Filgrastim

1 INDICATIONS AND USAGE NYPOZI 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 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 [see Clinical Studies (14.1) ]. 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) [see Clinical Studies (14.2) ]. 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 [see Clinical Studies (14.3) ]. 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 [see Clinical Studies (14.4) ]. 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 [see Clinical Studies (14.5) ]. 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 [see Clinical Studies (14.6) ].

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.

2 DOSAGE AND ADMINISTRATION 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. See Full Prescribing Information for recommended dosage adjustments and timing of administration ( 2.1 ) Patients with cancer undergoing bone marrow transplantation: 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 10 mcg/kg/day subcutaneous injection ( 2.3 ) Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis ( 2.3 ) Patients with congenital neutropenia Recommended starting dose is 6 mcg/kg subcutaneous injection twice daily ( 2.4 ) Patients with cyclic or idiopathic neutropenia Recommended starting dose is 5 mcg/kg subcutaneous injection daily ( 2.4 ) Patients acutely exposed to myelosuppressive doses of radiation 10 mcg/kg/day subcutaneous injection ( 2.5 ) Direct administration of less than 0.3 mL (180 mcg) 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 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 [see Warnings and Precautions (5.10) ]. Administer NYPOZI at least 24 hours after cytotoxic chemotherapy. Do not administer NYPOZI 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 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. Monitor CBCs and platelet counts frequently following marrow transplantation. During the period of neutrophil recovery‚ titrate the daily dosage of NYPOZI against the neutrophil response (see Table 1). 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 3 at any time during the 5 mcg/kg/day administration‚ increase NYPOZI to 10 mcg/kg/day‚ and then follow the above steps. When ANC greater than 1,000/mm 3 for 3 consecutive days Reduce to 5 mcg/kg/day a Then, if ANC remains greater than 1,000/ mm 3 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 do

6 ADVERSE REACTIONS 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Tanvex BioPharma USA at 1-833-826-8398 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) * 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 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 NYPOZI in patients with ARDS. ( 5.2 ) Serious allergic reactions, including anaphylaxis: Permanently discontinue NYPOZI in patients with serious allergic reactions. ( 5.3 ) Fatal sickle cell crises: Discontinue NYPOZI if sickle cell crisis occurs. ( 5.4 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NYPOZI if causality is likely. ( 5.5 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using NYPOZI in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.8 ) Thrombocytopenia: Monitor platelet counts. ( 5.9 ) 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 NYPOZI 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 NYPOZI in patients with serious allergic reactions. NYPOZI 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 NYPOZI 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 NYPOZI. 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 NYPOZI 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 NYPOZI therapy. MDS and AML have been reported to occur in the natural history of congenital neutrope

4 CONTRAINDICATIONS NYPOZI 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 )

10 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.