Zarxio

filgrastim-sndz · Injection, Solution · Intravenous, Subcutaneous

Prescription (Rx) Leukocyte Growth Factor

Uses

1 INDICATIONS AND USAGE ZARXIO 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 ( 1.1 )
• Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) ( 1.2 )
• 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) ( 1.3 )
• Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis ( 1.4 )
• 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 ( 1.5 )
• Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) ( 1.6 ) 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy ZARXIO 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 Studies ( 14.1 )] . 1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy ZARXIO 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) [see Clinical Studies ( 14.2 )] . 1.3 Patients with Cancer Undergoing Bone Marrow Transplantation ZARXIO 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 [see Clinical Studies ( 14.3 )]. 1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy ZARXIO is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies ( 14.4 )] . 1.5 Patients with Severe Chronic Neutropenia ZARXIO 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 [see Clinical Studies ( 14.5 )] . 1.6 Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) ZARXIO is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies ( 14.6 )].

Dosage and administration

• Patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML o Recommended starting dose is 5 mcg/kg/day subcutaneous injection, short intravenous infusion (15 to 30 minutes), or continuous intravenous infusion. See Full Prescribing Information for recommended dosage adjustments and timing of administration ( 2.1 )
• Patients with cancer undergoing bone marrow transplantation o 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. See Full Prescribing Information for recommended dosage adjustments and timing of administration. ( 2.2 )
• Patients undergoing autologous peripheral blood progenitor cell collection and therapy o 10 mcg/kg/day subcutaneous injection ( 2.3 ) o Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis ( 2.3 )
• Patients with congenital neutropenia o Recommended starting dose is 6 mcg/kg subcutaneous injection twice daily ( 2.4 )
• Patients with cyclic or idiopathic neutropenia o Recommended starting dose is 5 mcg/kg subcutaneous injection daily ( 2.4 )
• Patients acutely exposed to myelosuppressive doses of radiation o 10 mcg/kg/day subcutaneous injection ( 2.5 )
• Direct administration of less than 0.3 mL (180 mcg) using ZARXIO prefilled syringe is not recommended due to potential for dosing errors ( 2.6 ) 2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of ZARXIO 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 ZARXIO 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 ZARXIO if the ANC increases beyond 10‚000/mm 3 [see Warnings and Precautions ( 5.10 )] . Administer ZARXIO at least 24 hours after cytotoxic chemotherapy. Do not administer ZARXIO within the 24-hour period prior to chemotherapy [see Warnings and Precautions ( 5.13 )] . A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of ZARXIO therapy. Therefore, to ensure a sustained therapeutic response‚ administer ZARXIO 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 ZARXIO 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 ZARXIO 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 ZARXIO at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Monitor CBCs and platelet counts frequently following marrow transplantation. During the period of neutrophil recovery‚ titrate the daily dosage of ZARXIO against the neutrophil response (see Table 1). Table 1. Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count ZARXIO Dosage Adjustment When ANC greater than 1,000/mm 3 for 3 consecutive days Reduce to 5 mcg/kg/day If ANC decreases to less than 1,000/mm 3 at any time during the 5 mcg/kg/day administration‚ increase ZARXIO to 10 mcg/kg/day‚ and then follow the above steps. Then, if ANC remains greater than 1,000/mm 3 for 3 more consecutive days Discontinue ZARXIO 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 ZARXIO for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer ZARXIO for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of ZARXIO administration and leukapheresis schedule have not been established‚ administration of filgrastim for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective [see Clinical Studies ( 14.4 )] . Monitor neutrophil counts after 4 days of ZARXIO‚ and discontinue ZARXIO 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 ZARXIO 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 ZARXIO 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).

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS ZARXIO is a clear, colorless to slightly yellowish solution available as: Vial:
• Injection: 300 mcg/mL in a single-dose vial
• Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial Prefilled Syringe:
• Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe
• Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe Vial
• Injection: 300 mcg/mL in a single-dose-vial ( 3 )
• Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose-vial ( 3 ) Prefilled Syringe
• Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe ( 3 )
• Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe ( 3 )

Contraindications

4 CONTRAINDICATIONS ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products [see Warnings and Precautions ( 5.3 )] . Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products. ( 4 )

Warnings and precautions

• Fatal splenic rupture : Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. ( 5.1 )
• Acute respiratory distress syndrome (ARDS) : Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS. ( 5.2 )
• Serious allergic reactions, including anaphylaxis : Permanently discontinue ZARXIO in patients with serious allergic reactions. ( 5.3 )
• Fatal sickle cell crises : Discontinue ZARXIO if sickle cell crisis occurs. ( 5.4 )
• Glomerulonephritis : Evaluate and consider dose-reduction or interruption of ZARXIO if causality is likely. ( 5.5 )
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) : Monitor patients with breast and lung cancer using ZARXIO in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.8 )
• Thrombocytopenia : Monitor platelet counts. ( 5.9 )
• Aortitis: Aortitis has been reported in patients receiving filgrastim products. Discontinue ZARXIO if aortitis is suspected. ( 5.15 ) 5.1 Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS. 5.3 Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions. ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products. 5.4 Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue ZARXIO if sickle cell crisis occurs. 5.5 Glomerulonephritis Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose-reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO. 5.6 Alveolar Hemorrhage and Hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim products. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication. 5.7 Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.8 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) Patients with Severe Chronic Neutropenia Confirm the diagnosis of SCN before initiating ZARXIO therapy. MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products 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. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim products administration in patients with abnormal cytogenetics or MDS are unknown. Monitor patients for signs and symptoms of MDS/AML in these settings. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered. Patients with Breast and Lung Cancer MDS and AML have been associated with the use of filgrastim products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings. 5.9 Thrombocytopenia Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts. 5.10 Leukocytosis Patients with Cancer Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm 3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm 3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy.

Side effects

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
• Splenic Rupture [see Warnings and Precautions ( 5.1 )]
• Acute Respiratory Distress Syndrome [see Warnings and Precautions ( 5.2 )]
• Serious Allergic Reactions [see Warnings and Precautions ( 5.3 )]
• Sickle Cell Disorders [see Warnings and Precautions ( 5.4 )]
• Glomerulonephritis [see Warnings and Precautions ( 5.5 )]
• Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions ( 5.6 )]
• Capillary Leak Syndrome [see Warnings and Precautions ( 5.7 )]
• Myelodysplastic Syndrome [see Warnings and Precautions ( 5.8 )]
• Acute Myeloid Leukemia [see Warnings and Precautions ( 5.8 )]
• Thrombocytopenia [see Warnings and Precautions ( 5.9 )]
• Leukocytosis [see Warnings and Precautions ( 5.10 )]
• Cutaneous Vasculitis [see Warnings and Precautions ( 5.11 )]
• Aortitis [see Warnings and Precautions ( 5.15 )] 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. ( 6.1 )
• With AML (≥ 2% difference in incidence) are pain, epistaxis and rash. ( 6.1 )
• With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) is rash. ( 6.1 )
• Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia and headache. ( 6.1 )
• With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are pain, anemia, epistaxis, diarrhea, hypoesthesia and alopecia. ( 6.1 ) *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of ZARXIO has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.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 2 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 29 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) 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 Percent difference (Filgrastim – Placebo) was 4%. 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 1 to 7; and etoposide days 1 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 16 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.

Use in specific populations

8.1 Pregnancy Risk Summary Available data from published studies, including several observational studies of pregnancy outcomes in women exposed to filgrastim products and those who were unexposed, have not established an association with filgrastim product use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Reports in the scientific literature have described transplacental passage of filgrastim in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). In animal reproduction studies, effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. No maternal or fetal effects were observed in pregnant rats at doses up to 58 times the human doses. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Data Human Data Several observational studies based on the Severe Chronic Neutropenia International Registry (SCNIR) described pregnancy outcomes in women with severe chronic neutropenia (SCN) who were exposed to filgrastim products during pregnancy and women with SCN who were unexposed. No major differences were seen between treated and untreated women with respect to pregnancy outcome (including miscarriage and preterm labor), newborn complications (including birth weight), and infections. Methodological limitations of these studies include small sample size and lack of generalizability due to the underlying maternal condition. Animal Data Effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day, which is approximately 58 times higher than the human dose of 10 mcg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day). 8.2 Lactation Risk Summary There is published literature documenting transfer of filgrastim into human milk. There are a few case reports describing the use of filgrastim in breastfeeding mothers with no adverse effects noted in the infants. There are no data on the effects of filgrastim products on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZARXIO and any potential adverse effects on the breastfed child from ZARXIO or from the underlying maternal condition. 8.4 Pediatric Use ZARXIO 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 using ZARXIO prefilled syringe is not recommended due to the potential for dosing errors. For direct administration of doses less than 0.3 mL (180 mcg) use ZARXIO single-dose vial. In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 to 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 ZARXIO have been established in pediatric patients with SCN [see Clinical Studies ( 14.5 )] . 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 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 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage ( 1.5 ), Dosage and Administration ( 2.6 ), and Clinical Studies ( 14.5 )] . 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.

Pregnancy

Pediatric use

8.4 Pediatric Use ZARXIO 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 using ZARXIO prefilled syringe is not recommended due to the potential for dosing errors. For direct administration of doses less than 0.3 mL (180 mcg) use ZARXIO single-dose vial. In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 to 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 ZARXIO have been established in pediatric patients with SCN [see Clinical Studies ( 14.5 )] . 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 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 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage ( 1.5 ), Dosage and Administration ( 2.6 ), and Clinical Studies ( 14.5 )] . 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 product administration is unknown [see Warnings and Precautions ( 5.8 ) and Adverse Reactions ( 6 )] . The use of ZARXIO 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 [see Dosage and Administration ( 2.1 to 2.4 ) and Clinical Studies ( 14.6 )] .

Geriatric use

8.5 Geriatric Use 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 65 and older to determine whether elderly subjects respond differently from younger subjects.

Overdosage

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.

Description

Filgrastim-sndz is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. Filgrastim-sndz is produced by Escherichia coli ( E coli ) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Filgrastim-sndz 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 filgrastim-sndz is produced in E coli ‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell. ZARXIO (filgrastim-sndz) injection is a sterile‚ clear‚ colorless to slightly yellowish‚ preservative-free liquid containing filgrastim-sndz at a specific activity of 1 x 10 8 U/mg (as measured by a proliferation assay). The product is available in single-dose vials and single-dose prefilled syringes for subcutaneous or intravenous use. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim-sndz. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-sndz. The ZARXIO drug product has a pH of 4.4. See Table 4 below for product composition of each single-dose vial and prefilled syringe. Table 4. Product Composition 300 mcg/mL Vial 480 mcg/1.6 mL Vial 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe Filgrastim-sndz 300 mcg 480 mcg 300 mcg 480 mcg Glutamic Acid 1.471 mg 2.354 mg 0.736 mg 1.178 mg Polysorbate 80 0.04 mg 0.064 mg 0.02 mg 0.032 mg Sorbitol 50 mg 80 mg 25 mg 40 mg Sodium hydroxide q.s. q.s. q.s. q.s. Water for Injection USP q.s. ad* ad 1 mL ad 1.6 mL ad 0.5 mL ad 0.8 mL *q.s.: quantity sufficient to make

Mechanism of action

12.1 Mechanism of Action Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation. Endogenous G-CSF is a lineage-specific colony-stimulating factor 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.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ZARXIO injection is a clear, colorless to slightly yellowish, preservative-free solution supplied as: Vial: The vial is supplied in a carton containing one single-dose vial providing:
• 300 mcg/mL of filgrastim-sndz solution (NDC 61314-246-71)
• 480 mcg/1.6 mL (300 mcg/mL) of filgrastim-sndz solution (NDC 61314-266-73) The vial stopper is not made with natural rubber latex. Prefilled syringe (BD UltraSafe Passive ® Needle Guard): Single-dose prefilled syringe with a 29 gauge, ½ inch needle and with BD UltraSafe Passive ® Needle Guard, containing 300 mcg/0.5 mL of filgrastim-sndz solution.
• Pack of 1 prefilled syringe (NDC 61314-318-63)
• Pack of 10 (multipack) prefilled syringes (NDC 61314-318-69) Single-dose prefilled syringe with a 29 gauge, ½ inch needle and with BD UltraSafe Passive ® Needle Guard, containing 480 mcg/0.8 mL of filgrastim-sndz solution.
• Pack of 1 prefilled syringe (NDC 61314-326-63)
• Pack of 10 (multipack) prefilled syringes (NDC 61314-326-69) The prefilled syringe with safety guard is not made with natural rubber latex. Storage: Store ZARXIO in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original pack to protect from light. Do not leave ZARXIO in direct sunlight. Avoid shaking. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard ZARXIO if frozen more than once.

Patient information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of ZARXIO vial and prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire prefilled syringe. 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 ZARXIO or whether the patient would benefit from a different ZARXIO presentation. Advise patients of the following risks and potential risks with ZARXIO:
• Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their physician immediately [see Warnings and Precautions ( 5.1 )] .
• Dyspnea, with or without fever, progressing to Acute Respiratory Distress Syndrome, may occur. Advise patients to report dyspnea to their physician immediately [see Warnings and Precautions ( 5.2 )] .
• Serious allergic reactions may occur, which may be signaled by rash‚ facial edema‚ wheezing‚ dyspnea‚ hypotension‚ or tachycardia. Advise patients to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions ( 5.3 )] .
• In patients with sickle cell disease, sickle cell crisis and death have occurred. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of human granulocyte colony-stimulating factors [see Warnings and Precautions ( 5.4 )] .
• Glomerulonephritis may occur. Symptoms include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their physician immediately [see Warnings and Precautions ( 5.5 )] .
• There may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with congenital neutropenia who receive filgrastim products and in patients with breast and lung cancer who receive filgrastim products in conjunction with chemotherapy and/or radiation therapy. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Advise patients to report to their physician signs and symptoms of MDS/AML [see Warnings and Precautions ( 5.8 )].
• Cutaneous vasculitis may occur, which may be signaled by purpura or erythema. Advise patients to report signs or symptoms of vasculitis to their physician immediately [see Warnings and Precautions ( 5.11 )] .
• Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately [see Warnings and Precautions ( 5.15 )] . Advise patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) that efficacy studies of filgrastim products for this indication could not be conducted in humans for ethical and feasibility reasons and that, therefore, approval of this use was based on efficacy studies conducted in animals [see Clinical Studies ( 14.6 )]. Instruct patients who self-administer ZARXIO using the prefilled syringe or single-dose vial of the:
• Importance of following the applicable Instructions for Use.
• Dangers of reusing needles, syringes or unused portions of single-dose vials.
• Importance of following local requirements for proper disposal of used syringes, needles, and unused vials.
• Importance of informing the healthcare provider if difficulty occurs when measuring or administering partial contents of the ZARXIO prefilled syringe. If difficulties occur, use of the ZARXIO vial may be considered.
• Difference in product concentration of the ZARXIO prefilled syringe in comparison to the ZARXIO vial. When switching patients from the ZARXIO prefilled syringe to the ZARXIO vial, or vice versa, ensure that patients understand the correct volume to be administered since the concentration of ZARXIO differs between the prefilled syringe and the vial. ZARXIO ® (filgrastim-sndz) UltraSafe and UltraSafe Passive are registered trademarks of Safety Syringes, Inc. BD is a registered trademark of Becton, Dickinson and Company. Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003

Label text from the FDA structured product label by Sandoz Inc. (revised Aug 29, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Filgrastim in 2 products

Zarxio NDC products (2)

NDC	Strength & form	Labeler	Type
61314-318	Filgrastim 300 ug/.5mL Injection, Solution	Sandoz Inc.	BLA
61314-326	Filgrastim 480 ug/.8mL Injection, Solution	Sandoz Inc.	BLA