ZARZIO

Filgrastim is a short-acting recombinant, non-pegylated human granulocyte colony-stimulating factor (G-CSF) analog produced by recombinant DNA technology.

It has an amino acid sequence identical to endogenous G-CSF, but it is non-glycosylated unlike the endogenous G-CSF and has an N-terminal methionine added in the sequence for expression in E. Coli.

G-CSF is a glycoprotein that regulates the production and release of neutrophils from the bone marrow.

Filgrastim mimics the biological actions of

G-CSF to increase the levels of neutrophils in the blood.

It has a number of therapeutic uses, including the management and prevention of infections and febrile neutropenia in patients receiving myelosuppressive chemotherapy or radiation therapy.

It is also used to manage severe chronic neutropenia and mobilize hematopoietic progenitor cells to the peripheral blood for collection by leukapheresis in patients undergoing peripheral blood progenitor cell collection and therapy.

Filgrastim was approved in the

US in and there are biosimilars available with similar therapeutic indications.

Tbo-filgrastim was approved by the FDA on August 29, 2012.

Filgrastim-sndz was approved on

March 6, 2015 12 and filgrastim-ayow was approved on March 2, 2022.

A long-acting, pegylated G-CSF, pegfilgrastim, was made available to increase the duration of action of the drug.

Filgrastim 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.

Filgrastim is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia.

Filgrastim is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.

Filgrastim is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Filgrastim is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.

Filgrastim is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Filgrastim is used to reduce the incidence, severity and duration of neutropenia and febrile neutropenia in patients undergoing cytotoxic chemotherapy.

In clinical trials in patients, filgrastim reduced the duration of febrile neutropenia, antibiotic use, and hospitalization after induction chemotherapy for acute myelogenous leukemia or myeloablative therapy followed by bone marrow transplantation; however, the incidence of fever and documented infections were not reduced in either setting.

Filgrastim is also used to mobilize hematopoietic progenitor cells into the peripheral blood in order to reduce the risk for bleeding complications and the need for platelet transfusions.

Recipients of allogeneic

PBPCs mobilized with filgrastim experienced significantly more rapid hematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.

Filgrastim causes a dose-dependent increase in circulating neutrophil counts within 24 hours of administration.

Filgrastim can also cause a minor increase in monocyte and lymphocyte counts, but the clinical significance of these effects is unknown.

In some patients, filgrastim also caused a minor increase in the number of circulating eosinophils and basophils relative to baseline; however, these patients may already have had elevated eosinophils and basophils prior to filgrastim treatment.

Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within one to two days, and to normal levels within one to seven days.

As with other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.

Filgrastim exhibits nonlinear pharmacokinetics.

Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of and 49 ng/mL‚ respectively‚ within 2-8 hours.

Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11-20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation.

The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.

After intravenous administration, the volume of distribution averaged 150 mL/kg.

There is no evidence of drug accumulation.

Like other

G-CSF compounds, filgrastim is cleared from plasma via neutrophil-mediated clearance involving internalization via G-CSF receptors and degradation within the neutrophil.

Filgrastim is also subject to extracellular proteolytic degradation by neutrophil elastase: this enzyme rapidly cleaves filgrastim and renders it inactive. 6, 7.

There is limited information available; however, filgrastim is subject to renal elimination.

After intravenous administration, the elimination half-life of filgrastim was approximately 3.5 hours in both normal subjects and patients with cancer.

Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives.

The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following filgrastim dosages of 3.45 mcg/kg).

rates of filgrastim were approximately 0.5-0.7 mL/minute/kg after intravenous administration.

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The oral

LD in mouse and rat was >3 mg/kg.

There is limited information regarding filgrastim overdose.

The maximum tolerated dose of filgrastim has not been determined.

In clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ white blood cell counts greater than 100,000/mm 3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects.

Patients in the bone marrow transplantation 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.

is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.

Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.

Patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML Recommended starting dose is 5 mcg/kg/day by subcutaneous injection, short intravenous infusion (15 to 30 minutes), or continuous intravenous infusion.

Information for recommended dosage adjustments and timing of administration Patients with cancer undergoing bone marrow transplantation: 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours.

Information for recommended dosage adjustments and timing of administration Patients undergoing autologous peripheral blood progenitor cell collection and therapy 10 mcg/kg/day subcutaneous injection Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis Patients with congenital neutropenia Recommended starting dose is 6 mcg/kg subcutaneous injection twice daily Patients with cyclic or idiopathic neutropenia Recommended starting dose is 5 mcg/kg subcutaneous injection daily Patients acutely exposed to myelosuppressive doses of radiation 10 mcg/kg/day subcutaneous injection Direct administration of less than 0.3 mL (180 mcg) is not recommended due to potential for dosing errors 2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of NYPOZI is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection, by short intravenous infusion (15 to 30 minutes), or by continuous intravenous infusion.

Obtain a complete blood count (CBC) and platelet count before instituting NYPOZI therapy and monitor twice weekly during therapy.

Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the absolute neutrophil count (ANC) nadir.

Recommend stopping NYPOZI if the

ANC increases beyond 10‚000/mm 3.

NYPOZI at least 24 hours after cytotoxic chemotherapy.

Do not administer

NYPOZI within the 24-hour period prior to chemotherapy.

A transient increase in neutrophil count is typically seen to 2 days after initiation of filgrastim therapy.

Therefore, to ensure a sustained therapeutic response‚ administer NYPOZI daily for up to 2 weeks or until the ANC has reached 10‚000/mm 3 following the expected chemotherapy-induced neutrophil nadir.

The duration of

NYPOZI therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. 2.2 Dosage in Patients with Cancer Undergoing Bone Marrow Transplantation The recommended dosage of NYPOZI following bone marrow transplantation (BMT) is 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours.

Administer the first dose of

NYPOZI at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.

CBCs and platelet counts frequently following marrow transplantation.

During the period of neutrophil recovery‚ titrate the daily dosage of NYPOZI against the neutrophil response.

Table 1.

Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count NYPOZI Dosage Adjustment a If ANC decreases to less than 1000/mm at any time during the 5 mcg/kg/day administration‚ increase NYPOZI to 10 mcg/kg/day‚ and then follow the above steps.

ANC greater than 1,000/mm for 3 consecutive days Reduce to 5 mcg/kg/day a Then, if ANC remains greater than 1,000/ mm for 3 more consecutive days Discontinue NYPOZI Then, if ANC decreases to less than 1,000/mm 3 Resume at 5 mcg/kg/day 2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy The recommended dosage of NYPOZI for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection.

NYPOZI for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis.

Although the optimal duration of

NYPOZI administration and leukapheresis schedule have not been established‚ administration of filgrastim for to 7 days with leukaphereses on days 5‚ 6‚ and was found to be safe and effective.

Monitor neutrophil counts after 4 days of NYPOZI and discontinue NYPOZI if the white blood cell (WBC) count rises to greater than 100‚000/mm 3. 2.4 Dosage in Patients with Severe Chronic Neutropenia Prior to starting NYPOZI in patients with suspected chronic neutropenia, confirm the diagnosis of severe chronic neutropenia (SCN) by evaluating serial CBCs with differential and platelet counts‚ and evaluating bone marrow morphology and karyotype.

The use of NYPOZI prior to confirmation of a correct diagnosis of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition‚ other than SCN‚ causing the neutropenia.

The recommended starting dosage in patients with Congenital Neutropenia is 6 mcg/kg as a twice daily subcutaneous injection and the recommended starting dosage in patients with Idiopathic or Cyclic Neutropenia is 5 mcg/kg as a single daily subcutaneous injection.

Dosage Adjustments in Patients with Severe Chronic Neutropenia Chronic daily administration is required to maintain clinical benefit.

Individualize the dosage based on the patient's clinical course as well as ANC.

In the

SCN postmarketing surveillance study, the reported median daily doses of filgrastim were: 6 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 filgrastim greater than or equal to 100 mcg/kg/day. Monitor CBCs for Dosage Adjustments During the initial 4 weeks of NYPOZI therapy and during the 2 weeks following any dosage adjustment‚ monitor CBCs with differential and platelet counts.

Once a patient is clinically stable‚ monitor CBCs with differential and platelet counts monthly during the first year of treatment.

Thereafter, if the patient is clinically stable, less frequent routine monitoring is recommended. 2.5 Dosage in Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) The recommended dose of NYPOZI is 10 mcg/kg as a single daily subcutaneous injection for patients exposed to myelosuppressive doses of radiation.

NYPOZI as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).

Estimate a patient's absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.

Obtain a baseline CBC and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm for 3 consecutive CBCs.

Do not delay administration of NYPOZI if a CBC is not readily available.

Continue administration of NYPOZI until the

ANC remains greater than 1,000/mm for 3 consecutive CBCs or exceeds 10,000/mm 3 after a radiation-induced nadir. 2.6 Important Administration Instructions NYPOZI is supplied in single-dose prefilled syringes (for subcutaneous or intravenous use) .

Prior to use‚ remove the prefilled syringe from the refrigerator and allow NYPOZI to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours.

Discard any prefilled syringe left at room temperature for greater than 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

NYPOZI if particulates or discoloration are observed.

Discard unused portion of

NYPOZI in prefilled syringes.

Do not save unused drug for later administration.

NYPOZI subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock.

If patients or caregivers are to administer NYPOZI, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the prefilled syringe.

Training by a healthcare professional should aim to demonstrate to those patients and caregivers how to measure the dose using the prefilled syringe, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use for the NYPOZI prefilled syringe with BD UltraSafe Passive™ Needle Guard.

If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NYPOZI.

NYPOZI prefilled syringe with BD UltraSafe

Passive™ Needle Guard is not designed to allow for direct administration of doses of less than 0.3 mL (180 mcg).

The spring-mechanism of the needle guard apparatus affixed to the prefilled syringe interferes with the visibility of the graduation markings on the syringe barrel corresponding to 0.1 mL and 0.2 mL.

The visibility of these markings is necessary to accurately measure doses of NYPOZI less than 0.3 mL (180 mcg) for direct administration to patients.

Thus, the direct administration to patients requiring doses of less than 0.3 mL (180 mcg) is not recommended due to the potential for dosing errors.

If required for intravenous administration, NYPOZI may be diluted in 5% Dextrose Injection to a concentration of 15 mcg/mL.

NYPOZI diluted to 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 plus Albumin (Human), NYPOZI is compatible with polyvinylchloride and polyolefin.

Do not dilute with Sodium Chloride

Injection at any time, because the product may precipitate.

NYPOZI solution can be stored at room temperature for up to 14 hours.

This 14 hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

If the patient or caregiver misses a dose of NYPOZI, instruct them to contact their healthcare provider.

(filgrastim-txid) injection is a clear, colorless to slightly yellowish, preservative-free solution supplied as prefilled syringes: Single-dose‚ preservative-free, prefilled syringes with 29 gauge, half inch needle with a BD UltraSafe Passive™ Needle Guard, containing 300 mcg/0.5 mL of filgrastim-txid.

Carton of 1 prefilled syringe (NDC 69097-430-67) Carton of 10 prefilled syringes (NDC 69097-430-96) Single-dose‚ preservative-free, prefilled syringes with 29 gauge, half inch needle with a BD UltraSafe Passive™ Needle Guard, containing 480 mcg/0.8 mL of filgrastim-txid.

Carton of 1 prefilled syringe (NDC 69097-429-67) Carton of 10 prefilled syringes (NDC 69097-429-96) Storage: Store NYPOZI in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not leave

NYPOZI in direct sunlight.

Avoid shaking.

Do not freeze.

Transport via pneumatic tube has not been studied.

Prior to injection‚ NYPOZI may be allowed to reach room temperature for a maximum of 24 hours.

NYPOZI prefilled syringe with BD UltraSafe

Passive™ Needle Guard may not accurately measure volumes less than 0.3 mL due to the needle spring mechanism design.

Therefore, the direct administration of a volume less than 0.3 mL (180 mcg) is not recommended due to the potential for dosing errors.

In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 – 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous filgrastim at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8).

The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim.

In this population‚ filgrastim was well tolerated.

There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with filgrastim therapy; however, the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

The safety and effectiveness of filgrastim have been established in pediatric patients with SCN.

In a phase 3 study (Study 7) to assess the safety and efficacy of filgrastim in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied.

Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and were adolescents (12 to 16 years of age).

Additional information is available from a

SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study.

Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 - 17) .

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 filgrastim treatment.

Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

Pediatric patients with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic filgrastim treatment.

The relationship of these events to filgrastim products administration is unknown.

The use of filgrastim to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on studies of filgrastim conducted in animals and clinical data supporting the use of filgrastim in other approved indications.

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of filgrastim treated-patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Clinical studies of filgrastim in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged and older to determine whether elderly subjects respond differently from younger subjects.