NEUPOGEN

Filgrastim-txid, a leukocyte growth factor, is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E. coli.

Because filgrastim-txid is produced in

E. coli ‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

NYPOZI (filgrastim-txid) injection is a sterile‚ clear‚ colorless to slightly yellowish‚ preservative-free liquid containing filgrastim-txid at a specific activity of 1.3 ± 0.3 × 10 8 IU/mg (as measured by a cell mitogenesis assay).

The product is available in single-dose prefilled syringes for subcutaneous or intravenous use.

The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-txid.

The pH is 4.0.

See table below for product composition of each single-dose prefilled syringe. 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe filgrastim-txid 300 mcg 480 mcg glacial acetic acid 0.254 mg 0.41 mg polysorbate 80 0.062 mg 0.1 mg sodium acetate 0.02 mg 0.032 mg sorbitol 25 mg 40 mg water for Injection USP q.s. ad 0.5 mL 0.8 mL quantity sufficient to make.

is a leukocyte growth factor 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 Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) 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 (BMT) Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis Reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy NYPOZI 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. 1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy NYPOZI 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 (AML) . 1.3 Patients with Cancer Undergoing Bone Marrow Transplantation NYPOZI 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. 1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy NYPOZI is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. 1.5 Patients with Severe Chronic Neutropenia NYPOZI 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. 1.6 Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) NYPOZI is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation.

G-CSF is a lineage-specific colony-stimulating factor that is produced by monocytes‚ fibroblasts, and endothelial cells.

G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody-dependent killing, and the increased expression of some cell surface antigens).

G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage. 12.2 Pharmacodynamics In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ administration of filgrastim resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of to 70 mcg/kg/day. This increase in neutrophil counts was observed whether filgrastim was administered intravenous (1 to 70 mcg/kg twice daily), subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/kg/day).

With discontinuation of filgrastim 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 filgrastim; however, the percentage of monocytes in the differential count remained within the normal range.

Absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of filgrastim.

Increases in lymphocyte counts following filgrastim administration have been reported in some normal subjects and patients with cancer.

White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift), including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir.

In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed.

Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection. 12.3 Pharmacokinetics Filgrastim products exhibit nonlinear pharmacokinetics.

Clearance is dependent on filgrastim product concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of filgrastim products and is diminished by neutropenia.

In addition, filgrastim products are cleared by the kidney.

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 to 8 hours.

After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and subjects with cancer.

Clearance rate of filgrastim was approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives.

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

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

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

Specific Populations Patients Acutely Exposed to Myelosuppressive Doses of Radiation The pharmacokinetics of filgrastim products is not available in patients acutely exposed to myelosuppressive doses of radiation.

Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to filgrastim in non-human primates at 10 mcg/kg dose of filgrastim, appears to be similar to that in humans at 5 mcg/kg. Simulations conducted using the population pharmacokinetic model indicates that the exposures to filgrastim at a filgrastim dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.

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

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end stage renal disease (n=4 per group), higher serum concentrations were observed in subjects with end-stage renal disease.

However, dose adjustment in patients with renal impairment is not necessary.

Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n = 12/group).

The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B).

Therefore, NYPOZI dose adjustment in patients with hepatic impairment is not necessary. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of filgrastim or of other filgrastim products.

While available data suggest that a small proportion of patients developed binding antibodies to filgrastim products, the nature and specificity of these antibodies has not been adequately studied.

In clinical studies using filgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333).

In these 11 patients, no evidence of a neutralizing response was observed using a cell based bioassay.

Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of filgrastim products is unknown.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Splenic Rupture Acute Respiratory Distress Syndrome Serious Allergic Reactions Sickle Cell.

Disorders Glomerulonephritis Alveolar Hemorrhage and Hemoptysis Capillary Leak Syndrome Myelodysplastic Syndrome Acute Myeloid Leukemia Thrombocytopenia Leukocytosis Cutaneous Vasculitis Aortitis Most common adverse reactions in patients: With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are pyrexia, pain, rash, cough, and dyspnea.

AML (≥ 2% difference in incidence) are pain, epistaxis and rash.

With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) is rash.

Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia and headache.

With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are pain, anemia, epistaxis, diarrhea, hypoesthesia and alopecia.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy The following adverse reaction data in Table are from three randomized, placebo-controlled studies in patients with: small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1) small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3).

A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m 2 (Study 1), 240 mcg/m 2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157).

The patients in these studies were median age 61 (range to 78) years and 64% were male.

The ethnicity was 95% Caucasian, 4% African American, and 1% Asian.

Table 2.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo) System Organ Class Preferred Term Filgrastim (N = 294) Placebo (N = 157) * Percent difference (Filgrastim – Placebo) was 4%.

Blood and lymphatic system disorders

Thrombocytopenia 38% 29% Gastrointestinal disorders Nausea 43% 32% General disorders and administration site conditions Pyrexia 48% 29% Chest pain 13% 6% Pain 12% 6% Fatigue 20% 10% Musculoskeletal and connective tissue disorders Back pain 15% 8% Arthralgia 9% 2% Bone pain 11% 6% Pain in extremity * 7% 3% Nervous system disorders Dizziness 14% 3% Respiratory, thoracic and mediastinal disorders Cough 14% 8% Dyspnea 13% 8% Skin and subcutaneous tissue disorders Rash 14% 5%.

Investigations Blood lactate dehydrogenase increased 6% 1% Blood alkaline phosphatase increased 6% 1% Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days to 7; and etoposide days to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide.

The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n = 257) or placebo (n = 261).

The median age was 54 (range to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment-controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6).

Patients receiving autologous bone marrow transplantation only were included in the analysis.

A total of 100 patients received either 30 mcg/kg/day as a 4-hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24-hour infusion (Study 6) filgrastim (n = 72), no treatment control or placebo (n = 28).

The median age was 30 (range to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection The adverse reaction data in Table are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis.

Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7.

The dosage of filgrastim ranged between to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion.

The median age was 39 (range to 67) years, and 48% were male.

Table 3.

Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients) System Organ Class Preferred Term Mobilization Phase (N = 166) Musculoskeletal and connective tissue disorders Bone pain 30% General disorders and administration site conditions Pyrexia 16%.

Investigations Blood alkaline phosphatase increased 11% Nervous system disorders Headache 10% Adverse Reactions in Patients with Severe Chronic Neutropenia The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4-month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment.

The median age was 12 years (range 7 months to 76 years) and 46% were male.

The dosage of filgrastim was determined by the category of neutropenia.

Initial dosage of filgrastim

Idiopathic neutropenia: 3.6 mcg/kg/day Cyclic neutropenia: 6 mcg/kg/day Congenital neutropenia: 6 mcg/kg/day divided 2 times per day The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of filgrastim products.

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 and splenomegaly (enlarged spleen) acute respiratory distress syndrome anaphylaxis sickle cell disorders glomerulonephritis alveolar hemorrhage and hemoptysis capillary leak syndrome leukocytosis cutaneous vasculitis Sweet's syndrome (acute febrile neutrophilic dermatosis) decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with filgrastim products myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy aortitis extramedullary hematopoiesis.

The maximum tolerated dose of filgrastim products has not been determined.

In filgrastim clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 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

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.

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.