NEUPOGEN

Filgrastim is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. Filgrastim is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Filgrastim has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli . Because filgrastim is produced in E coli ‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell. NEUPOGEN injection is a sterile‚ clear‚ colorless‚ preservative-free liquid containing filgrastim at a specific activity of 1.0 ± 0.6 × 10 8 U/mg (as measured by a cell mitogenesis assay). The product is available in single-dose vials for subcutaneous or intravenous use and prefilled syringes for subcutaneous use. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim. The NEUPOGEN drug product has a pH of 4.0. See table below for product composition of each single-dose vial or prefilled syringe. 300 mcg/mL Vial 480 mcg/1.6 mL Vial 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe filgrastim 300 mcg 480 mcg 300 mcg 480 mcg acetate 0.59 mg 0.94 mg 0.295 mg 0.472 mg polysorbate 80 0.04 mg 0.064 mg 0.02 mg 0.032 mg sodium 0.035 mg 0.056 mg 0.0175 mg 0.028 mg sorbitol 50 mg 80 mg 25 mg 40 mg water for Injection USP q.s. ad quantity sufficient to make. 1 mL 1.6 mL 0.5 mL 0.8 mL

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) ] .

Patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML Recommended starting dose is 5 mcg/kg/day subcutaneous injection, short intravenous infusion (15 to 30 minutes), or continuous intravenous infusion. See Full Prescribing Information for recommended dosage adjustments and timing of administration ( 2.1 ) Patients with cancer undergoing bone marrow transplantation 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. See Full Prescribing Information for recommended dosage adjustments and timing of administration ( 2.2 ) Patients undergoing autologous peripheral blood progenitor cell collection and therapy 10 mcg/kg/day subcutaneous injection ( 2.3 ) Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis ( 2.3 ) Patients with congenital neutropenia Recommended starting dose is 6 mcg/kg subcutaneous injection twice daily ( 2.4 ) Patients with cyclic or idiopathic neutropenia Recommended starting dose is 5 mcg/kg subcutaneous injection daily ( 2.4 ) Patients acutely exposed to myelosuppressive doses of radiation 10 mcg/kg/day subcutaneous injection ( 2.5 ) 2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of NEUPOGEN is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection‚ by short intravenous infusion (15 to 30 minutes)‚ or by continuous intravenous infusion. Obtain a complete blood count (CBC) and platelet count before instituting NEUPOGEN therapy and monitor twice weekly during therapy. Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the absolute neutrophil count (ANC) nadir. Recommend stopping NEUPOGEN if the ANC increases beyond 10‚000/mm 3 [see Warnings and Precautions (5.10) ] . Administer NEUPOGEN at least 24 hours after cytotoxic chemotherapy. Do not administer NEUPOGEN within the 24-hour period prior to chemotherapy [see Warnings and Precautions (5.13) ] . A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of NEUPOGEN therapy. Therefore, to ensure a sustained therapeutic response‚ administer NEUPOGEN daily for up to 2 weeks or until the ANC has reached 10‚000/mm 3 following the expected chemotherapy-induced neutrophil nadir. The duration of NEUPOGEN therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. 2.2 Dosage in Patients with Cancer Undergoing Bone Marrow Transplantation The recommended dosage of NEUPOGEN following bone marrow transplantation (BMT) is 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. Administer the first dose of NEUPOGEN at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Monitor CBCs and platelet counts frequently following marrow transplantation. During the period of neutrophil recovery‚ titrate the daily dosage of NEUPOGEN against the neutrophil response (see Table 1 ) . Table 1. Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count NEUPOGEN Dosage Adjustment When ANC greater than 1,000/mm 3 for 3 consecutive days Reduce to 5 mcg/kg/day If ANC decreases to less than 1,000/mm 3 at any time during the 5 mcg/kg/day administration‚ increase NEUPOGEN to 10 mcg/kg/day‚ and then follow the above steps. Then, if ANC remains greater than 1,000/mm 3 for 3 more consecutive days Discontinue NEUPOGEN Then, if ANC decreases to less than 1,000/mm 3 Resume at 5 mcg/kg/day 2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy The recommended dosage of NEUPOGEN for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer NEUPOGEN for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of NEUPOGEN administration and leukapheresis schedule have not been established‚ administration of NEUPOGEN for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective [see Clinical Studies (14.4) ] . Monitor neutrophil counts after 4 days of NEUPOGEN‚ and discontinue NEUPOGEN if the white blood cell (WBC) count rises to greater than 100‚000/mm 3 . 2.4 Dosage in Patients with Severe Chronic Neutropenia Prior to starting NEUPOGEN in patients with suspected chronic neutropenia, confirm the diagnosis of severe chronic neutropenia (SCN) by evaluating serial CBCs with differential and platelet counts‚ and evaluating bone marrow morphology and karyotype. The use of NEUPOGEN prior to confirmation of a correct diagnosis of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition‚ other than SCN‚ causing the neutropenia. The recommended starting dosage in patients with Congenital Neutropenia is 6 mcg/kg as a twice daily subcutaneous injection and the recommended starting dosage in patients with Idiopathic or Cyclic Neutropenia is 5 mcg/kg as a single daily subcutaneous injection. Dosage Adjustments in Patients with Severe Chronic Neutropenia Chronic daily administration is required to maintain clinical benefit. Individualize the dosage based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of NEUPOGEN were: 6 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of NEUPOGEN greater than or equal to 100 mcg/kg/day. Monitor CBCs for Dosage Adjustments During the initial 4 weeks of NEUPOGEN therapy and during the 2 weeks following any dosage adjustment‚ monitor CBCs with differential and platelet counts. Once a patient is clinically stable‚ monitor CBCs with differential and platelet counts monthly during the first year of treatment. Thereafter, if the patient is clinically stable, less frequent routine monitoring is recommended. 2.5 Dosage in Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) The recommended dose of NEUPOGEN is 10 mcg/kg as a single daily subcutaneous injection for patients exposed to myelosuppressive doses of radiation. Administer NEUPOGEN as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy). Estimate a patient's absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics. Obtain a baseline CBC and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm 3 for 3 consecutive CBCs. Do not delay administration of NEUPOGEN if a CBC is not readily available. Continue administration of NEUPOGEN until the ANC remains greater than 1,000/mm 3 for 3 consecutive CBCs or exceeds 10,000/mm 3 after a radiation-induced nadir. 2.6 Important Administration Instructions NEUPOGEN is supplied in single-dose vials (for subcutaneous use or intravenous infusion) and single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths (3) ] . Prior to use‚ remove the vial or prefilled syringe from the refrigerator and allow NEUPOGEN to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours. Discard any vial or prefilled syringe left at room temperature for greater than 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit (the solution is clear and colorless). Do not administer NEUPOGEN if particulates or discoloration are observed. Discard unused portion of NEUPOGEN in vials or prefilled syringes; do not re-enter the vial. Do not save unused drug for later administration. Subcutaneous Injection Inject NEUPOGEN subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer NEUPOGEN, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the vial or prefilled syringe [see Patient Counseling Information (17) ] . Training by the healthcare provider should aim to demonstrate to those patients and caregivers how to measure the dose of NEUPOGEN, and the focus should be on ensuring that a patient or caregiver can successfully perform all the steps in the Instructions for Use for the vial or prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NEUPOGEN or whether the patient would benefit from a different NEUPOGEN presentation. If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the NEUPOGEN prefilled syringe, use of the NEUPOGEN vial may be considered. If the patient or caregiver misses a dose of NEUPOGEN, instruct them to contact their healthcare provider. Administration Instructions for the Prefilled Syringe Persons with latex allergies should not administer the NEUPOGEN prefilled syringe, because the needle cap contains dry natural rubber (derived from latex). Administration Instructions for Dilution (Vial Only) If required for intravenous administration‚ NEUPOGEN (vial only) may be diluted in 5% Dextrose Injection, USP from a concentration of 300 mcg/mL to 5 mcg/mL (do not dilute to a final concentration less than 5 mcg/mL). NEUPOGEN diluted to concentrations from 5 mcg/mL to 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% Dextrose Injection, USP or 5% Dextrose plus Albumin (Human)‚ NEUPOGEN is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes. Do not dilute with saline at any time because the product may precipitate. Diluted NEUPOGEN solution can be stored at room temperature for up to 24 hours. This 24-hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

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 )

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) ] Aortitis [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) System Organ Class Preferred Term 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 events with ≥ 5% higher incidence in NEUPOGEN patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic 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 cytotoxic 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. Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in NEUPOGEN Patients) System Organ Class Preferred Term Mobilization Phase (N = 166) Musculoskeletal and connective tissue disorders Bone pain 30% General disorders and administration site conditions Pyrexia 16% Investigations Blood alkaline phosphatase increased 11% Nervous system disorders Headache 10% Adverse Reactions in Patients with Severe Chronic Neutropenia The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving NEUPOGEN (Study 7). 123 patients were randomized to a 4-month observation period followed by subcutaneous NEUPOGEN treatment or immediate subcutaneous NEUPOGEN treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of NEUPOGEN was determined by the category of neutropenia. Initial dosage of NEUPOGEN: Idiopathic neutropenia: 3.6 mcg/kg/day Cyclic neutropenia: 6 mcg/kg/day Congenital neutropenia: 6 mcg/kg/day divided 2 times per day The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. Adverse reactions with ≥ 5% higher incidence in NEUPOGEN patients compared to patients receiving no NEUPOGEN included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the NEUPOGEN arm, total infection related events were lower in NEUPOGEN-treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of NEUPOGEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1) ] acute respiratory distress syndrome [see Warnings and Precautions (5.2) ] anaphylaxis [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) ] leukocytosis [see Warnings and Precautions (5.10) ] cutaneous vasculitis [see Warnings and Precautions (5.11) ] Sweet's syndrome (acute febrile neutrophilic dermatosis) decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with NEUPOGEN myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.8) ] aortitis [see Warnings and Precautions (5.15) ] extramedullary hematopoiesis

Store NEUPOGEN at 2°C to 8°C (36°F to 46°F) in the carton to protect from light. Do not leave NEUPOGEN in direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard NEUPOGEN if frozen more than once. Avoid shaking. Transport via a pneumatic tube has not been studied.