RELEUKO

1 INDICATIONS AND USAGE RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO 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) RELEUKO is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.6) ] .

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 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) using RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO if the ANC increases beyond 10‚000/mm 3 [see Warnings and Precautions ( 5.10 )]. Administer RELEUKO at least 24 hours after cytotoxic chemotherapy. Do not administer RELEUKO 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 RELEUKO therapy. Therefore, to ensure a sustained therapeutic response administer RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO against the neutrophil response (see Table 1). Table 1. Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count RELEUKO Dosage Adjustment 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 RELEUKO Then, if ANC decreases to less than 1,000/mm 3 Resume at 5 mcg/kg/day a If ANC decreases to less than 1,000/mm 3 at any time during the 5 mcg/kg/day administration‚ increase RELEUKO to 10 mcg/kg/day‚ and then follow the above steps. 2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell…

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 RELEUKO in patients with ARDS. ( 5.2 ) Serious allergic reactions, including anaphylaxis: Permanently discontinue RELEUKO in patients with serious allergic reactions. ( 5.3 ) Fatal sickle cell crises: Discontinue RELEUKO if sickle cell crisis occurs. ( 5.4 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of RELEUKO if causality is likely. ( 5.5 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using RELEUKO 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 RELEUKO 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 RELEUKO 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 RELEUKO in patients with serious allergic reactions. RELEUKO 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 RELEUKO 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 RELEUKO. 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 RELEUKO 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 Conf…

4 CONTRAINDICATIONS RELEUKO 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 )

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 to 4% and 15 to 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).

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 Precautious ( 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: ( 6.1 ) With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are pyrexia, pain, rash, cough, and dyspnea. With 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. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835 5472, option 3 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. * 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 RELEUKO ® 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. 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 4…