Neupogen

Colony-stimulating Factors

Filgrastim may be administered as a subcutaneous injection, a short intravenous (IV) infusion, or as a continuous IV infusion.
Administer filgrastim at least 24 hours before or 24 hours after chemotherapy.
Do not shake vials or prefilled syringes.
Store vials or prefilled syringes in the refrigerator (2 to 8 degrees C; 36 and 46 degrees F) in the carton. Protect from light.
Avoid freezing filgrastim products. If frozen (Neupogen, Nivestym, or Zarxio only), thaw in the refrigerator; throw away if the product has been frozen more than once.
Prior to use, allow filgrastim vials or prefilled syringes to reach room temperature for least 30 minutes; discard any vial or prefilled syringe exposed to room temperature for more than 24 hours.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Products are for single-use; do not re-enter the vial or save unused drug for later administration.

Dilute prior to intravenous (IV) use.
Dilution
After calculating/selecting the appropriate dose, dilute the filgrastim vial (concentration of 300 mcg/mL) in 5% Dextrose Injection to a final concentration of 5 mcg/mL or more. Do NOT dilute with 0.9% Sodium Chloride Injection; the product may precipitate.
Use a glass bottle, a polyvinyl chloride (PCV) or polyolefin IV bag, or a polypropylene syringe as a container for the diluted solution.
To protect the absorption of filgrastim to the plastic container in diluted solutions at concentrations of 5 to 15 mcg/mL, add albumin to a final concentration of 2 mg/mL.
Storage after dilution: Diluted filgrastim IV solutions may be stored at room temperature for up to 24 hours (Neupogen, Nivestym, or Zarxio) or up to 4 hours (Releuko); the total storage time includes the infusion time.
IV Infusion
Administer the diluted IV infusion over 15 to 30 minutes or as a continuous IV infusion given over 24 hours.

Single-dose vials or prefilled-syringes may be used for subcutaneous injections.
Patient or caregiver may administer after being properly trained on storage, preparation, and administration technique. Follow instructions for use provided by manufacturer.
No dilution is necessary.
Subcutaneous Injection Using Prefilled Syringe
Do not activate the needle guard prior to injection; pull the needle cover straight off.
The Nivestym, Zarxio, and Releuka prefilled syringes are not designed to administer doses less than 0.3 mL (180 mcg).
Inject filgrastim in a recommended subcutaneous injection site (i.e., the outer area of the upper arm, the abdomen excluding the 2-inch area around the navel, the front of the middle thigh, and the upper outer areas of the buttocks).
Do not recap the needle; slide the needle guard over the needle until the needle is completely covered and the needle guard clicks into place.
Subcutaneous Injection Using Single-Use Vials
Withdraw the contents of the filgrastim vial into a syringe.
Inject filgrastim subcutaneously in a recommended injection site (i.e., the outer area of the upper arm, the abdomen excluding the 2-inch area around the navel, the front of the middle thigh, and the upper outer areas of the buttocks).

angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
splenic rupture / Delayed / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
sickle-cell crisis / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
capillary leak syndrome / Early / Incidence not known
vasculitis / Delayed / Incidence not known
aortitis / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
leukemia / Delayed / Incidence not known
extramedullary hematopoiesis / Delayed / Incidence not known

thrombocytopenia / Delayed / 5.0-38.0
bone pain / Delayed / 5.0-30.0
dyspnea / Early / 0-13.0
chest pain (unspecified) / Early / 5.0-13.0
antibody formation / Delayed / 3.0-3.0
splenomegaly / Delayed / 5.0
anemia / Delayed / 5.0
erythema / Early / 2.0
hypertension / Early / 5.0
peripheral edema / Delayed / 5.0
constipation / Delayed / 2.0
wheezing / Rapid / Incidence not known
hemoptysis / Delayed / Incidence not known
bleeding / Early / Incidence not known
hypoxia / Early / Incidence not known
hematuria / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
edema / Delayed / Incidence not known
hypoalbuminemia / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
osteoporosis / Delayed / Incidence not known

fever / Early / 5.0-48.0
nausea / Early / 43.0-43.0
back pain / Delayed / 2.0-15.0
cough / Delayed / 0-14.0
rash / Early / 5.0-14.0
dizziness / Early / 14.0-14.0
headache / Early / 10.0-10.0
arthralgia / Delayed / 5.0-9.0
leukocytosis / Delayed / 2.0-2.0
maculopapular rash / Early / 2.0
alopecia / Delayed / 5.0
asthenia / Delayed / 5.0
fatigue / Early / 20.0
malaise / Early / 5.0
muscle cramps / Delayed / 5.0
musculoskeletal pain / Early / 5.0
hypoesthesia / Delayed / 5.0
vomiting / Early / 5.0
anorexia / Delayed / 5.0
diarrhea / Early / 2.0
epistaxis / Delayed / 2.0
infection / Delayed / 5.0
insomnia / Early / 5.0
abdominal pain / Early / Incidence not known

Neupogen, Nivestym, Releuko, Zarxio

Rx

Granulocyte colony-stimulating factor
Used to reduce the duration of neutropenia and incidence of infection in patients receiving myelosuppressive chemotherapy or myeloablative chemotherapy followed by bone marrow transplant; also used for the mobilization of peripheral blood progenitor cells for leukapheresis, for the treatment of severe chronic neutropenia, and to improve survival following acute radiation exposure
Acute respiratory distress syndrome, fatal splenic rupture, and glomerulonephritis have been reported

No dosage adjustment is necessary.

No dosage adjustment is necessary.

Abemaciclib: (Major) Do not administer abemaciclib for at least 48 hours after the last dose of colony stimulating factors, if required. Hematologic toxicities should also be resolved to grade 2 or less prior to resuming treatment with abemaciclib.
Aldesleukin, IL-2: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Alemtuzumab: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Alpha interferons: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Altretamine: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
Antimetabolites: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Betibeglogene Autotemcel: (Major) Avoid administration of filgrastim for 21 days after betibeglogene autotemcel infusion.
Bexarotene: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Chlorambucil: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim, is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
Cladribine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Clofarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with filgrastim, G-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF.
Docetaxel: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Estramustine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Fludarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Ibritumomab Tiuxetan: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Lithium: (Moderate) Lithium prompts the release of neutrophils and should be used with caution during filgrastim therapy. White blood cell counts above 100,000 cells/mm3 represent a medical emergency because of the risk of serious adverse effects such as brain infarction, respiratory failure, intracranial hemorrhage, retinal hemorrhage, myocardial infarction, and acute limb ischemia. Patients receiving lithium and filgrastim or pegfilgrastim should have more frequent monitoring of WBC counts.
Lomustine, CCNU: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Mercaptopurine, 6-MP: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Methotrexate: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Natural Antineoplastics: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Nelarabine: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Paclitaxel: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Pentostatin: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Tositumomab: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Tretinoin, ATRA: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.

Filgrastim (E. coli)/Neupogen/Nivestym/Releuko/Zarxio Intravenous Inj Sol: 0.5mL, 0.8mL, 1mL, 1.6mL, 300mcg, 480mcg
Filgrastim (E. coli)/Neupogen/Nivestym/Releuko/Zarxio Subcutaneous Inj Sol: 0.5mL, 0.8mL, 1mL, 1.6mL, 300mcg, 480mcg

NOTE: Maximum daily dosage is indication dependent.

30 mcg/kg/day IV. Subcutaneous, 24 mcg/kg/day (rarely, 100 mcg/kg/day subcutaneously or higher in patients with severe congenital neutropenia).

30 mcg/kg/day IV. Subcutaneous, 24 mcg/kg/day (rarely, 100 mcg/kg/day subcutaneously or higher in patients with severe congenital neutropenia).

Subcutaneous, 15 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

Subcutaneous, 15 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

7 to 11 months: Subcutaneous, 12 mcg/kg/day (rarely, 100 mcg/kg/day or higher in patients with severe congenital neutropenia).

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein involved in the regulation and production of neutrophils in response to host defense needs. Filgrastim has the same biologic activity as native G-CSF. The production of G-CSF can be induced by exposure to bacterial cell wall proteins, endotoxin, or proinflammatory cytokines (e.g., interleukin (IL)-1, IL-17, interferon gamma, or tumor necrosis factor). Cells responsible for the production of G-CSF include monocytes and macrophages, endothelial cells, fibroblasts, and bone marrow stromal cells. Normally, G-CSF plasma levels are low or undetectable, but in response to bacterial stimuli, the levels are rapidly and markedly elevated. G-CSF acts on a specific receptor located on hematopoietic progenitor cells and mature neutrophils. G-CSF is also important for the survival of multilineage hematopoietic stem cells, but it cannot sustain their proliferation or differentiation.
 
Administration of exogenous G-CSF results in increased total neutrophil counts, including mature, banded, and precursor neutrophils, without increasing the number of basophils, eosinophils, or monocytes. The rise in neutrophils is due to increased production by the bone marrow and not increased survival of neutrophils. Morphological changes in neutrophils, including densely staining secondary cytoplasmic granules and Dohle bodies, have been observed following administration of exogenous G-CSF. The morphological changes are similar to those seen in neutrophils during infection and are consistent with changes seen in functionally "primed" neutrophils. G-CSF activates polymorphic neutrophils (PMNs) by mobilizing secretory vesicles and inducing the release of granules, which enhance bacterial cytotoxicity. G-CSF also affects selected neutrophil functions including enhanced phagocytic ability, priming of cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some functions associated with cell surface antigens. Exogenous G-CSF increases the number of circulating hematopoietic progenitor cells in a dose-dependent manner. Hematopoietic stem and progenitor cell mobilization is thought to be related to the ability of G-CSF to downregulate endothelial intercellular adhesion molecule 1 (ICAM-1), and upregulate vascular cell adhesion molecule-1.

Filgrastim is administered intravenously (IV) or subcutaneously. Pharmacokinetic data are similar in healthy subjects and cancer patients. The volume of distribution averaged 150 mL/kg. Clearance is nonlinear and is dependent on drug concentration and neutrophil count. G-CSF receptor-mediated clearance is saturated by a high concentration of filgrastim and clearance is diminished by neutropenia. Filgrastim is cleared by the kidney. The elimination half-life is approximately 3.5 hours, and the clearance is about 0.5 to 0.7 mL/minute/kg following IV filgrastim administration. The half-life of filgrastim is similar following IV (231 minutes) or subcutaneous (210 minutes) administration. Additionally, single IV doses or daily IV doses resulted in comparable half-life values.
A dose-dependent increase in circulating neutrophil counts occurred following filgrastim administration (dose range, 1 to 70 mcg/kg/day) in patients with nonmyeloid malignancies. This dose-dependent neutrophil increase occurred with IV (1 to 70 mcg/kg twice daily), subcutaneous (1 to 3 mcg/kg once daily), or continuous subcutaneous infusion (3 to 11 mcg/kg/day) administration. In most cases, the neutrophil count returned to baseline within 4 days of stopping filgrastim.
Affected cytochrome P450 isoenzymes and drug transporters: None

The steady-state concentration was achieved and there was no evidence of drug accumulation when filgrastim 20 mcg/kg/day was given as a continuous 24-hour IV infusion over 11 to 20 days.

The absolute bioavailability of filgrastim is 60% to 70% following subcutaneous administration. The peak concentration (Cmax) was 4 and 49 nanograms/mL following subcutaneous filgrastim doses of 3.45 mcg/kg and 11.5 mcg/kg, respectively. The time to peak concentration (Tmax) ranged from 2 to 8 hours.

The potential risk to the fetus with the use of filgrastim during pregnancy is unknown; there are no adequate and well-controlled clinical studies in pregnant women. Several observational studies have shown no major differences in pregnancy outcome (including miscarriage and preterm labor), neonatal complications (including birth weight), and infections between treated and untreated women. No malformations were observed during animal studies. Reduced embryo-fetal survival and increased fetal abortion were observed in pregnant rabbits who received filgrastim doses that were 2- to 10-times higher than doses used in humans.

The transfer of filgrastim into human milk has been documented in published literature. However, no adverse effects in breast-feeding infants have been noted. The effects of filgrastim on human milk production are unknown. Other recombinant filgrastim products are poorly secreted into breast milk, and filgrastim is not orally absorbed by neonates. Consider the benefits of breast-feeding compared with the risk of a potential adverse event in the infant prior to administering filgrastim in a lactating woman.