony-stimulating factor (G-CSF) receptor through which filgrastim acts has also been found on tumor cell lines. The possibility that filgrastim acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When NEUPOGEN is used to mobilize PBPC, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied, and the limited data available are inconclusive.

5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of NEUPOGEN given simultaneously with chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to chemotherapy, do not use NEUPOGEN in the period 24 hours before through 24 hours after the administration of chemotherapy [see Dosage and Administration (2.2) ] . The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. […]

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Splenic Rupture [see Warnings and Precautions (5.1) ] Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2) ] Serious Allergic Reactions [see Warnings and Precautions (5.3) ] Sickle Cell Disorders [see Warnings and Precautions (5.4) ] Glomerulonephritis [see Warnings and Precautions (5.5) ] Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6) ] Capillary Leak Syndrome [see Warnings and Precautions (5.7) ] Myelodysplastic Syndrome [see Warnings and Precautions (5.8) ] Acute Myeloid Leukemia [see Warnings and Precautions (5.8) ] Thrombocytopenia [see Warnings and Precautions (5.9) ] Leukocytosis [see Warnings and Precautions (5.10) ] Cutaneous Vasculitis [see Warnings and Precautions (5.11) ] Large and Medium Vessel Arteritis [see Warnings and Precautions (5.15) ] Most common adverse reactions in patients: With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are pyrexia, pain, rash, cough, and dyspnea. ( 6.1 ) With AML (≥ 2% difference in incidence) are pain, epistaxis and rash. ( 6.1 ) With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) is rash. ( 6.1 ) Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia and headache. ( 6.1 ) With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are pain, anemia, epistaxis, diarrhea, hypoesthesia and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with: small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide, doxorubicin, and etoposide (Study 1) small cell lung cancer receiving ifosfamide, doxorubicin, and etoposide (Study 2), and non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3). A total of 451 patients were randomized to receive subcutaneous NEUPOGEN 230 mcg/m 2 (Study 1), 240 mcg/m 2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian. Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in NEUPOGEN Compared to Placebo) Body System Adverse Reactions NEUPOGEN (N = 294) Placebo (N = 157) Blood and lymphatic system disorders Thrombocytopenia 38% 29% Gastrointestinal disorders Nausea 43% 32% General disorders and administration site conditions Pyrexia 48% 29% Chest pain 13% 6% Pain 12% 6% Fatigue 20% 10% Musculoskeletal and connective tissue disorders Back pain 15% 8% Arthralgia 9% 2% Bone pain 11% 6% Pain in extremity Percent difference (NEUPOGEN – Placebo) was 4%. 7% 3% Nervous system disorders Dizziness 14% 3% Respiratory, thoracic and mediastinal disorders Cough 14% 8% Dyspnea 13% 8% Skin and subcutaneous tissue disorders Rash 14% 5% Investigations Blood lactate dehydrogenase increased 6% 1% Blood alkaline phosphatase increased 6% 1% Adverse reactions with ≥ 5% higher incidence in NEUPOGEN patients compared to placebo and associated with the sequelae of the underlying malignancy or chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia. Adverse Reactions in Patients with Acute Myeloid Leukemia Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day NEUPOGEN (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male. Adverse reactions with ≥ 2% higher incidence in NEUPOGEN patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular. Adverse events with ≥ 2% higher incidence in NEUPOGEN patients compared to placebo and associated with the sequelae of the underlying malignancy or chemotherapy included diarrhea, constipation, and transfusion reaction. Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment-controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4-hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24-hour infusion (Study 6) NEUPOGEN (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male. Adverse reactions with ≥ 5% higher incidence in NEUPOGEN patients compared to patients receiving no NEUPOGEN included rash and hypersensitivity. Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in NEUPOGEN patients compared to patients receiving no NEUPOGEN included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia. Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: NEUPOGEN was administered for 6 to 8 days, in most cases the apheresis procedure occurred on days 5, 6, and 7. The dosage of NEUPOGEN ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male. Table 3. […]

8.1 Pregnancy Risk Summary Available data from published studies, including several observational studies of pregnancy outcomes in women exposed to filgrastim products and those who were unexposed, have not established an association with NEUPOGEN use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data ] . Reports in the scientific literature have described transplacental passage of NEUPOGEN in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). In animal reproduction studies, effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. No maternal or fetal effects were observed in pregnant rats at doses up to 58 times the human doses. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Several observational studies based on the Severe Chronic Neutropenia International Registry (SCNIR) described pregnancy outcomes in women with severe chronic neutropenia (SCN) who were exposed to filgrastim products during pregnancy and women with SCN who were unexposed. No major differences were seen between treated and untreated women with respect to pregnancy outcome (including miscarriage and preterm labor), newborn complications (including birth weight), and infections. Methodological limitations of these studies include small sample size and lack of generalizability due to the underlying maternal condition. Animal Data Effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day, which is approximately 58 times higher than the human dose of 10 mcg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day).

8.2 Lactation Risk Summary There is published literature documenting transfer of filgrastim into human milk. There are a few case reports describing the use of filgrastim in breastfeeding mothers with no adverse effects noted in the infants. There are no data on the effects of filgrastim on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NEUPOGEN and any potential adverse effects on the breastfed child from NEUPOGEN or from the underlying maternal condition.

8.4 Pediatric Use In patients with cancer receiving myelosuppressive chemotherapy, 15 pediatric patients median age 2.6 (range 1.2 to 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide, cisplatin, doxorubicin, and etoposide) followed by subcutaneous NEUPOGEN at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8). The pharmacokinetics of NEUPOGEN in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of NEUPOGEN. In this population, NEUPOGEN was well tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with NEUPOGEN therapy; however, the only consistently reported adverse event was musculoskeletal pain, which is no different from the experience in the adult population. The safety and effectiveness of NEUPOGEN have been established in pediatric patients with SCN [see Clinical Studies (14.5) ] . In a phase 3 study (Study 7) to assess the safety and efficacy of NEUPOGEN in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage (1.5) , Dosage and Administration (2.6) , and Clinical Studies (14.5) ] . Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of NEUPOGEN treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function. Pediatric patients with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic NEUPOGEN treatment. The relationship of these events to NEUPOGEN administration is unknown [see Warnings and Precautions (5.8) and Adverse Reactions (6) ] . The use of NEUPOGEN to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on studies conducted in animals and clinical data supporting the use of NEUPOGEN in other approved indications [see Dosage and Administration (2.1 to 2.4) and Clinical Studies (14.6) ] .

8.5 Geriatric Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of NEUPOGEN-treated patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Clinical studies of NEUPOGEN in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

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 that is produced by monocytes, fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functions (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some cell surface antigens). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage.