NDC 54868-3050 Neupogen

NDC Product Code 54868-3050

NDC CODE: 54868-3050

Proprietary Name: Neupogen What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Filgrastim is a man-made version of a certain natural substance made in your body. It is used to help your body make more white blood cells. White blood cells are important to help you fight off infections. Filgrastim is given to people whose ability to make white blood cells is reduced (for instance, due to chemotherapy, chronic neutropenia, or exposure to large amounts of radiation). It is also used in certain treatment procedures (such as bone marrow/stem cell transplant). This monograph is about the following filgrastim products: filgrastim, tbo-filgrastim, filgrastim-sndz, and filgrastim-aafi.

NDC Code Structure

  • 54868 - Physicians Total Care, Inc.

NDC 54868-3050-0

Package Description: 10 SYRINGE in 1 BOX > .8 mL in 1 SYRINGE

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Neupogen with NDC 54868-3050 is a product labeled by Physicians Total Care, Inc.. The product's dosage form is and is administered via form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1649944, 1649946, 727535, 727537, 727544 and 727545.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SODIUM POLYMETAPHOSPHATE (UNII: P1BM4ZH95L)
  • SORBITOL (UNII: 506T60A25R)
  • WATER (UNII: 059QF0KO0R)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SODIUM POLYMETAPHOSPHATE (UNII: P1BM4ZH95L)
  • SORBITOL (UNII: 506T60A25R)
  • WATER (UNII: 059QF0KO0R)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SODIUM POLYMETAPHOSPHATE (UNII: P1BM4ZH95L)
  • SORBITOL (UNII: 506T60A25R)
  • WATER (UNII: 059QF0KO0R)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc.
Labeler Code: 54868
Start Marketing Date: 08-14-2006 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Filgrastim, Filgrastim-sndz, Tbo-filgrastim Injection

Filgrastim, Filgrastim-sndz, Tbo-filgrastim Injection is pronounced as (fil gra' stim)

Why is filgrastim, filgrastim-sndz, tbo-filgrastim injection medication prescribed?
Filgrastim, filgrastim-sndz, and tbo-filgrastim are used to decrease the chance of infection in people who have certain types of cancer and are receiving chemotherapy med...
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* Please review the disclaimer below.

Neupogen Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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/1.0 mL
Vial480 mcg/1.6 mL
Vial300 mcg/0.5 mL
Syringe480 mcg/0.8 mL
SyringeFilgrastim300 mcg480 mcg300 mcg480 mcgAcetate0.59 mg0.94 mg0.295 mg0.472 mgSorbitol50.0 mg80.0 mg25.0 mg40.0 mgPolysorbate 800.04 mg0.064 mg0.02 mg0.032 mgSodium0.035 mg0.056 mg0.0175 mg0.028 mgWater for InjectionUSP q.s. ad1.0 mL1.6 mL0.5 mL0.8 mL

Clinical Pharmacology

Colony-stimulating
FactorsColony-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 ExperienceFilgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and
mice as part of a preclinical toxicology program which included single-dose
acute‚ repeated-dose subacute‚ subchronic‚ and chronic studies. Single-dose
administration of Filgrastim by the oral‚ intravenous (IV)‚ subcutaneous (SC)‚
or intraperitoneal (IP) routes resulted in no significant toxicity in mice‚
rats‚ hamsters‚ or monkeys. Although no deaths were observed in mice‚ rats‚ or
monkeys at dose levels up to 3450 mcg/kg or in hamsters using single doses up to
approximately 860 mcg/kg‚ deaths were observed in a subchronic (13-week) study
in monkeys. In this study‚ evidence of neurological symptoms was seen in monkeys
treated with doses of Filgrastim greater than 1150 mcg/kg/day for up to 18 days.
Deaths were seen in 5 of the 8 treated animals and were associated with 15- to
28-fold increases in peripheral leukocyte counts‚ and neutrophil-infiltrated
hemorrhagic foci were seen in both the cerebrum and cerebellum. In contrast‚ no
monkeys died following 13 weeks of daily IV administration of Filgrastim at a
dose level of 115 mcg/kg. In an ensuing 52-week study‚ one 115 mcg/kg dosed
female monkey died after 18 weeks of daily IV administration of Filgrastim.
Death was attributed to cardiopulmonary insufficiency.In subacute‚ repeated-dose studies‚ changes observed were attributable to the
expected pharmacological actions of Filgrastim (ie‚ dose-dependent increases in
white cell counts‚ increased circulating segmented neutrophils‚ and increased
myeloid:erythroid ratio in bone marrow). In all species‚ histopathologic
examination of the liver and spleen revealed evidence of ongoing extramedullary
granulopoiesis; increased spleen weights were seen in all species and appeared
to be dose-related. A dose-dependent increase in serum alkaline phosphatase was
observed in rats‚ and may reflect increased activity of osteoblasts and
osteoclasts. Changes in serum chemistry values were reversible following
discontinuation of treatment.In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and
for 13 weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6
of 32 animals)‚ articular swelling of the hind legs was observed. Some degree of
hind leg dysfunction was also observed; however‚ symptoms reversed following
cessation of dosing. In rats‚ osteoclasis and osteoanagenesis were found in the
femur‚ humerus‚ coccyx‚ and hind legs (where they were accompanied by synovitis)
after IV treatment for 4 weeks (115 to 1150 mcg/kg/day)‚ and in the sternum
after IV treatment for 13 weeks (115 to 575 mcg/kg/day). These effects reversed
to normal within 4 to 5 weeks following cessation of treatment.In the 52-week chronic‚ repeated-dose studies performed in rats (IP injection
up to 57.5 mcg/kg/day)‚ and cynomolgus monkeys (IV injection of up to 115
mcg/kg/day)‚ changes observed were similar to those noted in the subacute
studies. Expected pharmacological actions of Filgrastim included dose-dependent
increases in white cell counts‚ increased circulating segmented neutrophils and
alkaline phosphatase levels‚ and increased myeloid:erythroid ratios in the bone
marrow. Decreases in platelet counts were also noted in primates. In no animals
tested were hemorrhagic complications observed. Rats displayed dose-related
swelling of the hind limb‚ accompanied by some degree of hind limb dysfunction;
osteopathy was noted microscopically. Enlarged spleens (both species) and livers
(monkeys)‚ reflective of ongoing extramedullary granulopoiesis‚ as well as
myeloid hyperplasia of the bone marrow‚ were observed in a dose-dependent
manner.Pharmacologic Effects of
NEUPOGEN®In phase 1 studies involving 96 patients with various nonmyeloid
malignancies‚ NEUPOGEN® administration resulted in a
dose-dependent increase in circulating neutrophil counts over the dose range of
1 to 70 mcg/kg/day.9-11 This increase in neutrophil
counts was observed whether NEUPOGEN® was administered IV
(1 to 70 mcg/kg twice daily)‚9 SC (1 to 3 mcg/kg once
daily)‚11 or by continuous SC infusion (3 to 11
mcg/kg/day).10 With discontinuation of NEUPOGEN® therapy‚ neutrophil counts returned to baseline‚ in most
cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured
by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration
under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the
chemotaxin) activity in vitro.The absolute monocyte count was reported to increase in a dose-dependent
manner in most patients receiving NEUPOGEN®; however‚ the
percentage of monocytes in the differential count remained within the normal
range. In all studies to date‚ absolute counts of both eosinophils and basophils
did not change and were within the normal range following administration of
NEUPOGEN®. Increases in lymphocyte counts following
NEUPOGEN® administration have been reported in some
normal subjects and cancer patients.White blood cell (WBC) differentials obtained during clinical trials have
demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚
including the appearance of promyelocytes and myeloblasts‚ usually during
neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle
bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have
been observed. Such changes were transient and were not associated with clinical
sequelae, nor were they necessarily associated with infection.PharmacokineticsAbsorption 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 ChemotherapyNEUPOGEN® 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 less than 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] less than 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 less than 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 ofMalignacyRegimenChemotherapy DoseNo. Pts.TrialPhaseNEUPOGEN® Daily
Dosage*Small CellLung CancerCyclophosphamide1 g/m2/day21034 - 8 mcg/kg SCDoxorubicin50 mg/m2/daydays 4 - 17Etoposide120 mg/m2/day x 3q 21 daysSmall CellLung Cancer11Ifosfamide5 g/m2/day121/25.75 - 46 mcg/kg IVDoxorubicin50 mg/m2/daydays 4 - 17Etoposide120 mg/m2/day x 3Mesna8 g/m2/dayq 21 daysUrothelial     |Cancer12Methotrexate30 mg/m2/day x 2401/23.45 - 69 mcg/kg IVVinblastine3 mg/m2/day x 2days 4 - 11Doxorubicin30 mg/m2/dayCisplatin70 mg/m2/dayq 28 daysVarious     |Nonmyeloid     |Malignancies13Cyclophosphamide2.5 g/m2/day x 2181/223 - 69 mcg/kg† IVEtoposide500 mg/m2/day x 3days 8 - 28Cisplatin50 mg/m2/day x 3q 28 daysBreast/Ovarian                    |Cancer14Doxorubicin‡75 mg/m221211.5 mcg/kg IV100 mg/m2days 2 - 9125 mg/m25.75 mcg/kg IV150 mg/m2days 10 - 12q 14 daysNeuroblastomaCyclophosphamide150 mg/m2 x 71225.45 - 17.25 mcg/kg SCDoxorubicin35 mg/m2days 6 - 1975 mg/m2Cisplatin90 mg/m2q 28 days(cycles 1‚3‚5)§*   NEU® doses were those that accelerated neutrophil
production. Doses which provided no additional acceleration beyond that achieved
at the next lower dose are not reported. †   Lowest dose(s) tested in the study.‡   Patients received doxorubicin at either 75‚ 100‚ 125‚ or 150 mg/m2. §   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 ChemotherapyIn 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 greater than or equal to 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 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 TransplantIn two 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 less than 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 less than 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 less than 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 less than 0.001) and time to recovery of ANC to greater than or equal to 500/mm3 (21 days
in the control group and 16 days in the treatment group‚ p less than 0.001).In three 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 greater than or equal 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 PatientsAll 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 greater than 10-fold over baseline and then remained elevated with
leukapheresis.Progenitor Cell Levels in Peripheral Blood by Mobilization DayNo.SamplesMedian(25% - 75%)No.SamplesMedian(25% - 75%)No.SamplesMedian(25% - 75%)Day 11118(13 - 62)2042(15 - 151)200.13(0.02 - 0.66)Day 2722(3 - 61)n/a*n/a*n/a*n/a*Day 310138(39 - 364)n/a*n/a*n/a*n/a*Day 418365(158 - 864)18576(108 - 1819)172.11(0.58 - 3.93)Day 536781(391 - 1608)21960 (72 - 1677)223.16(1.08 - 6.11)Day 646505(199 - 1397)22756(70 - 3486)222.67(1.09 - 4.40)Day 737333(111 - 938)22597(118 - 2009)212.64(0.78 - 4.22)Day 8      15383(94 - 815)1251(10 -746)121.61(0.38 - 4.31)*   n/a = not availableIn three 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 two 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
following table. 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 greater than 20‚000/mm3 (median 16 vs 23 days)‚ a
significantly shorter time to recovery of a sustained ANC greater than or equal to 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-sponsoredStudy 1N = 13Amgen-sponsoredStudy 2N = 22Amgen-sponsoredStudy 3N = 27Non-Amgen-sponsored Study N = 39Median PBPC/kg Collected         MNC9.5 x 1089.5 x 1088.1 x 10810.3 x 108CD34+n/a*3.1 x 1062.8 x 1066.2 x 106CFU-GM            63.9 x 10425.3 x 10432.6 x 104n/a*Days to ANC ≥ 500/mm3 Median9101110Range8 - 108 - 159 - 387 - 40Days to Plt. ≥ 20,00/mm3 Median1012.51615.5Range7 - 1610 - 308 - 527 - 63*   n/a = not availableThree of the 101 patients (3%) did not achieve the criteria for engraftment
as defined by a platelet count greater than or equal to 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 (greater than or equal to 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
NeutropeniaSevere 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 Incidence* (events) or Duration (days) per 28-day PeriodControlPatients†NEUPOGEN®-treated Patientsp-valueIncidence of Infection0.500.20less than 0.001Incidence of Fever0.250.20less than 0.001Duration of Fever0.630.200.005Incidence ofOropharyngeal Ulcers0.260.00less than 0.001Incidence of Antibiotic Use0.490.20less than 0.001*   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.†   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 ChemotherapyNEUPOGEN® 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 ChemotherapyNEUPOGEN® 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 TransplantNEUPOGEN® 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 TherapyNEUPOGEN® 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
NeutropeniaNEUPOGEN® 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.

Warnings

Allergic ReactionsAllergic-type reactions occurring on initial or subsequent
treatment have been reported in less than 1 in 4000 patients treated with
NEUPOGEN®. These have generally been characterized by
systemic symptoms involving at least 2 body systems‚ most often skin (rash‚
urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular
(hypotension‚ tachycardia). Some reactions occurred on initial exposure.
Reactions tended to occur within the first 30 minutes after administration and
appeared to occur more frequently in patients receiving NEUPOGEN® IV. Rapid resolution of symptoms occurred in most cases after
administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine.
Symptoms recurred in more than half the patients who were rechallenged.SPLENIC RUPTURESPLENIC RUPTURE, INCLUDING
FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEUPOGEN®. INDIVIDUALS RECEIVING NEUPOGEN® WHO
REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN
ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress
Syndrome (ARDS)Acute respiratory distress syndrome (ARDS) has been reported in
patients receiving NEUPOGEN®, and is postulated to be
secondary to an influx of neutrophils to sites of inflammation in the lungs.
Patients receiving NEUPOGEN® who develop fever, lung
infiltrates, or respiratory distress should be evaluated for the possibility of
ARDS. In the event that ARDS occurs, NEUPOGEN® should be
withheld until resolution of ARDS or discontinued. Patients should receive
appropriate medical management for this condition.Alveolar Hemorrhage and
HemoptysisAlveolar hemorrhage manifesting as pulmonary infiltrates and
hemoptysis requiring hospitalization has been reported in healthy donors
undergoing peripheral blood progenitor cell (PBPC) mobilization. Hemoptysis
resolved with discontinuation of NEUPOGEN®. The use of
NEUPOGEN® for PBPC mobilization in healthy donors is not
an approved indication.Sickle Cell DisordersSevere sickle cell crises, in some cases resulting in death, have
been associated with the use of NEUPOGEN® in patients
with sickle cell disorders. Only physicians qualified by specialized training or
experience in the treatment of patients with sickle cell disorders should
prescribe NEUPOGEN® for such patients, and only after
careful consideration of the potential risks and benefits.Patients With Severe Chronic
NeutropeniaThe safety and efficacy of NEUPOGEN® in
the treatment of neutropenia due to other hematopoietic disorders (eg‚
myelodysplastic syndrome [MDS]) have not been established. Care should be taken
to 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.17 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 (see ADVERSE
REACTIONS). 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. If a patient with SCN develops
abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing
NEUPOGEN® should be carefully considered.

Precautions

  • GeneralSimultaneous Use With Chemotherapy
  • And Radiation TherapyThe safety and efficacy of NEUPOGEN® given
  • Simultaneously with cytotoxic chemotherapy have not been established. Because of
  • The potential sensitivity of rapidly dividing myeloid cells to cytotoxic
  • Chemotherapy‚ do not use NEUPOGEN® in the period 24 hours
  • Before through 24 hours after the administration of cytotoxic chemotherapy (see
  • DOSAGE AND
  • ADMINISTRATION).The efficacy of NEUPOGEN® has not been evaluated in
  • Patients receiving chemotherapy associated with delayed myelosuppression (eg,
  • Nitrosoureas) or with mitomycin C or with myelosuppressive doses of
  • Antimetabolites such as 5-fluorouracil.The safety and efficacy of NEUPOGEN® have not been
  • Evaluated in patients receiving concurrent radiation therapy. Simultaneous use
  • Of NEUPOGEN® with chemotherapy and radiation therapy
  • Should be avoided.Potential Effect on Malignant
  • CellsNEUPOGEN® is a growth factor that
  • Primarily stimulates neutrophils. However‚ the possibility that NEUPOGEN® can act as a growth factor for any tumor type cannot be
  • Excluded. In a randomized study evaluating the effects of NEUPOGEN® versus placebo in patients undergoing remission induction for
  • AML, there was no significant difference in remission rate, disease-free, or
  • Overall survival (see CLINICAL
  • EXPERIENCE).The safety of NEUPOGEN® in chronic myeloid leukemia
  • (CML) and myelodysplasia has not been established.When NEUPOGEN® is used to mobilize PBPC‚ tumor cells
  • May be released from the marrow and subsequently collected in the leukapheresis
  • Product. The effect of reinfusion of tumor cells has not been well studied‚ and
  • The limited data available are inconclusive.LeukocytosisCancer Patients Receiving
  • Myelosuppressive ChemotherapyWhite blood cell counts of 100‚000/mm3 or
  • Greater were observed in approximately 2% of patients receiving NEUPOGEN® at doses above 5 mcg/kg/day. There were no reports of adverse
  • Events associated with this degree of leukocytosis. In order to avoid the
  • Potential complications of excessive leukocytosis‚ a CBC is recommended twice
  • Per week during NEUPOGEN® therapy (see LABORATORY
  • MONITORING).Premature Discontinuation of
  • NEUPOGEN® TherapyCancer Patients Receiving
  • Myelosuppressive ChemotherapyA transient increase in neutrophil counts is typically seen 1 to
  • 2 days after initiation of NEUPOGEN® therapy. However‚
  • For a sustained therapeutic response‚ NEUPOGEN® therapy
  • Should be continued following chemotherapy until the post nadir ANC reaches
  • 10‚000/mm3. Therefore‚ the premature discontinuation of
  • NEUPOGEN® therapy‚ prior to the time of recovery from the
  • Expected neutrophil nadir‚ is generally not recommended (see DOSAGE AND
  • ADMINISTRATION).ImmunogenicityAs with all therapeutic proteins, there is a potential for
  • Immunogenicity. The incidence of antibody development in patients receiving
  • NEUPOGEN® has not been adequately determined. While
  • Available data suggest that a small proportion of patients developed binding
  • Antibodies to Filgrastim, the nature and specificity of these antibodies has not
  • Been adequately studied. In clinical studies comparing NEUPOGEN® and Neulasta®, the incidence of
  • Antibodies binding to NEUPOGEN® was 3% (11/333). In these
  • 11 patients, no evidence of a neutralizing response was observed using a
  • Cell-based bioassay. The detection of antibody formation is highly dependent on
  • The sensitivity and specificity of the assay, and the observed incidence of
  • Antibody positivity in an assay may be influenced by several factors including
  • Timing of sampling, sample handling, concomitant medications, and underlying
  • Disease. Therefore, comparison of the incidence of antibodies to NEUPOGEN® with the incidence of antibodies to other products may be
  • Misleading.Cytopenias resulting from an antibody response to exogenous growth factors
  • Have been reported on rare occasions in patients treated with other recombinant
  • Growth factors. There is a theoretical possibility that an antibody directed
  • Against Filgrastim may cross-react with endogenous G-CSF, resulting in
  • Immune-mediated neutropenia; however, this has not been reported in clinical
  • Studies or in post-marketing experience. Patients who develop hypersensitivity
  • To Filgrastim (NEUPOGEN®) may have allergic or
  • Hypersensitivity reactions to other E coli-derived
  • Proteins. Cutaneous VasculitisCutaneous vasculitis has been reported in patients treated with
  • NEUPOGEN®. In most cases‚ the severity of cutaneous
  • Vasculitis was moderate or severe. Most of the reports involved patients with
  • SCN receiving long-term NEUPOGEN® therapy. Symptoms of
  • Vasculitis generally developed simultaneously with an increase in the ANC and
  • Abated when the ANC decreased. Many patients were able to continue NEUPOGEN® at a reduced dose.Information for Patients and
  • CaregiversPatients should be referred to the “Information for Patients and
  • Caregivers” labeling included with the package insert in each dispensing pack of
  • NEUPOGEN® vials or NEUPOGEN®
  • Prefilled syringes. The “Information for Patients and Caregivers” labeling
  • Provides information about neutrophils and neutropenia and the safety and
  • Efficacy of NEUPOGEN®. It is not intended to be a
  • Disclosure of all known or possible effects.Laboratory MonitoringCancer Patients Receiving
  • Myelosuppressive ChemotherapyA CBC and platelet count should be obtained prior to
  • Chemotherapy‚ and at regular intervals (twice per week) during NEUPOGEN® therapy. Following cytotoxic chemotherapy‚ the neutrophil
  • Nadir occurred earlier during cycles when NEUPOGEN® was
  • Administered‚ and WBC differentials demonstrated a left shift‚ including the
  • Appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe
  • Neutropenia was reduced‚ and was followed by an accelerated recovery in the
  • Neutrophil counts.Cancer Patients Receiving Bone
  • Marrow TransplantFrequent CBCs and platelet counts are recommended (at least 3
  • Times per week) following marrow transplantation.Patients With Severe Chronic
  • NeutropeniaDuring the initial 4 weeks of NEUPOGEN®
  • Therapy and during the 2 weeks following any dose adjustment‚ a CBC with
  • Differential and platelet count should be performed twice weekly. Once a patient
  • Is clinically stable‚ a CBC with differential and platelet count should be
  • Performed monthly during the first year of treatment. Thereafter, if clinically
  • Stable, routine monitoring with regular CBCs (ie, as clinically indicated but at
  • Least quarterly) is recommended. Additionally, for those patients with
  • Congenital neutropenia, annual bone marrow and cytogenetic evaluations should be
  • Performed throughout the duration of treatment (see WARNINGS,
  • ADVERSE
  • REACTIONS).In clinical trials‚ the following laboratory results were observed:Cyclic fluctuations in the neutrophil counts were frequently observed in
  • Patients with congenital or idiopathic neutropenia after initiation of
  • NEUPOGEN® therapy.
  • Platelet counts were generally at the upper limits of normal prior to
  • NEUPOGEN® therapy. With NEUPOGEN®
  • Therapy‚ platelet counts decreased but usually remained within normal limits
  • (see ADVERSE
  • REACTIONS).
  • Early myeloid forms were noted in peripheral blood in most patients‚
  • Including the appearance of metamyelocytes and myelocytes. Promyelocytes and
  • Myeloblasts were noted in some patients.
  • Relative increases were occasionally noted in the number of circulating
  • Eosinophils and basophils. No consistent increases were observed with
  • NEUPOGEN® therapy.
  • As in other trials‚ increases were observed in serum uric acid‚ lactic
  • Dehydrogenase‚ and serum alkaline phosphatase. Drug InteractionDrug interactions between NEUPOGEN® and
  • Other drugs have not been fully evaluated. Drugs which may potentiate the
  • Release of neutrophils‚ such as lithium‚ should be used with caution.Increased hematopoietic activity of the bone marrow in response to growth
  • Factor therapy has been associated with transient positive bone imaging changes.
  • This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis,
  • Impairment of FertilityThe carcinogenic potential of NEUPOGEN®
  • Has not been studied. NEUPOGEN® failed to induce
  • Bacterial gene mutations in either the presence or absence of a drug
  • Metabolizing enzyme system. NEUPOGEN® had no observed
  • Effect on the fertility of male or female rats‚ or on gestation at doses up to
  • 500 mcg/kg.Pregnancy Category CNEUPOGEN® has been shown to have adverse
  • Effects in pregnant rabbits when given in doses 2 to 10 times the human dose.
  • Since there are no adequate and well-controlled studies in pregnant women, the
  • Effect, if any, of NEUPOGEN® on the developing fetus or
  • The reproductive capacity of the mother is unknown. However, the scientific
  • Literature describes transplacental passage of NEUPOGEN®
  • When administered to pregnant rats during the latter part of gestation18 and apparent transplacental passage of NEUPOGEN® when administered to pregnant humans by ≤ 30 hours prior to
  • Preterm delivery (≤ 30 weeks gestation).19 NEUPOGEN® should be used during pregnancy only if the potential benefit
  • Justifies the potential risk to the fetus.In rabbits‚ increased abortion and embryolethality were observed in animals
  • Treated with NEUPOGEN® at 80 mcg/kg/day. NEUPOGEN® administered to pregnant rabbits at doses of 80 mcg/kg/day
  • During the period of organogenesis was associated with increased fetal
  • Resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body
  • Weight‚ live births‚ and food consumption. External abnormalities were not
  • Observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies
  • In pregnant rats have shown that NEUPOGEN® was not
  • Associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when
  • Administered by daily IV injection during the period of organogenesis at dose
  • Levels up to 575 mcg/kg/day.In Segment III studies in rats‚ offspring of dams treated at > 20
  • Mcg/kg/day exhibited a delay in external differentiation (detachment of auricles
  • And descent of testes) and slight growth retardation‚ possibly due to lower body
  • Weight of females during rearing and nursing. Offspring of dams treated at 100
  • Mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced
  • 4-day survival rate.Nursing MothersIt is not known whether NEUPOGEN® is
  • Excreted in human milk. Because many drugs are excreted in human milk‚ caution
  • Should be exercised if NEUPOGEN® is administered to a
  • Nursing woman.Pediatric UseIn a phase 3 study to assess the safety and efficacy of
  • NEUPOGEN® in the treatment of SCN, 120 patients with a
  • Median age of 12 years were studied. Of the 120 patients, 12 were infants (1
  • Month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were
  • Adolescents (12 to 16 years of age). Additional information is available from a
  • SCN postmarketing surveillance study, which includes long-term follow-up of
  • Patients in the clinical studies and information from additional patients who
  • Entered directly into the postmarketing surveillance study. Of the 531 patients
  • In the surveillance study as of 31 December 1997, 32 were infants, 200 were
  • Children, and 68 were adolescents (see CLINICAL
  • EXPERIENCE, INDICATIONS AND
  • USAGE, LABORATORY
  • MONITORING, DOSAGE AND
  • ADMINISTRATION).Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome,
  • Congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed
  • Cytogenetic abnormalities and have undergone transformation to MDS and AML while
  • Receiving chronic NEUPOGEN® treatment. The relationship
  • Of these events to NEUPOGEN® administration is unknown
  • (see WARNINGS,
  • ADVERSE
  • REACTIONS). Long-term follow-up data from the postmarketing surveillance study suggest
  • That height and weight are not adversely affected in patients who received up to
  • 5 years of NEUPOGEN® treatment. Limited data from
  • Patients who were followed in the phase 3 study for 1.5 years did not suggest
  • Alterations in sexual maturation or endocrine function. The safety and efficacy in neonates and patients with autoimmune neutropenia
  • Of infancy have not been established.In the cancer setting‚ 12 pediatric patients with neuroblastoma have received
  • Up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide
  • Chemotherapy concurrently with NEUPOGEN®; in this
  • Population‚ NEUPOGEN® was well tolerated. There was one
  • Report of palpable splenomegaly associated with NEUPOGEN®
  • Therapy; however‚ the only consistently reported adverse event was
  • Musculoskeletal pain‚ which is no different from the experience in the adult
  • Population.Geriatric UseAmong 855 subjects enrolled in 3 randomized, placebo-controlled
  • Trials of NEUPOGEN® use following myelosuppressive
  • Chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or
  • Older. No overall differences in safety or effectiveness were observed between
  • These subjects and younger subjects, and other clinical experience has not
  • Identified differences in the responses between elderly and younger patients.
  • Clinical studies of NEUPOGEN® in other approved
  • Indications (ie, bone marrow transplant recipients, PBPC mobilization, and SCN)
  • Did not include sufficient numbers of subjects aged 65 and older to determine
  • Whether elderly subjects respond differently from younger subjects.

Adverse Reactions

  • Clinical Trial
  • ExperienceCancer Patients Receiving
  • Myelosuppressive ChemotherapyIn clinical trials involving over 350 patients receiving
  • NEUPOGEN® following nonmyeloablative cytotoxic
  • Chemotherapy‚ most adverse experiences were the sequelae of the underlying
  • Malignancy or cytotoxic chemotherapy. In all phase 2 and 3 trials‚ medullary
  • Bone pain‚ reported in 24% of patients‚ was the only consistently observed
  • Adverse reaction attributed to NEUPOGEN® therapy. This
  • Bone pain was generally reported to be of mild-to-moderate severity‚ and could
  • Be controlled in most patients with non-narcotic analgesics; infrequently‚ bone
  • Pain was severe enough to require narcotic analgesics. Bone pain was reported
  • More frequently in patients treated with higher doses (20 to 100 mcg/kg/day)
  • Administered IV‚ and less frequently in patients treated with lower SC doses of
  • NEUPOGEN® (3 to 10 mcg/kg/day).In the randomized‚ double-blind‚ placebo-controlled trial of NEUPOGEN® therapy following combination chemotherapy in patients (n =
  • 207) with small cell lung cancer‚ the following adverse events were reported
  • During blinded cycles of study medication (placebo or NEUPOGEN® at 4 to 8 mcg/kg/day). Events are reported as
  • Exposure-adjusted since patients remained on double-blind NEUPOGEN® a median of 3 cycles versus 1 cycle for placebo.% of Blinded Cycles With
  • EventsNEUPOGEN®N = 384 Patient CyclesPlaceboN = 257
  • Patient CyclesEventNausea/Vomiting5764Skeletal Pain2211Alopecia1827Diarrhea1423Neutropenic Fever1335Mucositis1220Fever1211Fatigue1116Anorexia911Dyspnea911Headache79Cough68Skin Rash69Chest Pain56Generalized Weakness47Sore Throat49Stomatitis510Constipation510Pain (Unspecified)27In this study‚ there were no serious‚ life-threatening‚ or fatal adverse
  • Reactions attributed to NEUPOGEN® therapy. Specifically‚
  • There were no reports of flu-like symptoms‚ pleuritis‚ pericarditis‚ or other
  • Major systemic reactions to NEUPOGEN®.Spontaneously reversible elevations in uric acid‚ lactate dehydrogenase‚ and
  • Alkaline phosphatase occurred in 27% to 58% of 98 patients receiving blinded
  • NEUPOGEN® therapy following cytotoxic chemotherapy;
  • Increases were generally mild-to-moderate. Transient decreases in blood pressure
  • (less than 90/60 mmHg)‚ which did not require clinical treatment‚ were reported in 7
  • Of 176 patients in phase 3 clinical studies following administration of
  • NEUPOGEN®. Cardiac events (myocardial infarctions‚
  • Arrhythmias) have been reported in 11 of 375 cancer patients receiving
  • NEUPOGEN® in clinical studies; the relationship to
  • NEUPOGEN® therapy is unknown. No evidence of interaction
  • Of NEUPOGEN® with other drugs was observed in the course
  • Of clinical trials (see PRECAUTIONS).
  • There has been no evidence for the development of antibodies or of a blunted
  • Or diminished response to NEUPOGEN® in treated patients‚
  • Including those receiving NEUPOGEN® daily for almost 2
  • Years.Patients With Acute Myeloid
  • LeukemiaIn a randomized phase 3 clinical trial, 259 patients received
  • NEUPOGEN® and 262 patients received placebo
  • Postchemotherapy. Overall, the frequency of all reported adverse events was
  • Similar in both the NEUPOGEN® and placebo groups (83% vs
  • 82% in Induction 1; 61% vs 64% in Consolidation 1). Adverse events reported more
  • Frequently in the NEUPOGEN®-treated group included:
  • Petechiae (17% vs 14%), epistaxis (9% vs 5%), and transfusion reactions (10% vs
  • 5%). There were no significant differences in the frequency of these events.There were a similar number of deaths in each treatment group during
  • Induction (25 NEUPOGEN® vs 27 placebo). The primary
  • Causes of death included infection (9 vs 18), persistent leukemia (7 vs 5), and
  • Hemorrhage (6 vs 3). Of the hemorrhagic deaths, 5 cerebral hemorrhages were
  • Reported in the NEUPOGEN® group and 1 in the placebo
  • Group. Other serious nonfatal hemorrhagic events were reported in the
  • Respiratory tract (4 vs 1), skin (4 vs 4), gastrointestinal tract (2 vs 2),
  • Urinary tract (1 vs 1), ocular (1 vs 0), and other nonspecific sites (2 vs 1).
  • While 19 (7%) patients in the NEUPOGEN® group and 5 (2%)
  • Patients in the placebo group experienced severe or fatal hemorrhagic events,
  • Overall, hemorrhagic adverse events were reported at a similar frequency in both
  • Groups (40% vs 38%). The time to transfusion-independent platelet recovery and
  • The number of days of platelet transfusions were similar in both groups.Cancer Patients Receiving Bone
  • Marrow TransplantIn clinical trials‚ the reported adverse effects were those
  • Typically seen in patients receiving intensive chemotherapy followed by bone
  • Marrow transplant (BMT). The most common events reported in both control and
  • Treatment groups included stomatitis, nausea, and vomiting‚ generally of
  • Mild-to-moderate severity and were considered unrelated to NEUPOGEN®. In the randomized studies of BMT involving 167 patients who
  • Received study drug‚ the following events occurred more frequently in patients
  • Treated with Filgrastim than in controls: nausea (10% vs 4%)‚ vomiting (7% vs
  • 3%)‚ hypertension (4% vs 0%)‚ rash (12% vs 10%)‚ and peritonitis (2% vs 0%).
  • None of these events were reported by the investigator to be related to
  • NEUPOGEN®. One event of erythema nodosum was reported
  • Moderate in severity and possibly related to NEUPOGEN®.Generally‚ adverse events observed in nonrandomized studies were similar to
  • Those seen in randomized studies‚ occurred in a minority of patients, and were
  • Of mild-to-moderate severity. In one study (n = 45)‚ 3 serious adverse events
  • Reported by the investigator were considered possibly related to NEUPOGEN®. These included 2 events of renal insufficiency and 1 event
  • Of capillary leak syndrome. The relationship of these events to NEUPOGEN® remains unclear since they occurred in patients with
  • Culture-proven infection with clinical sepsis who were receiving potentially
  • Nephrotoxic antibacterial and antifungal therapy.Cancer Patients Undergoing
  • Peripheral Blood Progenitor Cell Collection and TherapyIn clinical trials‚ 126 patients received NEUPOGEN® for PBPC mobilization. In this setting‚ NEUPOGEN® was generally well tolerated. Adverse events related to
  • NEUPOGEN® consisted primarily of mild-to-moderate
  • Musculoskeletal symptoms‚ reported in 44% of patients. These symptoms were
  • Predominantly events of medullary bone pain (33%). Headache was reported related
  • To NEUPOGEN® in 7% of patients. Transient increases in
  • Alkaline phosphatase related to NEUPOGEN® were reported
  • In 21% of the patients who had serum chemistries measured; most were
  • Mild-to-moderate.All patients had increases in neutrophil counts during mobilization‚
  • Consistent with the biological effects of NEUPOGEN®. Two
  • Patients had a WBC count greater than 100‚000/mm3. No sequelae
  • Were associated with any grade of leukocytosis.Sixty-five percent of patients had mild-to-moderate anemia and 97% of
  • Patients had decreases in platelet counts; 5 patients (out of 126) had decreased
  • Platelet counts to less than 50‚000/mm3. Anemia and
  • Thrombocytopenia have been reported to be related to leukapheresis; however‚ the
  • Possibility that NEUPOGEN® mobilization may contribute to
  • Anemia or thrombocytopenia has not been ruled out.Patients With Severe Chronic
  • NeutropeniaMild-to-moderate bone pain was reported in approximately 33% of
  • Patients in clinical trials. This symptom was readily controlled with
  • Non-narcotic analgesics. Generalized musculoskeletal pain was also noted in
  • Higher frequency in patients treated with NEUPOGEN®.
  • Palpable splenomegaly was observed in approximately 30% of patients. Abdominal
  • Or flank pain was seen infrequently, and thrombocytopenia (less than 50‚000/mm3) was noted in 12% of patients with palpable spleens. Fewer
  • Than 3% of all patients underwent splenectomy‚ and most of these had a prestudy
  • History of splenomegaly. Fewer than 6% of patients had thrombocytopenia (less than 50‚000/mm3) during NEUPOGEN®
  • Therapy‚ most of whom had a pre-existing history of thrombocytopenia. In most
  • Cases‚ thrombocytopenia was managed by NEUPOGEN® dose
  • Reduction or interruption. An additional 5% of patients had platelet counts
  • Between 50‚000 and 100‚000/mm3. There were no associated
  • Serious hemorrhagic sequelae in these patients. Epistaxis was noted in 15% of
  • Patients treated with NEUPOGEN®‚ but was associated with
  • Thrombocytopenia in 2% of patients. Anemia was reported in approximately 10% of
  • Patients‚ but in most cases appeared to be related to frequent diagnostic
  • Phlebotomy‚ chronic illness, or concomitant medications. Other adverse events
  • Infrequently observed and possibly related to NEUPOGEN®
  • Therapy were: injection site reaction‚ rash‚ hepatomegaly‚ arthralgia‚
  • Osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and
  • Exacerbation of some pre-existing skin disorders (eg‚ psoriasis).Cytogenetic abnormalities, transformation to MDS, and AML have been observed
  • In patients treated with NEUPOGEN® for SCN (see WARNINGS,
  • PRECAUTIONS:
  • Pediatric
  • Use). As of 31 December 1997, data were available from a
  • Postmarketing surveillance study of 531 SCN patients with an average follow-up
  • Of 4.0 years. Based on analysis of these data, the risk of developing MDS and
  • AML appears to be confined to the subset of patients with congenital
  • Neutropenia. A life-table analysis of these data revealed that the cumulative
  • Risk of developing leukemia or MDS by the end of the 8th year of NEUPOGEN® treatment in a patient with congenital neutropenia was 16.5%
  • (95% C.I. = 9.8%, 23.3%); this represents an annual rate of approximately 2%.
  • Cytogenetic abnormalities, most commonly involving chromosome 7, have been
  • Reported in patients treated with NEUPOGEN® who had
  • Previously documented normal cytogenetics. It is unknown whether the development
  • Of cytogenetic abnormalities, MDS, or AML is related to chronic daily
  • NEUPOGEN® administration or to the natural history of
  • Congenital neutropenia. It is also unknown if the rate of conversion in patients
  • Who have not received NEUPOGEN® is different from that of
  • Patients who have received NEUPOGEN®. Routine monitoring
  • Through regular CBCs is recommended for all SCN patients. Additionally, annual
  • Bone marrow and cytogenetic evaluations are recommended in all patients with
  • Congenital neutropenia (see LABORATORY
  • MONITORING).Postmarketing ExperienceThe following adverse reactions have been identified during
  • Postapproval 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 (see WARNINGS:
  • Splenic
  • Rupture)
  • Acute respiratory distress syndrome (ARDS) (see WARNINGS:
  • Acute Respiratory
  • Distress Syndrome)
  • Alveolar hemorrhage and hemoptysis (see WARNINGS:
  • Alveolar Hemorrhage
  • And Hemoptysis)
  • Sickle cell crisis (see WARNINGS:
  • Sickle Cell
  • Disorders)
  • Cutaneous vasculitis (see PRECAUTIONS:
  • Cutaneous
  • Vasculitis)
  • Sweet’s syndrome (acute febrile neutrophilic dermatosis)

Overdosage

In cancer patients receiving NEUPOGEN® as
an adjunct to myelosuppressive chemotherapy‚ it is recommended‚ to avoid the
potential risks of excessive leukocytosis‚ that NEUPOGEN®
therapy be discontinued if the ANC surpasses 10‚000/mm3
after the chemotherapy-induced ANC nadir has occurred. Doses of NEUPOGEN® that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit.The maximum tolerated dose of NEUPOGEN® has not been
determined. Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase
3 study of nonmyeloablative chemotherapy. Patients in the BMT studies received
up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of
the dose response curve above daily doses of greater than 10 mcg/kg/day.In NEUPOGEN® clinical trials of cancer patients
receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not
associated with any reported adverse clinical effects.In cancer patients receiving myelosuppressive chemotherapy‚ discontinuation
of NEUPOGEN® therapy usually results in a 50% decrease in
circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels
in 1 to 7 days.

Dosage And Administration

NEUPOGEN® is supplied in either vials or
in prefilled syringes with UltraSafe® Needle Guards.
Following administration of NEUPOGEN® from the prefilled
syringe, the UltraSafe® Needle Guard should be activated
to prevent accidental needle sticks. To activate the UltraSafe® Needle Guard, place your hands behind the needle, grasp the
guard with one hand, and slide the guard forward until the needle is completely
covered and the guard clicks into place. NOTE: If an audible click is not heard, the needle guard may not be
completely activated. The prefilled syringe should be disposed of by
placing the entire prefilled syringe with guard activated into an approved
puncture-proof container.Cancer Patients Receiving
Myelosuppressive ChemotherapyThe recommended starting dose of NEUPOGEN®
is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚
by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV
infusion. A CBC and platelet count should be obtained before instituting
NEUPOGEN® therapy‚ and monitored twice weekly during
therapy. Doses may be increased in increments of 5 mcg/kg for each chemotherapy
cycle‚ according to the duration and severity of the ANC nadir.NEUPOGEN® should be administered no earlier than 24
hours after the administration of cytotoxic chemotherapy. NEUPOGEN® should not be administered in the period 24 hours before the
administration of chemotherapy (see PRECAUTIONS).
NEUPOGEN® should be administered daily for up to 2 weeks‚
until the ANC has reached 10‚000/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. NEUPOGEN® therapy should be discontinued if the
ANC surpasses 10‚000/mm3 after the expected
chemotherapy-induced neutrophil nadir (see PRECAUTIONS).
In phase 3 trials‚ efficacy was observed at doses of 4 to 8 mcg/kg/day.Cancer Patients Receiving Bone
Marrow TransplantThe recommended dose of NEUPOGEN®
following BMT is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a
continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of
NEUPOGEN® should be administered at least 24 hours after
cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.During the period of neutrophil recovery‚ the daily dose of NEUPOGEN® should be titrated against the neutrophil response as
follows:Absolute Neutrophil CountNEUPOGEN® Dose AdjustmentWhen ANC greater than 1000/mm3 for 3 consecutive daysReduce to 5 mcg/kg/day*then:If ANC remains greater than 1000/mm3for 3 more consecutive daysDiscontinue NEUPOGEN®then:If ANC decreases to less than 1000/mm3Resume at 5 mcg/kg/day*    If ANC decreases to less than 1000/mm3 at any time during the
5 mcg/kg/day administration‚ NEUPOGEN® should be
increased to 10 mcg/kg/day‚ and the above steps should then be followed.Peripheral Blood Progenitor Cell
Collection and Therapy in Cancer PatientsThe recommended dose of NEUPOGEN® for the
mobilization of PBPC is 10 mcg/kg/day SC‚ either as a bolus or a continuous
infusion. It is recommended that NEUPOGEN® be given for
at least 4 days before the first leukapheresis procedure and continued until the
last leukapheresis. Although the optimal duration of NEUPOGEN® administration and leukapheresis schedule have not been
established‚ administration of NEUPOGEN® for 6 to 7 days
with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective (see
CLINICAL
EXPERIENCE for schedules used in clinical trials). Neutrophil counts
should be monitored after 4 days of NEUPOGEN®, and
NEUPOGEN® dose modification should be considered for
those patients who develop a WBC count greater than  100‚000/mm3.In all clinical trials of NEUPOGEN® for the
mobilization of PBPC‚ NEUPOGEN® was also administered
after reinfusion of the collected cells (see CLINICAL
EXPERIENCE).Patients With Severe Chronic
NeutropeniaNEUPOGEN® should be administered to those
patients in whom a diagnosis of congenital‚ cyclic‚ or idiopathic neutropenia
has been definitively confirmed. Other diseases associated with neutropenia
should be ruled out.Starting Dose: Congenital Neutropenia: The recommended daily starting dose is 6 mcg/kg BID
SC every day.Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5
mcg/kg as a single injection SC every day.Dose Adjustments:Chronic daily administration is required to maintain clinical benefit.
Absolute neutrophil count should not be used as the sole indication of efficacy.
The dose should be individually adjusted based on the patients’ clinical course
as well as ANC. In the SCN postmarketing surveillance study, the reported median
daily doses of NEUPOGEN® were: 6.0 mcg/kg (congenital
neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic
neutropenia). In rare instances, patients with congenital neutropenia have
required doses of NEUPOGEN® greater than or equal to 100 mcg/kg/day. DilutionIf required‚ NEUPOGEN® may be diluted in
5% dextrose. NEUPOGEN® diluted to concentrations between
5 and 15 mcg/mL should be protected from adsorption to plastic materials by the
addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in
5% dextrose or 5% dextrose plus Albumin (Human)‚ NEUPOGEN® is compatible with glass bottles‚ PVC and polyolefin IV bags‚
and polypropylene syringes.Dilution of NEUPOGEN® to a final concentration of less
than 5 mcg/mL is not recommended at any time. Do not dilute
with saline at any time; product may precipitate.StorageNEUPOGEN® should be stored in the
refrigerator at 2° to 8°C (36° to 46°F). Avoid shaking. Prior to injection‚
NEUPOGEN® may be allowed to reach room temperature for a
maximum of 24 hours. Any vial or prefilled syringe left at room temperature for
greater than 24 hours should be discarded. Parenteral drug products should be
inspected visually for particulate matter and discoloration prior to
administration‚ whenever solution and container permit; if particulates or
discoloration are observed‚ the container should not be used.

How Supplied

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

References

  • Zsebo KM‚ Cohen AM‚ Murdock DC‚ et al. Recombinant human granulocyte
  • Colony-stimulating factor: Molecular and biological characterization. Immunobiol. 1986;172:175-184.
  • Welte K‚ Bonilla MA‚ Gillio AP‚ et al. Recombinant human G-CSF: Effects on
  • Hematopoiesis in normal and cyclophosphamide treated primates. J Exp Med. 1987;165:941-948.
  • Duhrsen U‚ Villeval JL‚ Boyd J‚ et al. Effects of recombinant human
  • Granulocyte colony-stimulating factor on hematopoietic progenitor cells in
  • Cancer patients. Blood. 1988;72:2074-2081.
  • Souza LM‚ Boone TC‚ Gabrilove J‚ et al. Recombinant human granulocyte
  • Colony-stimulating factor: Effects on normal and leukemic myeloid cells. Science. 1986;232:61-65.
  • Weisbart RH‚ Kacena A‚ Schuh A‚ Golde DW. GM-CSF induces human neutrophil
  • IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism. Nature. 1988;332:647-648.
  • Kitagawa S‚ Yuo A‚ Souza LM‚ Saito M‚ Miura Y‚ Takaku F. Recombinant human
  • Granulocyte colony-stimulating factor enhances superoxide release in human
  • Granulocytes stimulated by chemotactic peptide. Biochem
  • Biophys Res Commun. 1987;1443:1146.
  • Glaspy JA‚ Baldwin GC‚ Robertson PA‚ et al. Therapy for neutropenia in hairy
  • Cell leukemia with recombinant human granulocyte colony-stimulating factor.
  • Ann Int Med. 1988;109:789-795.
  • Yuo A‚ Kitagawa S‚ Ohsaka A‚ et al. Recombinant human granulocyte
  • Colony-stimulating factor as an activator of human granulocytes: Potentiation of
  • Responses triggered by receptor-mediated agonists and stimulation of C3bi
  • Receptor expression and adherence. Blood.
  • 1989;74:2144-2149.
  • Gabrilove JL‚ Jakubowski A‚ Fain K‚ et al. Phase I study of granulocyte
  • Colony-stimulating factor in patients with transitional cell carcinoma of the
  • Urothelium. J Clin Invest. 1988;82:1454-1461.
  • Morstyn G‚ Souza L‚ Keech J‚ et al. Effect of granulocyte colony-stimulating
  • Factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988;1:667-672.
  • Bronchud MH‚ Scarffe JH‚ Thatcher N‚ et al. Phase I/II study of recombinant
  • Human granulocyte colony-stimulating factor in patients receiving intensive
  • Chemotherapy for small cell lung cancer. Br J Cancer.
  • 1987;56:809-813.
  • Gabrilove JL‚ Jakubowski A‚ Scher H‚ et al. Effect of granulocyte
  • Colony-stimulating factor on neutropenia and associated morbidity due to
  • Chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med. 1988;318:1414-1422.
  • Neidhart J‚ Mangalik A‚ Kohler W‚ et al. Granulocyte colony-stimulating
  • Factor stimulates recovery of granulocytes in patients receiving dose-intensive
  • Chemotherapy without bone-marrow transplantation. J Clin
  • Oncol. 1989;7:1685-1691.
  • Bronchud MH‚ Howell A‚ Crowther D‚ et al. The use of granulocyte
  • Colony-stimulating factor to increase the intensity of treatment with
  • Doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer. 1989;60:121-128.
  • Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind,
  • Placebo-controlled, phase III study of Filgrastim in remission induction and
  • Consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718.
  • Dale DC‚ Bonilla MA‚ Davis MW‚ et al. A
  • Randomized controlled phase III trial of recombinant human granulocyte
  • Colony-stimulating factor (Filgrastim) for treatment of severe chronic
  • Neutropenia. Blood. 1993;81:2496-2502.
  • Schroeder TM and Kurth R. Spontaneous chromosomal breakage and high
  • Incidence of leukemia in inherited disease. Blood.
  • 1971;37:96-112.
  • Medlock ES, Kaplan DL, Cecchini M, Ulich TR, del Castillo J, Andresen J.
  • Granulocyte colony-stimulating factor crosses the placenta and stimulates fetal
  • Rat granulopoiesis. Blood. 1993;81:916-922.
  • Calhoun DA, Rosa C, Christensen RD. Transplacental passage of recombinant
  • Human granulocyte colony-stimulating factor in women with an imminent preterm
  • Delivery. Am J Obstet Gynecol. 1996;174:1306-1311.
  • This product and its use are covered by the following US Patent
  • Nos.: 4,810,643; 4,999,291; 5,582,823; 5,580,755.[AMGEN LOGO]Manufactured by:Amgen Manufacturing, Limited, a subsidiary of Amgen Inc.One Amgen Center DriveThousand Oaks,
  • California 91320-17993xxxxxx© 1991-2007 Amgen Inc. All rights reserved.v.20.2 - Issue Date: 09/2007

Information For Patients

  • NEUPOGEN®(Filgrastim)Information for Patients and CaregiversThis patient package insert provides information and instructions
  • For people who will be receiving NEUPOGEN® and their
  • Caregivers. This patient package insert does not tell you everything about
  • NEUPOGEN®. You should discuss any questions you have
  • About treatment with NEUPOGEN® with your doctor. What is NEUPOGEN®?NEUPOGEN® is a man-made form of granulocyte
  • Colony-stimulating factor (G-CSF), which is made using the bacteria E coli. G-CSF is a substance naturally produced by the
  • Body. It stimulates the growth of neutrophils (nu-tro-fils), a type of white blood cell important in the
  • Body’s fight against infection.What is NEUPOGEN® used for?NEUPOGEN® is used to treat neutropenia (nu-tro-peen-ee-ah), a condition where the body makes too few
  • Neutrophils. Neutropenia may be a long-standing condition where your body does
  • Not make enough neutrophils, or it may be caused by drugs used to treat cancer.
  • In some cases, your body may make enough neutrophils, but as part of your
  • Treatment for cancer, your doctor may want to increase the number of certain
  • Blood cells (CD34 cells) and collect them. The cells are collected using a
  • Process called apheresis (ay-fer-ree-sis). These
  • Collected cells are given back to you after you receive very high doses of
  • Treatment for cancer to make your blood counts get back to normal more quickly.
  • How does NEUPOGEN® work?NEUPOGEN® works by helping your body make more
  • Neutrophils. To make sure NEUPOGEN® is working, your
  • Doctor will ask that you have regular blood tests to count the number of
  • Neutrophils you have. It is important that you follow your doctor’s instructions
  • About getting these tests. Who should not take
  • NEUPOGEN®?Do not take NEUPOGEN® if you are:Allergic to NEUPOGEN® (Filgrastim) or any of its
  • Ingredients. See the end of this leaflet for a list of ingredients in
  • NEUPOGEN®. Allergic to other medicines made using the bacteria E
  • Coli. Ask your doctor if you are not sure. What important information do I need to know about taking
  • NEUPOGEN®?NEUPOGEN® may reduce your chance of getting an
  • Infection, but does not prevent all infections. An infection can still happen
  • During the short time when your/your child's neutrophil levels are low. You must
  • Be alert and look for some of the common signs or symptoms of infection, such as
  • Fever, chills, rash, sore throat, diarrhea, or redness, swelling, or pain around
  • A cut or sore. If you/your child has any of these signs or symptoms during
  • Treatment with NEUPOGEN®, tell your doctor or nurse
  • Immediately.There is a possibility that you could have a reaction at an injection site.
  • If there is a lump, swelling, or bruising at an injection site that does not go
  • Away, call your doctor.If you have a sickle cell disorder, make sure that you tell your doctor
  • Before you start taking NEUPOGEN®. If you have a sickle
  • Cell crisis after getting NEUPOGEN®, tell your doctor
  • Right away.Make sure your doctor knows about all medicines, and herbal or vitamin
  • Supplements you are taking before starting NEUPOGEN®. If
  • You are taking lithium you may need more frequent blood tests. If you/your child are receiving NEUPOGEN® because you
  • Are also receiving chemotherapy, the last dose of NEUPOGEN® should be injected at least 24 hours before your next dose of
  • Chemotherapy. There is more information about NEUPOGEN® in the
  • Physician Package Insert. If you have any questions, you should talk to your
  • Doctor.What are possible serious side effects of NEUPOGEN®?Spleen Rupture. Your spleen may become enlarged and
  • Can rupture while taking NEUPOGEN®. A ruptured spleen can
  • Cause death. The spleen is located in the upper left section of your stomach
  • Area. Call your doctor right away if you or your child has pain in the left
  • Upper stomach area or left shoulder tip area. This pain could mean your or your
  • Child’s spleen is enlarged or ruptured. Serious Allergic Reactions. NEUPOGEN® can cause serious allergic reactions. These reactions can
  • Cause a rash over the whole body, shortness of breath, wheezing, dizziness,
  • Swelling around the mouth or eyes, fast pulse, and sweating. If you or your
  • Child starts to have any of these symptoms, stop using NEUPOGEN and call your
  • Doctor or seek emergency care right away. If you or your child has an allergic
  • Reaction during the injection of NEUPOGEN®, stop the
  • Injection right away.
  • A serious lung problem called acute respiratory distress
  • Syndrome (ARDS). Call your doctor or seek emergency care right away if
  • You or your child has shortness of breath, trouble breathing or a fast rate of
  • Breathing. What are the most common side effects of NEUPOGEN®?The most common side effect you/your child may experience is aching in the
  • Bones and muscles. This aching can usually be relieved by taking a non-aspirin
  • Pain reliever such as acetaminophen.Some people experience redness, swelling, or itching at the site of
  • Injection. This may be an allergy to the ingredients in NEUPOGEN®, or it may be a local reaction. If you are giving an
  • Injection to a child, look for signs of redness, swelling, or itching at the
  • Site of injection because they may not be able to tell you they are experiencing
  • A reaction. If you notice any signs of a local reaction, call your doctor.What about pregnancy or breastfeeding? NEUPOGEN® has not been studied in pregnant women, and
  • Its effects on unborn babies are not known. If you take NEUPOGEN® while you are pregnant, it is possible that small amounts of
  • It may get into your baby’s blood. It is not known if NEUPOGEN® can get into human breast milk.If you are pregnant, plan to become pregnant, think you may be pregnant, or
  • Are breast feeding, you should tell your doctor before using NEUPOGEN®.How to prepare and give a NEUPOGEN®
  • InjectionNEUPOGEN® should be injected at the same time each
  • Day. If you miss a dose contact your doctor or nurse.You must always use the correct dose of NEUPOGEN®. Too
  • Little NEUPOGEN® may not protect you against infections,
  • And too much NEUPOGEN® may cause too many neutrophils to
  • Be in your blood. Your doctor will determine your/your child’s correct dose
  • Based on your/your child's body weight. If you are giving someone else NEUPOGEN® injections,
  • It is important that you know how to inject NEUPOGEN®,
  • How much to inject, and how often to inject NEUPOGEN®.NEUPOGEN® is available as a liquid in vials or in
  • Prefilled syringes. When you receive your NEUPOGEN®,
  • Always check to see that:The name NEUPOGEN® appears on the package and vial or
  • Prefilled syringe label. The expiration date on the vial or prefilled syringe label has not passed.
  • You should not use a vial or prefilled syringe after the date
  • On the label.The strength of the NEUPOGEN® (number of micrograms
  • In the colored dot on the package containing the vial or prefilled syringe) is
  • The same as your doctor prescribed. The NEUPOGEN® liquid in the vial or in the prefilled
  • Syringe is clear and colorless. Do not use NEUPOGEN® if the contents of the vial or prefilled syringe
  • Appear discolored or cloudy, or if the vial or prefilled syringe appears to
  • Contain lumps, flakes, or particles.

Other

  • Only use the syringe that your doctor prescribes.Your doctor or nurse will give you instructions on how to measure the correct
  • Dose of NEUPOGEN®. This dose will be measured in
  • Milliliters. You should only use a syringe that is marked in tenths of
  • Milliliters, or mL (for example, 0.2 mL). The doctor or nurse may refer to an mL
  • As a cc (1 mL = 1 cc). If you do not use the correct syringe, you or your child
  • Could receive too much or too little NEUPOGEN®. Only use disposable syringes and needles. Use the syringes
  • Only once and dispose of them as instructed by your doctor or nurse.IMPORTANT: TO HELP AVOID POSSIBLE INFECTION, YOU SHOULD
  • FOLLOW THESE INSTRUCTIONS.Setting up for an
  • InjectionFind a clean flat working surface, such as a table.
  • Remove the vial or prefilled syringe of NEUPOGEN®
  • From the refrigerator. Allow NEUPOGEN® to reach room
  • Temperature (this takes about 30 minutes). Vials or prefilled syringes should be
  • Used only once. DO NOT SHAKE THE VIAL OR PREFILLED SYRINGE. Shaking may damage
  • The NEUPOGEN®. If the vial or prefilled syringe has been
  • Shaken vigorously, the solution may appear foamy and it should not be used.
  • Assemble the supplies you will need for an injection:
  • NEUPOGEN® vial and
  • Disposable syringe and needle
  • NEUPOGEN® prefilled
  • Syringe with transparent (clear) plastic orange needle guard attachedtwo alcohol swabs and one cotton ball or gauze padpuncture-proof disposal container4.  Wash your hands with soap and warm water.

HOW TO PREPARE THE DOSE OF NEUPOGEN®
IN VIALS OR PREFILLED SYRINGESIf you are using NEUPOGEN® in a vial, follow the
instructions in Section A. If you are using NEUPOGEN® in
a prefilled syringe, go to Section B. Section A. Preparing the dose of
NEUPOGEN® in a vial1.  Take the cap off the vial. Clean the rubber stopper with one alcohol swab.2.  Check the package containing the syringe. If the package has been opened or
damaged, do not use that syringe. Dispose of that syringe in the puncture-proof
disposal container. If the syringe package is undamaged, open the package and
remove the syringe.3.  Pull the needle cover straight off the syringe. Then, pull back the plunger and
draw air into the syringe. The amount of air drawn into the syringe should be
the same amount (mL or cc) as the dose of NEUPOGEN® that
your doctor prescribed.4.  Keep the vial on your flat working surface and insert the needle straight down
through the rubber stopper. Do not put the needle through the rubber stopper
more than once.5.  Push the plunger of the syringe down and inject the air from the syringe into
the vial of NEUPOGEN®.6.  Keeping the needle in the vial, turn the vial upside down. Make sure that the
NEUPOGEN® liquid is covering the tip of the needle.7.  Keeping the vial upside down, slowly pull back on the plunger to fill the
syringe with NEUPOGEN® liquid to the number (mL or cc)
that matches the dose your doctor prescribed.8.  Keeping the needle in the vial, check for air bubbles in the syringe. If there
are air bubbles, gently tap the syringe with your fingers until the air bubbles
rise to the top of the syringe. Then slowly push the plunger up to force the air
bubbles out of the syringe.9.  Keeping the tip of the needle in the liquid, once again pull the plunger back to
the number on the syringe that matches your dose. Check again for air bubbles.
The air in the syringe will not hurt you, but too large an air bubble can reduce
your dose of NEUPOGEN®. If there are still air bubbles,
repeat the steps above to remove them.10. Check again to make sure that you have the correct dose in the syringe. It is
important that you use the exact dose prescribed by your doctor. Remove the
syringe from the vial but do not lay it down or let the
needle touch anything. (Go to “Injecting the dose of NEUPOGEN®”).

  • Section B. Preparing the dose of
  • NEUPOGEN® in a prefilled syringeRemove the syringe from the package and the tray. Check to see that the
  • Plastic orange needle guard is covering the barrel of the glass syringe. DO NOT push the orange needle guard over the needle cover before
  • Injection. This may activate or lock the needle guard. If the orange
  • Needle guard is covering the needle that means it has been activated. Do NOT use
  • That syringe. Dispose of that syringe in the puncture-proof disposal container.
  • Use a new syringe from the package.Hold the syringe barrel through the needle guard windows with the needle
  • Pointing up. Holding the syringe with the needle pointing up helps to prevent
  • Medicine from leaking out of the needle. Carefully pull the needle cover
  • Straight off.
  • Check the syringe for air bubbles. If there are air bubbles, gently tap the
  • Syringe with your fingers until the air bubbles rise to the top of the syringe.
  • Slowly push the plunger up to force the air bubbles out of the syringe.
  • Push the plunger up to the number (mL) on the syringe that matches the dose
  • Of NEUPOGEN® that your doctor prescribed.
  • Check again to make sure the correct dose of NEUPOGEN® is in the syringe.
  • Gently place the prefilled syringe with the window flat on your clean
  • Working surface so that the needle does not touch anything. Selecting and preparing the injection siteChoose an injection site. Four recommended injection sites for NEUPOGEN® are:
  • The outer area of your upper arms
  • The abdomen, except for the two inch area around your navel
  • The front of your middle thighs
  • The upper outer areas of your buttocksChoose a new site each time you inject NEUPOGEN®.
  • Choosing a new site can help avoid soreness at any one site. Do not inject
  • NEUPOGEN® into an area that is tender, red, bruised, or
  • Hard or that has scars or stretch marks.Clean the injection site with a new alcohol swab.Injecting the dose of NEUPOGEN®For injecting the dose of NEUPOGEN® from a vial,
  • Remove the syringe and needle from the vial. For injecting the dose of
  • NEUPOGEN® from a prefilled syringe, pick up the prefilled
  • Syringe from your clean flat working surface by grabbing the sides of the needle
  • Guard with your thumb and forefinger.
  • Hold the syringe in the hand you will use to inject NEUPOGEN®. Use the other hand to pinch a fold of skin at the cleaned
  • Injection site. Note: If using a prefilled syringe with a
  • Needle guard, hold the syringe barrel through the needle guard windows when
  • Giving the injection.Holding the syringe like a pencil, use a quick “dart-like” motion to insert the
  • Needle either straight up and down (90 degree angle) or at a slight angle (45
  • Degrees) into the skin.After the needle is inserted, let go of the skin. Pull the plunger back
  • Slightly. If no blood appears, slowly push down on the plunger all the way,
  • Until all the NEUPOGEN® is injected. If
  • Blood comes into the syringe, do not inject NEUPOGEN®,
  • Because the needle has entered a blood vessel. Withdraw the syringe and
  • Discard it in the puncture-proof container. Repeat the steps to prepare a new
  • Syringe (or get a new prefilled syringe) and choose and clean a new injection
  • Site. Remember to check again for blood before injecting NEUPOGEN®.When the syringe is empty, pull the needle out of the skin and place a cotton
  • Ball or gauze over the injection site and press for several seconds.Use a prefilled syringe with the needle guard or a syringe and vial only
  • Once. If you are using a syringe, DO NOT put the needle cover (the cap) back on
  • The needle. Discard the vial with any remaining NEUPOGEN®
  • Liquid. Activating the Needle Guard for the
  • Prefilled syringe after the injection has been givenAfter injecting NEUPOGEN® from the prefilled syringe,
  • Do not recap the needle. Keep your hands behind the needle at all times. While
  • Holding the clear plastic finger grip of the syringe with one hand, grasp the
  • Orange needle guard with your free hand and slide the orange needle guard over
  • The needle until the needle is completely covered and the needle guard clicks
  • Into place. NOTE: If an audible click is not heard, the needle
  • Guard may not be completely activated.Place the prefilled syringe with the activated needle guard into a
  • Puncture-proof container for proper disposal as described below. Disposal of syringes, needles, vials
  • And needle guards You should always follow the instructions given by your doctor, nurse, or
  • Pharmacist on how to properly dispose of containers with used syringes, needles,
  • Vials and needle guards. There may be special state and local laws for disposal
  • Of used needles and syringes. Place all used needles, needle covers, syringes, and vials (empty or unused
  • Contents) into a “Sharps” container given to you by your doctor or pharmacist or
  • In a hard-plastic container with a screw-on cap, or a metal container with a
  • Plastic lid, such as a coffee can, labeled “used syringes.” If a metal container
  • Is used, cut a small hole in the plastic lid and tape the lid to the metal
  • Container. If a hard-plastic container is used, always screw the cap on tightly
  • After each use.
  • Do not use glass or clear plastic containers.
  • When the container is full, tape around the cap or lid to make sure the cap
  • Or lid does not come off. Do not throw the container in the
  • Household trash. Do not recycle.Always keep the container out of the reach of
  • Children. How should NEUPOGEN® be
  • Stored?NEUPOGEN® should be stored in the refrigerator at 2º
  • To 8ºC (36º to 46ºF), but not in the freezer. Avoid shaking NEUPOGEN®. If NEUPOGEN® is accidentally frozen,
  • Allow it to thaw in the refrigerator before giving the next dose. However, if it
  • Is frozen a second time, do not use it and contact your doctor or nurse for
  • Further instructions. NEUPOGEN® can be left out at room
  • Temperature for up to 24 hours. Do not leave NEUPOGEN® in
  • Direct sunlight. If you have any questions about storage or how to carry
  • NEUPOGEN® when you travel, contact your doctor, nurse, or
  • Pharmacist.What are the ingredients in NEUPOGEN®?Each syringe and vial contains Filgrastim in a sterile, clear, colorless,
  • Preservative-free solution containing acetate, sorbitol, polysorbate 80, and
  • Sodium.The needle cover on the single-use prefilled syringe contains dry natural
  • Rubber (latex), which should not be handled by persons sensitive to this
  • Substance.[Amgen Logo]Manufactured by:Amgen Manufacturing,
  • Limited,a subsidiary of Amgen Inc.One Amgen Center Drive Thousand
  • Oaks, California 91320-1799 U.S.A.3xxxxxx© 1991-2007 Amgen Inc. All rights reserved.v8.1 - Issue Date: 09/2007

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