Source: FDA, National Drug Code (US) Revision Year: 2021
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%.
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.
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)].
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.
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 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:
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:
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:
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.
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