NEUPOGEN - Amgen, Inc | Amgen Manufacturing Limited LLC

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)].

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)].

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)].

NEUPOGEN is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4)].

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)].

NEUPOGEN is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.6)].

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/mm³ [see Warnings and Precautions (5.10)].

Administer NEUPOGEN at least 24 hours after 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/mm³ 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.

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 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).

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/mm³.

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.

The recommended dosage 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/mm³ 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/mm³ for 3 consecutive CBCs or exceeds 10,000/mm³ after a radiation-induced nadir.

NEUPOGEN (for subcutaneous or intravenous use) is supplied in single-dose vials and single-dose prefilled syringes [see Dosage Forms and Strengths (3)].

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.

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.

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.

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.

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.

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.

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.

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.

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

Patients with Cancer Receiving Myelosuppressive Chemotherapy

White blood cell counts of 100,000/mm³ 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/mm³ 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/mm³ 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/mm³.

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.

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.

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. Avoid the simultaneous use of NEUPOGEN with chemotherapy and radiation therapy.

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.

Serious large and medium vessel arteritis, including aortitis, has been reported in patients receiving NEUPOGEN. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, headache, neck pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider arteritis in patients who develop these signs and symptoms without known etiology. Consider appropriate clinical management and discontinue NEUPOGEN as needed if arteritis is suspected.

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.

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)]
• Large and medium vessel arteritis, including aortitis [see Warnings and Precautions (5.15)]
• extramedullary hematopoiesis

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).

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.

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)].

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.

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. This increase in neutrophil counts was observed whether NEUPOGEN was administered intravenous (1 to 70 mcg/kg twice daily), subcutaneous (1 to 3 mcg/kg once daily), or by continuous subcutaneous infusion (3 to 11 mcg/kg/day). 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. 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 patients with cancer.

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.

Filgrastim exhibits nonlinear pharmacokinetics. Clearance is dependent on filgrastim concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of NEUPOGEN and is diminished by neutropenia. In addition, filgrastim is cleared by the kidney.

Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and cancer subjects. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses, over a 14-day period, resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes, following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes, following NEUPOGEN dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 to 20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated. The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.

Specific Populations

Patients Acutely Exposed to Myelosuppressive Doses of Radiation

The pharmacokinetics of filgrastim is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to filgrastim in non-human primates at 10 mcg/kg dose of NEUPOGEN, appears to be similar to that in humans at 5 mcg/kg. Simulations conducted using the population pharmacokinetic model indicates that the exposures to filgrastim at a NEUPOGEN dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.

Pediatric Patients

The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim [see Use in Specific Populations (8.4)].

Renal Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (n = 4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment

Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, filgrastim dose adjustment for patients with hepatic impairment is not necessary.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of NEUPOGEN or of other filgrastim products.

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 using NEUPOGEN, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell based bioassay. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of NEUPOGEN is unknown.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

The carcinogenic potential of filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats at doses up to 500 mcg/kg.

Filgrastim was administered to monkeys, dogs, hamsters, rats, and mice as part of a nonclinical toxicology program, which included studies up to 1-year duration.

In the repeated-dose studies, changes observed were attributable to the expected pharmacological actions of filgrastim (i.e., dose-dependent increases in white blood cell counts, increased circulating segmented neutrophils, and increased myeloid: erythroid ratio in bone marrow). Histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis, and dose-related increases in spleen weight were seen in all species. These changes all reversed after discontinuation of treatment.

The safety and efficacy of NEUPOGEN to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs were established in a randomized, double-blind, placebo-controlled trial conducted in patients with small cell lung cancer (Study 1).

In Study 1, patients received up to 6 cycles of intravenous chemotherapy including intravenous cyclophosphamide and doxorubicin on day 1; and etoposide on days 1, 2, and 3 of 21 day cycles. Patients were randomized to receive NEUPOGEN (n = 99) at a dose of 230 mcg/m² (4 to 8 mcg/kg/day) or placebo (n = 111). Study drug was administered subcutaneously daily beginning on day 4, for a maximum of 14 days. A total of 210 patients were evaluable for efficacy and 207 were evaluable for safety. The demographic and disease characteristics were balanced between arms with a median age of 62 (range 31 to 80) years; 64% males; 89% Caucasian; 72% extensive disease and 28% limited disease.

The main efficacy endpoint was the incidence of febrile neutropenia. Febrile neutropenia was defined as an ANC < 1,000/mm³ and temperature > 38.2°C. Treatment with NEUPOGEN resulted in a clinically and statistically significant reduction in the incidence of infection, as manifested by febrile neutropenia, 40% for NEUPOGEN-treated patients and 76% for placebo-treated patients (p < 0.001). There were also statistically significant reductions in the incidence and overall duration of infection manifested by febrile neutropenia; the incidence, severity and duration of severe neutropenia (ANC < 500/mm³); the incidence and overall duration of hospital admissions; and the number of reported days of antibiotic use.

The safety and efficacy of NEUPOGEN to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, double-blind, placebo-controlled, multi-center trial in patients with newly diagnosed, de novo AML (Study 4).

In Study 4 the initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous NEUPOGEN (n = 259) at a dose of 5 mcg/kg/day or placebo (n = 262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC ≥ 1,000/mm³ for 3 consecutive days or ≥ 10,000/mm³ for 1 day) or for a maximum of 35 days. The demographic and disease characteristics were balanced between arms with a median age of 54 (range 16 to 89) years; 54% males; initial white blood cell count (65% < 25,000/mm³ and 27% > 100,000/mm³); 29% unfavorable cytogenetics.

The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm³. Treatment with NEUPOGEN resulted in a clinically and statistically significant reduction in median number of days of severe neutropenia, NEUPOGEN-treated patients 14 days, placebo-treated patients 19 days (p = 0.0001: difference of 5 days (95% CI: −6.0, −4.0)). There was a reduction in the median duration of intravenous antibiotic use, NEUPOGEN-treated patients: 15 days versus placebo-treated patients: 18.5 days; a reduction in the median duration of hospitalization, NEUPOGEN-treated patients: 20 days versus placebo-treated patients: 25 days.

There were no statistically significant differences between the NEUPOGEN and the placebo groups in complete remission rate (69% - NEUPOGEN, 68% - placebo), median time to progression of all randomized patients (165 days - NEUPOGEN, 186 days - placebo), or median overall survival (380 days - NEUPOGEN, 425 days - placebo).

The safety and efficacy of NEUPOGEN to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of patients with lymphoma (Study 6 and Study 9). The safety and efficacy of NEUPOGEN to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo-controlled trial (Study 10).

In Study 6, patients with Hodgkin's disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU ("CVP"), and patients with non-Hodgkin's lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan ("BEAM"). There were 54 patients randomized 1:1:1 to control, NEUPOGEN 10 mcg/kg/day, and NEUPOGEN 30 mcg/kg/day as a 24-hour continuous infusion starting 24 hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin's disease and 31% non-Hodgkin's lymphoma.

The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm³. A statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm³) occurred in the NEUPOGEN-treated groups versus the control group (23 days in the control group, 11 days in the 10 mcg/kg/day group, and 14 days in the 30 mcg/kg/day group [11 days in the combined treatment groups, p = 0.004]).

In Study 9, patients with Hodgkin's disease and non-Hodgkin's lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU ("CVP"). There were 43 evaluable patients randomized to continuous subcutaneous infusion NEUPOGEN 10 mcg/kg/day (n = 19), NEUPOGEN 30 mcg/kg/day (n = 10) and no treatment (n = 14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin's disease and 72% non-Hodgkin's lymphoma.

The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm³) in the NEUPOGEN-treated groups versus the control group (21.5 days in the control group versus 10 days in the NEUPOGEN-treated groups, p < 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group versus 5 days in the NEUPOGEN-treated groups, p < 0.0001).

In Study 10, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive NEUPOGEN 300 mcg/m²/day (n = 33) or placebo (n = 37) days 5 through 28 after marrow infusion. The median age was 18 (range 1 to 45) years, 56% males. The underlying disease was: 67% hematologic malignancy, 24% aplastic anemia, 9% other. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group, p < 0.001) and time to recovery of ANC to ≥ 500/mm³ (21 days in the control group and 16 days in the treatment group, p < 0.001).

The safety and efficacy of NEUPOGEN to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using NEUPOGEN-mobilized autologous peripheral blood progenitor cells to autologous bone marrow (Study 11). Patients in all these trials underwent a similar mobilization/collection regimen: NEUPOGEN was administered for 6 to 7 days, in most cases the apheresis procedure occurred on days 5, 6, and 7. The dose of NEUPOGEN ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion.

Engraftment was evaluated in 64 patients who underwent transplantation using NEUPOGEN-mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count ≥ 20,000/mm³ by day 28. In clinical trials of NEUPOGEN for the mobilization of hematopoietic progenitor cells, NEUPOGEN was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (≥ 500/mm³) was reached. The rate of engraftment of these cells in the absence of NEUPOGEN post transplantation has not been studied.

Study 11 was a randomized, unblinded study of patients with Hodgkin's disease or non-Hodgkin's lymphoma undergoing myeloablative chemotherapy, 27 patients received NEUPOGEN-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. The preparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan ("BEAM"). Patients received daily NEUPOGEN 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin's disease and 43% non-Hodgkin's lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to NEUPOGEN-mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs 10 days).

The safety and efficacy of NEUPOGEN to reduce the incidence and duration of sequelae of neutropenia (that is fever, infections, oropharyngeal ulcers) in symptomatic adult and pediatric patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia was established in a randomized controlled trial conducted in patients with severe neutropenia (Study 7).

Patients eligible for Study 7 had a history of severe chronic neutropenia documented with an ANC < 500/mm³ on three occasions during a 6-month period, or in patients with cyclic neutropenia 5 consecutive days of ANC < 500/mm³ per cycle. In addition, patients must have experienced a clinically significant infection during the previous 12 months. Patients were randomized to a 4-month observation period followed by NEUPOGEN treatment or immediate NEUPOGEN treatment. The median age was 12 years (range 7 months to 76 years); 46% males; 34% idiopathic, 17% cyclic and 49% congenital neutropenia.

NEUPOGEN was administered subcutaneously. The dose of NEUPOGEN was determined by the category of neutropenia. Initial dose 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 dose was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

The main efficacy endpoint was response to NEUPOGEN treatment. ANC response from baseline (< 500/mm³) was defined as follows:

• Complete response: median ANC > 1,500/mm³
• Partial response: median ANC ≥ 500/mm³ and ≤ 1,500/mm³ with a minimum increase of 100%
• No response: median ANC < 500/mm³

There were 112 of 123 patients who demonstrated a complete or partial response to NEUPOGEN treatment.

Additional efficacy endpoints included a comparison between patients randomized to 4 months of observation and patients receiving NEUPOGEN of the following parameters:

• incidence of infection
• incidence of fever
• duration of fever
• incidence, duration, and severity of oropharyngeal ulcers
• number of days of antibiotic use

The incidence for each of these 5 clinical parameters was lower in the NEUPOGEN arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. An analysis of variance showed no significant interaction between treatment and diagnosis, suggesting that efficacy did not differ substantially in the different diseases. Although NEUPOGEN substantially reduced neutropenia in all patient groups, in patients with cyclic neutropenia, cycling persisted but the period of neutropenia was shortened to 1 day.

Efficacy studies of NEUPOGEN could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of NEUPOGEN for other approved indications [see Dosage and Administration (2.1 to 2.4)].

Because of the uncertainty associated with extrapolating animal efficacy data to humans, the selection of human dose for NEUPOGEN is aimed at providing exposures to filgrastim that exceed those observed in animal efficacy studies. The 10 mcg/kg daily dose is selected for humans exposed to myelosuppressive doses of radiation because the exposure associated with such a dose is expected to exceed the exposure associated with a 10 mcg/kg dose in non-human primates [see Clinical Pharmacology (12.3)]. The safety of NEUPOGEN at a daily dose of 10 mcg/kg has been assessed on the basis of clinical experience in approved indications.

The efficacy of NEUPOGEN was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. The planned sample size was 62 animals, but the study was stopped at the interim analysis with 46 animals because efficacy was established. Rhesus macaques were randomized to a control (n = 22) or treated (n = 24) group. Animals were exposed to total body irradiation of 7.4 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Starting on day 1 after irradiation, animals received daily subcutaneous injections of placebo (5% dextrose in water) or filgrastim (10 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥ 1,000/mm³ for 3 consecutive days, or ANC ≥ 10,000/mm³ for more than 2 consecutive days within study day 1 to 5, or ANC ≥ 10,000/mm³ any time after study day 5. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required.

Filgrastim significantly (at 0.023 level of significance) reduced 60-day mortality in the irradiated non-human primates: 21% mortality (5/24) in the filgrastim group compared to 59% mortality (13/22) in the control group.

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

Prefilled Syringes (SingleJect^®)

Single-dose, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe^® Needle Guard, containing 300 mcg/0.5 mL of filgrastim.

• Carton of 1 prefilled syringe (NDC 55513-924-91).
• Carton of 10 prefilled syringes (NDC 55513-924-10, NDC 55513-924-20).

Single-dose, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe^® Needle Guard, containing 480 mcg/0.8 mL of filgrastim.

• Carton of 1 prefilled syringe (NDC 55513-209-91).
• Carton of 10 prefilled syringes (NDC 55513-209-10, NDC 55513-209-20).

The needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex) [see Dosage and Administration (2.6)].

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

NEUPOGEN^® (filgrastim)