DailyMed Label: NEUPOGEN

DailyMed Label: Neupogen

2009

DailyMed Prescription

Neupogen

filgrastim

Physicians Total Care, Inc.

NDC: 54868-2522

NDC: 54868-2522

NDC: 54868-5020

NDC: 54868-5020

NDC: 54868-3050

NDC: 54868-3050

Filgrastim is a human granulocyte colony-stimulating factor (G-CSF)‚ produced by recombinant DNA technology. NEUPOGEN ® is the Amgen Inc. trademark for Filgrastim‚ which has been selected as the name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). NEUPOGEN ® is a 175 amino acid protein manufactured by recombinant DNA technology. 1 NEUPOGEN ® is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. NEUPOGEN ® 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 NEUPOGEN ® is produced in E coli‚ the product is nonglycosylated and thus differs from G-CSF isolated from a human cell. NEUPOGEN ® is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration containing Filgrastim at a specific activity of 1.0 ± 0.6 x 10 8 U/mg (as measured by a cell mitogenesis assay). The product is available in single use vials and prefilled syringes. The single use vials contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. The single use prefilled syringes contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single use vial or prefilled syringe. 300 mcg/ 1.0 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 Sorbitol 50.0 mg 80.0 mg 25.0 mg 40.0 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 Water for Injection USP q.s. ad 1.0 mL 1.6 mL 0.5 mL 0.8 mL

Cancer Patients 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 EXPERIENCE ). A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy‚ and twice per week (see LABORATORY MONITORING ) during NEUPOGEN ® therapy to avoid leukocytosis and to monitor the neutrophil count. In phase 3 clinical studies‚ NEUPOGEN ® therapy was discontinued when the ANC was ≥ 10‚000/mm 3 after the expected chemotherapy-induced nadir. 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 adults with AML. Cancer Patients Receiving Bone Marrow Transplant NEUPOGEN ® is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ eg‚ febrile neutropenia‚ in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation (see CLINICAL EXPERIENCE ). It is recommended that CBCs and platelet counts be obtained at a minimum of 3 times per week (see LABORATORY MONITORING ) following marrow infusion to monitor the recovery of marrow reconstitution. Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy NEUPOGEN ® is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment compared with collection by leukapheresis without mobilization or bone marrow harvest. After myeloablative chemotherapy‚ the transplantation of an increased number of progenitor cells can lead to more rapid engraftment‚ which may result in a decreased need for supportive care (see CLINICAL EXPERIENCE ). Patients With Severe Chronic Neutropenia NEUPOGEN ® is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (eg‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia (see CLINICAL EXPERIENCE ). It is essential that serial CBCs with differential and platelet counts‚ and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of NEUPOGEN ® therapy (see WARNINGS ). The use of NEUPOGEN ® prior to confirmation 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.

NEUPOGEN ® is supplied in either vials or in prefilled syringes with UltraSafe ® Needle Guards. Following administration of NEUPOGEN ® from the prefilled syringe, the UltraSafe ® Needle Guard should be activated to prevent accidental needle sticks. To activate the UltraSafe ® Needle Guard, place your hands behind the needle, grasp the guard with one hand, and slide the guard forward until the needle is completely covered and the guard clicks into place. NOTE: If an audible click is not heard, the needle guard may not be completely activated. The prefilled syringe should be disposed of by placing the entire prefilled syringe with guard activated into an approved puncture-proof container. Cancer Patients Receiving Myelosuppressive Chemotherapy The recommended starting dose of NEUPOGEN ® is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. A CBC and platelet count should be obtained before instituting NEUPOGEN ® therapy‚ and monitored twice weekly during therapy. Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. NEUPOGEN ® should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. NEUPOGEN ® should not be administered in the period 24 hours before the administration of chemotherapy (see PRECAUTIONS ). NEUPOGEN ® should be administered daily for up to 2 weeks‚ 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. NEUPOGEN ® therapy should be discontinued if the ANC surpasses 10‚000/mm 3 after the expected chemotherapy-induced neutrophil nadir (see PRECAUTIONS ). In phase 3 trials‚ efficacy was observed at doses of 4 to 8 mcg/kg/day. Cancer Patients Receiving Bone Marrow Transplant The recommended dose of NEUPOGEN ® following BMT is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of NEUPOGEN ® should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery‚ the daily dose of NEUPOGEN ® should be titrated against the neutrophil response as follows: Absolute Neutrophil Count NEUPOGEN ® Dose Adjustment When ANC greater than 1000/mm 3 for 3 consecutive days Reduce to 5 mcg/kg/day * then: If ANC remains greater than 1000/mm 3 for 3 more consecutive days Discontinue NEUPOGEN ® then: If ANC decreases to less than 1000/mm 3 Resume at 5 mcg/kg/day *    If ANC decreases to less than 1000/mm 3 at any time during the 5 mcg/kg/day administration‚ NEUPOGEN ® should be increased to 10 mcg/kg/day‚ and the above steps should then be followed. Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients The recommended dose of NEUPOGEN ® for the mobilization of PBPC is 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that NEUPOGEN ® be given for at least 4 days before the first leukapheresis procedure and continued 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 EXPERIENCE for schedules used in clinical trials). Neutrophil counts should be monitored after 4 days of NEUPOGEN ® , and NEUPOGEN ® dose modification should be considered for those patients who develop a WBC count greater than  100‚000/mm 3 . In all clinical trials of NEUPOGEN ® for the mobilization of PBPC‚ NEUPOGEN ® was also administered after reinfusion of the collected cells (see CLINICAL EXPERIENCE ). Patients With Severe Chronic Neutropenia NEUPOGEN ® should be administered to those patients in whom a diagnosis of congenital‚ cyclic‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out. Starting Dose: Congenital Neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC every day. Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg as a single injection SC every day. Dose Adjustments: Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patients’ clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of NEUPOGEN ® were: 6.0 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. Dilution If required‚ NEUPOGEN ® may be diluted in 5% dextrose. NEUPOGEN ® diluted to concentrations between 5 and 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 or 5% dextrose plus Albumin (Human)‚ NEUPOGEN ® is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes. Dilution of NEUPOGEN ® to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate. Storage NEUPOGEN ® should be stored in the refrigerator at 2° to 8°C (36° to 46°F). Avoid shaking. Prior to injection‚ NEUPOGEN ® may be allowed to reach room temperature for a maximum of 24 hours. Any vial or prefilled syringe left at room temperature for greater than 24 hours should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration‚ whenever solution and container permit; if particulates or discoloration are observed‚ the container should not be used.

NEUPOGEN ® is contraindicated in patients with known hypersensitivity to E coli -derived proteins‚ Filgrastim‚ or any component of the product.

General Simultaneous Use With Chemotherapy and Radiation Therapy The safety and efficacy of NEUPOGEN ® given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use NEUPOGEN ® in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION ). The efficacy of NEUPOGEN ® has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas) or with mitomycin C or with myelosuppressive doses of antimetabolites such as 5-fluorouracil. The safety and efficacy of NEUPOGEN ® have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of NEUPOGEN ® with chemotherapy and radiation therapy should be avoided. Potential Effect on Malignant Cells NEUPOGEN ® is a growth factor that primarily stimulates neutrophils. However‚ the possibility that NEUPOGEN ® can act as a growth factor for any tumor type cannot be excluded. In a randomized study evaluating the effects of NEUPOGEN ® versus placebo in patients undergoing remission induction for AML, there was no significant difference in remission rate, disease-free, or overall survival (see CLINICAL EXPERIENCE ). The safety of NEUPOGEN ® 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. Leukocytosis Cancer Patients Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm 3 or greater were observed in approximately 2% of patients receiving NEUPOGEN ® at doses above 5 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis‚ a CBC is recommended twice per week during NEUPOGEN ® therapy (see LABORATORY MONITORING ). Premature Discontinuation of NEUPOGEN ® Therapy Cancer Patients Receiving Myelosuppressive Chemotherapy A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of NEUPOGEN ® therapy. However‚ for a sustained therapeutic response‚ NEUPOGEN ® therapy should be continued following chemotherapy until the post nadir ANC reaches 10‚000/mm 3 . Therefore‚ the premature discontinuation of NEUPOGEN ® therapy‚ prior to the time of recovery from the expected neutrophil nadir‚ is generally not recommended (see DOSAGE AND ADMINISTRATION ). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving NEUPOGEN ® has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim, the nature and specificity of these antibodies has not been adequately studied. In clinical studies comparing NEUPOGEN ® and Neulasta ® , the incidence of antibodies binding to NEUPOGEN ® was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to NEUPOGEN ® with the incidence of antibodies to other products may be misleading. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against Filgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience. Patients who develop hypersensitivity to Filgrastim (NEUPOGEN ® ) may have allergic or hypersensitivity reactions to other E coli -derived proteins. 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. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue NEUPOGEN ® at a reduced dose. Information for Patients and Caregivers Patients should be referred to the “Information for Patients and Caregivers” labeling included with the package insert in each dispensing pack of NEUPOGEN ® vials or NEUPOGEN ® prefilled syringes. The “Information for Patients and Caregivers” labeling provides information about neutrophils and neutropenia and the safety and efficacy of NEUPOGEN ® . It is not intended to be a disclosure of all known or possible effects. Laboratory Monitoring Cancer Patients Receiving Myelosuppressive Chemotherapy A CBC and platelet count should be obtained prior to chemotherapy‚ and at regular intervals (twice per week) during NEUPOGEN ® therapy. Following cytotoxic chemotherapy‚ the neutrophil nadir occurred earlier during cycles when NEUPOGEN ® was administered‚ and WBC differentials demonstrated a left shift‚ including the appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe neutropenia was reduced‚ and was followed by an accelerated recovery in the neutrophil counts. Cancer Patients Receiving Bone Marrow Transplant Frequent CBCs and platelet counts are recommended (at least 3 times per week) following marrow transplantation. Patients With Severe Chronic Neutropenia During the initial 4 weeks of NEUPOGEN ® therapy and during the 2 weeks following any dose adjustment‚ a CBC with differential and platelet count should be performed twice weekly. Once a patient is clinically stable‚ a CBC with differential and platelet count should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular CBCs (ie, as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment (see WARNINGS , ADVERSE REACTIONS ). In clinical trials‚ the following laboratory results were observed: Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of NEUPOGEN ® therapy. Platelet counts were generally at the upper limits of normal prior to NEUPOGEN ® therapy. With NEUPOGEN ® therapy‚ platelet counts decreased but usually remained within normal limits (see ADVERSE REACTIONS ). Early myeloid forms were noted in peripheral blood in most patients‚ including the appearance of metamyelocytes and myelocytes. Promyelocytes and myeloblasts were noted in some patients. Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with NEUPOGEN ® therapy. As in other trials‚ increases were observed in serum uric acid‚ lactic dehydrogenase‚ and serum alkaline phosphatase. Drug Interaction Drug interactions between NEUPOGEN ® and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of NEUPOGEN ® has not been studied. NEUPOGEN ® failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. NEUPOGEN ® had no observed effect on the fertility of male or female rats‚ or on gestation at doses up to 500 mcg/kg. Pregnancy Category C NEUPOGEN ® has been shown to have adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose. Since there are no adequate and well-controlled studies in pregnant women, the effect, if any, of NEUPOGEN ® on the developing fetus or the reproductive capacity of the mother is unknown. However, the scientific literature describes transplacental passage of NEUPOGEN ® when administered to pregnant rats during the latter part of gestation 18 and apparent transplacental passage of NEUPOGEN ® when administered to pregnant humans by ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). 19 NEUPOGEN ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rabbits‚ increased abortion and embryolethality were observed in animals treated with NEUPOGEN ® at 80 mcg/kg/day. NEUPOGEN ® administered to pregnant rabbits at doses of 80 mcg/kg/day during the period of organogenesis was associated with increased fetal resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body weight‚ live births‚ and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies in pregnant rats have shown that NEUPOGEN ® was not associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 mcg/kg/day. In Segment III studies in rats‚ offspring of dams treated at > 20 mcg/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation‚ possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced 4-day survival rate. Nursing Mothers It is not known whether NEUPOGEN ® is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if NEUPOGEN ® is administered to a nursing woman. Pediatric Use In a phase 3 study to assess the safety and efficacy of NEUPOGEN ® in the treatment of SCN, 120 patients with a median age of 12 years were studied. Of the 120 patients, 12 were infants (1 month to 2 years of age), 47 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 531 patients in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents (see CLINICAL EXPERIENCE , INDICATIONS AND USAGE , LABORATORY MONITORING , DOSAGE AND ADMINISTRATION ). 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 , ADVERSE REACTIONS ). 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. The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established. In the cancer setting‚ 12 pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide chemotherapy concurrently with NEUPOGEN ® ; in this population‚ NEUPOGEN ® was well tolerated. There was one report of palpable splenomegaly 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. Geriatric Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of NEUPOGEN ® use following 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, and other clinical experience has not identified differences in the responses between elderly and younger patients. Clinical studies of NEUPOGEN ® in other approved indications (ie, bone marrow transplant 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.

In clinical trials involving over 350 patients receiving NEUPOGEN

NEUPOGEN ® : Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration. Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration. Vials Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ( NDC 54868-2522-0 );  Dispensing packs of 10 ( NDC 54868-2522-1 ). Prefilled Syringes (SingleJect ® ) Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe ® Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ( NDC 54868-5020-0 ). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe ® Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ( NDC 54868-3050-0 ). The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). NEUPOGEN ® should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.

Colony-stimulating Factors 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 which is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ 2‚3 differentiation, 2‚4 and selected end-cell functional activation (including enhanced phagocytic ability‚ 5 priming of the cellular metabolism associated with respiratory burst‚ 6 antibody dependent killing, 7 and the increased expression of some functions associated with cell surface antigens 8 ). G-CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. Preclinical Experience Filgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a preclinical toxicology program which included single-dose acute‚ repeated-dose subacute‚ subchronic‚ and chronic studies. Single-dose administration of Filgrastim by the oral‚ intravenous (IV)‚ subcutaneous (SC)‚ or intraperitoneal (IP) routes resulted in no significant toxicity in mice‚ rats‚ hamsters‚ or monkeys. Although no deaths were observed in mice‚ rats‚ or monkeys at dose levels up to 3450 mcg/kg or in hamsters using single doses up to approximately 860 mcg/kg‚ deaths were observed in a subchronic (13-week) study in monkeys. In this study‚ evidence of neurological symptoms was seen in monkeys treated with doses of Filgrastim greater than 1150 mcg/kg/day for up to 18 days. Deaths were seen in 5 of the 8 treated animals and were associated with 15- to 28-fold increases in peripheral leukocyte counts‚ and neutrophil-infiltrated hemorrhagic foci were seen in both the cerebrum and cerebellum. In contrast‚ no monkeys died following 13 weeks of daily IV administration of Filgrastim at a dose level of 115 mcg/kg. In an ensuing 52-week study‚ one 115 mcg/kg dosed female monkey died after 18 weeks of daily IV administration of Filgrastim. Death was attributed to cardiopulmonary insufficiency. In subacute‚ repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of Filgrastim (ie‚ dose-dependent increases in white cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bone marrow). In all species‚ histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis; increased spleen weights were seen in all species and appeared to be dose-related. A dose-dependent increase in serum alkaline phosphatase was observed in rats‚ and may reflect increased activity of osteoblasts and osteoclasts. Changes in serum chemistry values were reversible following discontinuation of treatment. In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and for 13 weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6 of 32 animals)‚ articular swelling of the hind legs was observed. Some degree of hind leg dysfunction was also observed; however‚ symptoms reversed following cessation of dosing. In rats‚ osteoclasis and osteoanagenesis were found in the femur‚ humerus‚ coccyx‚ and hind legs (where they were accompanied by synovitis) after IV treatment for 4 weeks (115 to 1150 mcg/kg/day)‚ and in the sternum after IV treatment for 13 weeks (115 to 575 mcg/kg/day). These effects reversed to normal within 4 to 5 weeks following cessation of treatment. In the 52-week chronic‚ repeated-dose studies performed in rats (IP injection up to 57.5 mcg/kg/day)‚ and cynomolgus monkeys (IV injection of up to 115 mcg/kg/day)‚ changes observed were similar to those noted in the subacute studies. Expected pharmacological actions of Filgrastim included dose-dependent increases in white cell counts‚ increased circulating segmented neutrophils and alkaline phosphatase levels‚ and increased myeloid:erythroid ratios in the bone marrow. Decreases in platelet counts were also noted in primates. In no animals tested were hemorrhagic complications observed. Rats displayed dose-related swelling of the hind limb‚ accompanied by some degree of hind limb dysfunction; osteopathy was noted microscopically. Enlarged spleens (both species) and livers (monkeys)‚ reflective of ongoing extramedullary granulopoiesis‚ as well as myeloid hyperplasia of the bone marrow‚ were observed in a dose-dependent manner. Pharmacologic Effects of NEUPOGEN ® In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ NEUPOGEN ® administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. 9-11 This increase in neutrophil counts was observed whether NEUPOGEN ® was administered IV (1 to 70 mcg/kg twice daily)‚ 9 SC (1 to 3 mcg/kg once daily)‚ 11 or by continuous SC infusion (3 to 11 mcg/kg/day). 10 With discontinuation of NEUPOGEN ® therapy‚ neutrophil counts returned to baseline‚ in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro. The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving NEUPOGEN ® ; however‚ the percentage of monocytes in the differential count remained within the normal range. In all studies to date‚ absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of NEUPOGEN ® . Increases in lymphocyte counts following NEUPOGEN ® administration have been reported in some normal subjects and cancer patients. White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection. Pharmacokinetics Absorption and clearance of NEUPOGEN ® 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. Continuous IV infusion of 20 mcg/kg of NEUPOGEN ® over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentrations of 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 NEUPOGEN ® were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes‚ following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ following NEUPOGEN ® doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of NEUPOGEN ® with no evidence of drug accumulation over the time period investigated. Pharmacokinetic data in geriatric patients (≥ 65 years) are not available.

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