NEUPOGEN® Filgrastim -
NEUPOGEN® PRESCRIBING INFORMATION
DESCRIPTION
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 108 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/ 480 mcg/ 300 mcg/ 480 mcg/
1.0 mL Vial 1.6 mL Vial 0.5 mL Syringe 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
Tween®80 0.004% 0.004% 0.004% 0.004%
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
CLINICAL PHARMACOLOGY
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 antigens8). 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, as
well as 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.
CLINICAL EXPERIENCE
Cancer Patients Receiving Myelosuppressive Chemotherapy
NEUPOGEN® has been shown to be safe and effective in
accelerating the recovery of neutrophil counts following a
variety of chemotherapy regimens. In a phase 3 clinical trial
in small cell lung cancer, patients received SC administration
of NEUPOGEN® (4 to 8 mcg/kg/day, days 4 to 17) or placebo. In
this study, the benefits of NEUPOGEN® therapy were shown to be
prevention of infection as manifested by febrile neutropenia,
decreased hospitalization, and decreased IV antibiotic usage.
No difference in survival or disease progression was
demonstrated.
In the phase 3, randomized, double-blind, placebo-controlled
trial conducted in patients with small cell lung cancer,
patients were randomized to receive NEUPOGEN® (n = 99) or
placebo (n = 111) starting on day 4, after receiving standard
dose chemotherapy with cyclophosphamide, doxorubicin, and
etoposide. A total of 210 patients were evaluated for efficacy
and 207 evaluated for safety. Treatment with NEUPOGEN®
resulted in a clinically and statistically significant
reduction in the incidence of infection, as manifested by
febrile neutropenia; the incidence of at least one infection
over all cycles of chemotherapy was 76% (84/111) for
placebo-treated patients, versus 40% (40/99) for
NEUPOGEN®-treated patients (p < 0.001). The following
secondary analyses were also performed. The requirements for
in-patient hospitalization and antibiotic use were also
significantly decreased during the first cycle of
chemotherapy; incidence of hospitalization was 69% (77/111)
for placebo-treated patients in cycle 1, versus 52% (51/99)
for NEUPOGEN®-treated patients (p = 0.032). The incidence of
IV antibiotic usage was 60% (67/111) for placebo-treated
patients in cycle 1, versus 38% (38/99) for NEUPOGEN®-treated
patients (p = 0.003). The incidence, severity, and duration of
severe neutropenia (absolute neutrophil count [ANC] < 500/mm3)
following chemotherapy were all significantly reduced. The
incidence of severe neutropenia in cycle 1 was 84% (83/99) for
patients receiving NEUPOGEN® versus 96% (106/110) for patients
receiving placebo (p = 0.004). Over all cycles, patients
randomized to NEUPOGEN® had a 57% (286/500 cycles) rate of
severe neutropenia versus 77% (416/543 cycles) for patients
randomized to placebo. The median duration of severe
neutropenia in cycle 1 was reduced from 6 days (range 0 to 10
days) for patients receiving placebo to 2 days (range 0 to 9
days) for patients receiving NEUPOGEN® (p < 0.001). The mean
duration of neutropenia in cycle 1 was 5.64 ± 2.27 days for
patients receiving placebo versus 2.44 ± 1.90 days for
patients receiving NEUPOGEN®. Over all cycles, the median
duration of neutropenia was 3 days for patients randomized to
placebo versus 1 day for patients randomized to NEUPOGEN®. The
median severity of neutropenia (as measured by ANC nadir) was
72/mm3 (range 0/mm3 to 7912/mm3) in cycle 1 for patients
receiving NEUPOGEN® versus 38/mm3 (range 0/mm3 to 9520/mm3)
for patients receiving placebo (p = 0.012). The mean severity
of neutropenia in cycle 1 was 496/mm3 ± 1382/mm3 for patients
receiving NEUPOGEN® versus 204/mm3 ± 953/mm3 for patients
receiving placebo. Over all cycles, the ANC nadir for patients
randomized to NEUPOGEN® was 403/mm3, versus 161/mm3 for
patients randomized to placebo. Administration of NEUPOGEN®
resulted in an earlier ANC nadir following chemotherapy than
was experienced by patients receiving placebo (day 10 vs day
12). NEUPOGEN® was well-tolerated when given SC daily at doses
of 4 to 8 mcg/kg for up to 14 consecutive days following each
cycle of chemotherapy (see ADVERSE REACTIONS).
Several other phase 1/2 studies, which did not directly
measure the incidence of infection, but which did measure
increases in neutrophils, support the efficacy of NEUPOGEN®.
The regimens are presented to provide some background on the
clinical experience with NEUPOGEN®. No claim regarding the
safety or efficacy of the chemotherapy regimens is made. The
effects of NEUPOGEN® on tumor growth or on the anti-tumor
activity of the chemotherapy were not assessed. The doses of
NEUPOGEN® used in these studies are considerably greater than
those found to be effective in the phase 3 study described
above. Such phase 1/2 studies are summarized in the following
table.
Type of Malignancy Regimen Chemotherapy Dose No.Pts. Trial Phase NEUPOGEN® Daily Dosage a
Small Cell
Lung Cancer Cyclophosphamide 1 g/m2/day 210 3 4 - 8 mcg/kg SC
Doxorubicin 50 mg/m2/day days 4 - 17
Etoposide 120 mg/m2/day x 3
q 21 days
Small Cell
Lung Cancer11 Ifosfamide 5 g/m2/day 12 1/2 5.75 - 46 mcg/kg IV
Doxorubicin 50 mg/m2/day days 4 - 17
Etoposide 120 mg/m2/day x 3
Mesna 8 g/m2/day
q 21 days
Urothelial
Cancer12 Methotrexate 30 mg/m2/day x 2 40 1/2 3.45 - 69 mcg/kg IV
Vinblastine 3 mg/m2/day x 2 days 4 - 11
Doxorubicin 30 mg/m2/day
Cisplatin 70 mg/m2/day
q 28 days
Various
Nonmyeloid
Malignancies13 Cyclophosphamide 2.5 g/m2/day x 2 18 1/2 23 - 69 mcg/kgb IV
Etoposide 500 mg/m2/day x 3 days 8 - 28
Cisplatin 50 mg/m2/day x 3
q 28 days
Breast/Ovarian
Cancer14 Doxorubicinc 75 mg/m2 21 2 11.5 mcg/kg IV
100 mg/m2 days 2 - 9
125 mg/m2 5.75 mcg/kg IV
150 mg/m2 days 10 - 12
q 14 days
Neuroblastoma Cyclophosphamide 150 mg/m2 x 7 12 2 5.45 - 17.25 mcg/kg SC
Doxorubicin 35 mg/m2 days 6 - 19
Cisplatin 90 mg/m2
q 28 days
(cycles 1, 3, 5)d
a NEUPOGEN® doses were those that accelerated neutrophil
production. Doses which provided no additional
acceleration beyond that achieved at the next lower dose
are not reported.
b Lowest dose(s) tested in the study.
c Patients received doxorubicin at either 75, 100, 125,
or 150 mg/m2.
d Cycles 2,6 = cyclophosphamide 150 mg/m2 x 7 and
etoposide 280 mg/m2 x 3.
Cycle 4 = cisplatin 90 mg/m2 x 1 and etoposide 280 mg/m2 x
3.
Patients With Acute Myeloid Leukemia Receiving Induction or
Consolidation Chemotherapy
In a randomized, double-blind, placebo-controlled,
multi-center, phase 3 clinical trial, 521 patients (median age
54, range 16 to 89 years) were treated for de novo acute
myeloid leukemia (AML). Following a standard induction
chemotherapy regimen comprising daunorubicin, cytosine
arabinoside, and etoposide15 (DAV 3+7+5), patients received
either NEUPOGEN® at 5 mcg/kg/day or placebo, SC, from 24 hours
after the last dose of chemotherapy until neutrophil recovery
(ANC 1000/mm3 for 3 consecutive days or 10,000/mm3 for 1 day)
or for a maximum of 35 days.
Treatment with NEUPOGEN® significantly reduced the median time
to ANC recovery and the median duration of fever, antibiotic
use, and hospitalization following induction chemotherapy. In
the NEUPOGEN®-treated group, the median time from initiation
of chemotherapy to ANC recovery (ANC > 500/mm3) was 20 days
(vs 25 days in the control group, p = 0.0001), the median
duration of fever was reduced by 1.5 days (p = 0.009), and
there were statistically significant reductions in the
durations of IV antibiotic use and hospitalization. During
consolidation therapy (DAV 2+5+5), patients treated with
NEUPOGEN® also experienced significant reductions in the
incidence of severe neutropenia, time to neutrophil recovery,
the incidence and duration of fever, and in the durations of
IV antibiotic use and hospitalization. Patients treated with a
further course of standard (DAV 2+5+5) or high-dose cytosine
arabinoside consolidation also experienced significant
reductions in the duration of neutropenia.
There were no statistically significant differences between
NEUPOGEN® and placebo groups in complete remission rate (69%
NEUPOGEN® vs 68% placebo, p = 0.77), disease-free survival
(median 342 days NEUPOGEN® [n = 178], 322 days placebo [n =
177], p = 0.99), time to progression of all randomized
patients (median 165 days NEUPOGEN®, 186 days placebo, p =
0.87), or overall survival (median 380 days NEUPOGEN®, 425
days placebo, p = 0.83).
Cancer Patients Receiving Bone Marrow Transplant
In 2 separate randomized, controlled trials, patients with
Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) were
treated with myeloablative chemotherapy and autologous bone
marrow transplantation (ABMT). In one study (n = 54),
NEUPOGEN® was administered at doses of 10 or 30 mcg/kg/day; a
third treatment group in this study received no NEUPOGEN®. A
statistically significant reduction in the median number of
days of severe neutropenia (ANC < 500/mm3) occurred in the
NEUPOGEN®-treated group 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 the second study (n = 44, 43
patients evaluable), NEUPOGEN® was administered at doses of 10
or 20 mcg/kg/day; a third treatment group in this study
received no NEUPOGEN®. A statistically significant reduction
in the median number of days of severe neutropenia occurred in
the NEUPOGEN®-treated group versus the control group (21.5
days in the control group and 10 days in both treatment
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, 5 days in the 10 mcg/kg/day group, and 5.5 days
in the 20 mcg/kg/day group, [5 days in the combined treatment
groups, p < 0.0001]). Reductions in the number of days of
hospitalization and antibiotic use were also seen, although
these reductions were not statistically significant. There
were no effects on red blood cell or platelet levels.
In a randomized, placebo-controlled trial, 70 patients with
myeloid and nonmyeloid malignancies were treated with
myeloablative therapy and allogeneic bone marrow transplant
followed by 300 mcg/m2/day of a Filgrastim product. 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).
In 3 nonrandomized studies (n = 119), patients received ABMT
and treatment with NEUPOGEN®. One study (n = 45) involved
patients with breast cancer and malignant melanoma. A second
study (n = 39) involved patients with HD. The third study (n =
35) involved patients with NHL, acute lymphoblastic leukemia
(ALL), and germ cell tumor. In these studies, the recovery of
the ANC to > 500/mm3 ranged from a median of 11.5 to 13 days.
None of the conditioning regimens used in the ABMT studies
included radiation therapy.
While these studies were not designed to compare survival,
this information was collected and evaluated. The overall
survival and disease progression of patients receiving
NEUPOGEN® in these studies were similar to those observed in
the respective control groups and to historical data.
Peripheral Blood Progenitor Cell Collection and Therapy in
Cancer Patients
All patients in the Amgen-sponsored trials received a similar
mobilization/collection regimen: NEUPOGEN® was administered
for 6 to 7 days, with an apheresis procedure on days 5, 6, and
7 (except for a limited number of patients receiving apheresis
on days 4, 6, and 8). In a non-Amgen-sponsored study, patients
underwent mobilization to a target number of mononuclear cells
(MNC), with apheresis starting on day 5. There are no data on
the mobilization of peripheral blood progenitor cells (PBPC)
after days 4 to 5 that are not confounded by leukapheresis.
Mobilization: Mobilization of PBPC was studied in 50 heavily
pretreated patients (median number of prior cycles = 9.5) with
NHL, HD, or ALL (Amgen study 1). CFU-GM was used as the marker
for engraftable PBPC. The median CFU-GM level on each day of
mobilization was determined from the data available (CFU-GM
assays were not obtained on all patients on each day of
mobilization). These data are presented below.
The data from Amgen study 1 were supported by data from Amgen
study 2 in which 22 pretreated breast cancer patients (median
number of prior cycles = 3) were studied. Both the CFU-GM and
CD34+ cells reached a maximum on day 5 at > 10-fold over
baseline and then remained elevated with leukapheresis.
Progenitor Cell Levels in Peripheral Blood by Mobilization Day
Overall Study 1 Study 2 Study 2
CFU-GM/mL CFU-GM/mL CD34+ (x 104/mL)
No.Samples Median (25% - 75%) No. Samples Median (25% - 75%) No.Samples Median (25% - 75%)
Day 1 11 18 (13 - 62) 20 42 (15 - 151) 20 0.13 (0.02 - 0.66)
Day 2 7 22 (3 - 61) n/a n/a n/a n/a
Day 3 10 138 (39 - 364) n/a n/a n/a n/a
Day 4 18 365 (158 - 864) 18 576 (108 - 1819) 17 2.11 (0.58 - 3.93)
Day 5 36 781 (391 - 1608) 21 960 (72 - 1677) 22 3.16 (1.08 - 6.11)
Day 6 46 505 (199 - 1397) 22 756 (70 - 3486) 22 2.67 (1.09 - 4.40)
Day 7 37 333 (111 - 938) 22 597 (118 - 2009) 21 2.64 (0.78 - 4.22)
Day 8 15 383 (94 - 815) 12 51 (10 - 746) 12 1.61 (0.38 - 4.31)
n/a = not available
In 3 studies of patients with prior exposure to chemotherapy,
the median CFU-GM yield in the leukapheresis product ranged
from 20.9 to 32.7 x 104/kg body weight (n = 105). In 2 of
these studies where CD34+ yields in the leukapheresis product
were also determined, the median CD34+ yields were 3.11 and
2.80 x 106/kg, respectively (n = 56). In an additional study
of 18 chemotherapy-naive patients, the median CFU-GM yield was
123.4 x 104/kg.
Engraftment: Engraftment following NEUPOGEN®-mobilized PBPC is
summarized for 101 patients in the table below. In all
studies, a Cox regression model showed that the total number
of CFU-GM and/or CD34+ cells collected was a significant
predictor of time to platelet recovery.
In a randomized, unblinded study of patients with HD or NHL
undergoing myeloablative chemotherapy (Amgen study 3), 27
patients received NEUPOGEN®-mobilized PBPC followed by
NEUPOGEN® and 31 patients received ABMT followed by NEUPOGEN®.
Patients randomized to the NEUPOGEN®-mobilized PBPC group
compared to the ABMT group had significantly fewer days of
platelet transfusions (median 6 vs 10 days), a significantly
shorter time to a sustained platelet count > 20,000/mm3
(median 16 vs 23 days), a significantly shorter time to
recovery of a sustained ANC > 500/mm3 (median 11 vs 14 days),
significantly fewer days of red blood cell transfusions
(median 2 vs 3 days) and a significantly shorter duration of
posttransplant hospitalization.
Amgen-sponsored Amgen-sponsored Amgen-sponsored Non-Amgen-sponsored
Study 1 N = 13 Study 2 N = 22 Study 3 N = 27 Study 4 N = 39
Median PBPC/kg Collected MNC 9.5 x 108 9.5 x 108 8.1 x 108 10.3 x 108
CD34+ n/a 3.1 x 106 2.8 x 106 6.2 x 106
CFU-GM 63.9 x 104 25.3 x 104 32.6 x 104 n/a
Days to ANC > 500/mm3 Median 9 10 11 10
Range 8 - 10 8 - 15 9 - 38 7 - 40
Days to Plt. > 20,000/mm3 Median 10 12.5 16 15.5
Range 7 - 16 10 - 30 8 - 52 7 - 63
n/a = not available
Three of the 101 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 PBPC, NEUPOGEN® was administered to patients at 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®
posttransplantation has not been studied.
Patients With Severe Chronic Neutropenia
Severe chronic neutropenia (SCN) (idiopathic, cyclic, and
congenital) is characterized by a selective decrease in the
number of circulating neutrophils and an enhanced
susceptibility to bacterial infections.
The daily administration of NEUPOGEN® has been shown to be
safe and effective in causing a sustained increase in the
neutrophil count and a decrease in infectious morbidity in
children and adults with the clinical syndrome of SCN.16 In
the phase 3 trial, summarized in the following table, daily
treatment with NEUPOGEN® resulted in significant beneficial
changes in the incidence and duration of infection, fever,
antibiotic use, and oropharyngeal ulcers. In this trial, 120
patients with a median age of 12 years (range 1 to 76 years)
were treated.
Overall Significant Changes in Clinical Endpoints Median Incidencea (events) or Duration (days) per 28-day Period
Control Patientsb NEUPOGEN®-treated Patients p-value
Incidence of Infection 0.50 0.20 <0.001
Incidence of Fever 0.25 0.20 <0.001
Duration of Fever 0.63 0.20 0.005
Incidence of Oropharyngeal Ulcers 0.26 0.00 <0.001
Incidence of Antibiotic Use 0.49 0.20 <0.001
a Incidence values were calculated for each patient, and
are defined as the total number of events experienced
divided by the number of 28-day periods of exposure
(on-study). Median incidence values were then reported
for each patient group.
b Control patients were observed for a 4-month period.
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. All 3
diagnostic groups showed favorable trends in favor of
treatment. 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.
As a result of the lower incidence and duration of infections,
there was also a lower number of episodes of hospitalization
(28 hospitalizations in 62 patients in the treated group vs 44
hospitalizations in 60 patients in the control group over a
4-month period [p = 0.0034]). Patients treated with NEUPOGEN®
also reported a lower number of episodes of diarrhea, nausea,
fatigue, and sore throat.
In the phase 3 trial, untreated patients had a median ANC of
210/mm3 (range 0 to 1550/mm3). NEUPOGEN® therapy was adjusted
to maintain the median ANC between 1500 and 10,000/mm3.
Overall, the response to NEUPOGEN® was observed in 1 to 2
weeks. The median ANC after 5 months of NEUPOGEN® therapy for
all patients was 7460/mm3 (range 30 to 30,880/mm3). NEUPOGEN®
dosing requirements were generally higher for patients with
congenital neutropenia (2.3 to 40 mcg/kg/day) than for
patients with idiopathic (0.6 to 11.5 mcg/kg/day) or cyclic
(0.5 to 6 mcg/kg/day) neutropenia.
INDICATIONS AND USAGE
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/mm3 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.
CONTRAINDICATIONS
NEUPOGEN® is contraindicated in patients with known
hypersensitivity to E coli-derived proteins, Filgrastim, or
any component of the product.