RELEUKO- filgrastim_injection, solution

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. In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ filgrastim administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 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. 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 4 and 49 ng/mL‚ respectively‚ within 2 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 rates of filgrastim were approximately 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. Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 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 are 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. Pediatric Patients 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 [see Use in Specific Populations ( 8. 4 Renal Impairment 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. Hepatic Impairment 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, RELEUKO dose adjustment for patients with hepatic impairment is not necessary. 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 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.

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 Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML). 2 Reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e. ‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT). 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. , fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia. 5 Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) ( 1. 6 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 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 RELEUKO is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e. ‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies ( 14. 3 RELEUKO is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14. 4) RELEUKO is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e. ‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia [see Clinical Studies (14. 5) RELEUKO is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.

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 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. 6 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 3 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). 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 Reduce to 5 mcg/kg/day a Then, if ANC remains greater than 1,000/mm 3 Discontinue RELEUKO Then, if ANC decreases to less than 1,000/mm 3 Resume at 5 mcg/kg/day a 3 The recommended dosage of RELEUKO for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer RELEUKO for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of RELEUKO 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) 3 Prior to starting RELEUKO 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 RELEUKO 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 Monitor CBCs for Dosage Adjustments The recommended dose of RELEUKO is 10 mcg/kg as a single daily subcutaneous injection for patients exposed to myelosuppressive doses of radiation. Administer RELEUKO 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. , 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 3 Continue administration of RELEUKO until the ANC remains greater than 1,000/mm 3 3 RELEUKO is supplied in single-dose vials (for subcutaneous use or intravenous infusion) and single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths (3) Discard unused portion of RELEUKO in vials or prefilled syringes; do not re-enter the vial. Do not save unused drug for later administration. Subcutaneous Injection Inject RELEUKO subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer RELEUKO, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use [see Patient Counseling Information (17) Patient self-administration and administration by a caregiver may benefit from training by a healthcare professional. Training by the healthcare provider should aim to demonstrate to those patients and caregivers how to measure the dose of RELEUKO, and the focus should be on ensuring that a patient or caregiver can successfully perform all the steps in the Instructions for Use for the vial or 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 RELEUKO or whether the patient would benefit from a different RELEUKO presentation. If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the RELEUKO prefilled syringe, use of the RELEUKO vial may be considered. If the patient or caregiver misses a dose of RELEUKO, instruct them to contact their healthcare provider. Administration Instructions for the Prefilled Syringe The RELUEKO prefilled syringe with BD UltraSafe Plustrademark 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. The visibility of these markings is necessary to accurately measure doses of RELEUKO less than 0. 3 mL (180 mcg) for direct administration. 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. For direct administration of doses less than 0. 3 mL (180 mcg) use RELUEKO single-dose vial. Administration Instructions for Dilution (Vial Only) If required for intravenous administration‚ RELEUKO (vial only) may be diluted in 5% Dextrose Injection, USP from a concentration of 300 mcg/mL to 5 mcg/mL (do not dilute to a final concentration less than 5 mcg/mL). RELEUKO diluted to concentrations from 5 mcg/mL 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 Injection, USP or 5% Dextrose plus Albumin (Human)‚ RELEUKO is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes. Do not dilute with saline at any time because the product may precipitate. Diluted RELEUKO solution can be stored at room temperature for up to 4 hours. This 4-hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

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. 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 registered 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 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 2 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 Placebo 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 en dash 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 6% 1% Blood alkaline phosphatase 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 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 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 3 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 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male. 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. 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) [see Warnings and Precautions ( 5. 2 anaphylaxis [see Warnings and Precautions ( 5. 7 leukocytosis [see Warnings and Precautions ( 5. 11 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 [see Warnings and Precautions ( 5. 8 aortitis [see Warnings and Precautions ( 5. 15 extramedullary hematopoiesis.

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.

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 (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. 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 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). Risk Summary RELEUKO prefilled syringe with BD UltraSafe Plustrademark 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 RELEUKO 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 RELEUKO single-dose vial. In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2. 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 RELEUKO have been established in pediatric patients with SCN [see Clinical Studies ( 14. 5 [see Indications and Usage ( 1. 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 6 The use of RELEUKO 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. 6 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. , 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.

RELEUKO registered Single-Dose Vial Important Read the Patient Information for important information you need to know about RELEUKO before using these Instructions for Use. Before you use a RELEUKO vial, read this important information: Storing your RELEUKO vial Store the vial in the refrigerator between 36˚F to 46˚F (2˚C to 8˚C). Do not Keep the vial in the original pack to protect from light or physical damage. Take the vial out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. Throw away (dispose of) any vial that has been left at room temperature for longer than 24 hours. After you inject your dose, throw away (dispose of) any unused RELEUKO left in the vial. Do not Keep RELEUKO and all medicines out of the reach of children. Using your vial It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider. Make sure the name RELEUKO appears on the pack and vial label. Only use the vial 1 time. Discard (throw away) the vial with any remaining RELEUKO liquid. Do not Do not Do not Call your healthcare provider if you have any questions. Step 1: Prepare A On a clean, well-lit surface, place the vial at room temperature for 30 Do not Do not Do not Use the vial only 1 time. B Make sure the medicine in the vial is clear and colorless. Do not The medicine is cloudy or discolored or contains flakes or particles. The expiration date printed on the label has passed. In all cases, use a new vial and call your healthcare provider. C Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the: 1 Vial 1 Disposable syringe and needle 2 alcohol wipes 1 Cotton ball or gauze pad 1 Adhesive bandage Sharps disposal container Only use the disposable syringes and needles that your healthcare provider prescribes. Only use the syringes and needles 1 time. Discard (throw away) any used syringes and needles. See Step 5 Finish, for instructions about how to properly dispose of used syringes and needles. You should only use a syringe that is marked in tenths of milliliters (mL). Your healthcare provider will show you how to measure the correct dose of RELEUKO. This dose will be measured in milliliters (mL). Step 2: Get Ready D E F Pull back on the plunger and draw air into the syringe that is the same amount (mL) as the dose of RELEUKO that your healthcare provider prescribed. Important: G H I J K L M Step 3: Select and Prepare the Injection Site N You can use: Thigh Stomach area (abdomen), except for a 2 Upper outer area of your buttocks (only if someone else is giving you the injection) Outer area of upper arm (only if someone else is giving you the injection) Clean your injection site with a clean alcohol wipe. Let your skin dry. Do not If you want to use the same injection site, make sure it is not the same spot on the injection site area you used for a previous injection. Do not Step 4: Subcutaneous (under the skin) injection O P Important: Q R When done, gently pull the needle out of the injection site at the same 45 to 90 degree angle used to insert it. Step 5: Finish S Put your used syringes, needles, and vials in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) If you do not have an FDA-cleared sharps disposal container, you may use a household container that: is made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, is upright and stable during use, is leak-resistant, and is properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www. gov/safesharpsdisposal. Do not Do not Important: T If there is blood, press a cotton ball or gauze pad on your injection site. Do not This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by: Kashiv BioSciences, LLC Piscataway, NJ 08854 US License No. 2131 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 04-2022-01 image image image image image image image image image image image.

NONCLINICAL TOXICOLOGY
The carcinogenic potential of filgrastim products has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats at doses up to 500 mcg/kg. Filgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a nonclinical toxicology program, which included studies up to 1-year duration. In the repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of filgrastim (i. ‚ dose-dependent increases in white blood cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bone marrow). Histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis, and dose-related increases in spleen weight were seen in all species. These changes all reversed after discontinuation of treatment.
CLINICAL STUDIES
The safety and efficacy of filgrastim to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs were established in a randomized‚ double-blind‚ placebo-controlled trial conducted in patients with small cell lung cancer (Study 1). In Study 1, patients received up to 6 cycles of intravenous chemotherapy including intravenous cyclophosphamide and doxorubicin on day 1; and etoposide on days 1, 2, and 3 of 21 day cycles. Patients were randomized to receive filgrastim (n = 99) at a dose of 230 mcg/m 2 The main efficacy endpoint was the incidence of febrile neutropenia. Febrile neutropenia was defined as an ANC < 1,000/mm 3 3 The safety and efficacy of filgrastim to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, double-blind‚ placebo-controlled‚ multi-center trial in patients with newly diagnosed, de novo In Study 4 the initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous filgrastim (n = 259) at a dose of 5 mcg/kg/day or placebo (n = 262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC >= 1,000/mm 3 3 3 3 The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm 3 There were no statistically significant differences between the filgrastim and the placebo groups in complete remission rate (69% - filgrastim, 68% - placebo), median time to progression of all randomized patients (165 days - filgrastim, 186 days - placebo), or median overall survival (380 days en dash filgrastim, 425 days en dash placebo). The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of patients with lymphoma (Study 6 and Study 9). The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo-controlled trial (Study 10). In Study 6, patients with Hodgkin’s disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”), and patients with non-Hodgkin’s lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). There were 54 patients randomized 1:1:1 to control, filgrastim 10 mcg/kg/day, and filgrastim 30 mcg/kg/day as a 24-hour continuous infusion starting 24 hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin’s disease and 31% non-Hodgkin’s lymphoma. The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm 3 3 In Study 9, patients with Hodgkin’s disease and non-Hodgkin’s lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”). There were 43 evaluable patients randomized to continuous subcutaneous infusion filgrastim 10 mcg/kg/day (n = 19), filgrastim 30 mcg/kg/day (n = 10) and no treatment (n = 14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin’s disease and 72% non-Hodgkin’s lymphoma. The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm 3 In Study 10, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive filgrastim 300 mcg/m 2 3 The safety and efficacy of filgrastim to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using filgrastim -mobilized autologous peripheral blood progenitor cells to autologous bone marrow (Study 11). Patients in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 7 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dose of filgrastim ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion. Engraftment was evaluated in 64 patients who underwent transplantation using filgrastim -mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count >= 20‚000/mm3 by day 28. In clinical trials of filgrastim for the mobilization of hematopoietic progenitor cells‚ filgrastim was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (>= 500/mm3) was reached. The rate of engraftment of these cells in the absence of filgrastim post transplantation has not been studied. Study 11 was a randomized, unblinded study of patients with Hodgkin’s disease or non-Hodgkin’s lymphoma undergoing myeloablative chemotherapy‚ 27 patients received filgrastim-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. Thepreparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). Patients received daily filgrastim 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin’s disease and 43% non-Hodgkin’s lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to filgrastim -mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs 10 days). The safety and efficacy of filgrastim to reduce the incidence and duration of sequelae of neutropenia (that is fever‚ infections, oropharyngeal ulcers) in symptomatic adult and pediatric patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia was established in a randomized controlled trial conducted in patients with severe neutropenia (Study 7). Patients eligible for Study 7 had a history of severe chronic neutropenia documented with an ANC < 500/mm 3 3 Filgrastim was administered subcutaneously. The dose of filgrastim was determined by the category of neutropenia. 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 dose was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. The main efficacy endpoint was response to filgrastim treatment. ANC response from baseline (< 500/mm 3 Complete response: median ANC > 1,500/mm 3 Partial response: median ANC >= 500/mm 3 3 No response: median ANC < 500/mm 3 There were 112 of 123 patients who demonstrated a complete or partial response to filgrastim treatment. Additional efficacy endpoints included a comparison between patients randomized to 4 months of observation and patients receiving filgrastim of the following parameters: incidence of infection incidence of fever duration of fever incidence, duration, and severity of oropharyngeal ulcers number of days of antibiotic use The incidence for each of these 5 clinical parameters was lower in the filgrastim arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. An analysis of variance showed no significant interaction between treatment and diagnosis‚ suggesting that efficacy did not differ substantially in the different diseases. Although filgrastim substantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚ cycling persisted but the period of neutropenia was shortened to 1 day. Efficacy studies of filgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of filgrastim for other approved indications [see Dosage and Administration ( 2. 4 Because of the uncertainty associated with extrapolating animal efficacy data to humans, the selection of human dose for RELEUKO is aimed at providing exposures to filgrastim that exceed those observed in animal efficacy studies. The 10 mcg/kg daily dose is selected for humans exposed to myelosuppressive doses of radiation because the exposure associated with such a dose is expected to exceed the exposure associated with a 10 mcg/kg dose in non-human primates [see Clinical Pharmacology ( 12. 3 The efficacy of filgrastim was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. The planned sample size was 62 animals, but the study was stopped at the interim analysis with 46 animals because efficacy was established. Rhesus macaques were randomized to a control (n = 22) or treated (n = 24) group. Animals were exposed to total body irradiation of 7. 15 Gy delivered at 0. 03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Starting on day 1 after irradiation, animals received daily subcutaneous injections of placebo (5% dextrose in water) or filgrastim (10 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC >= 1,000/mm 3 3 3 Filgrastim significantly (at 0. 023 level of significance) reduced 60-day mortality in the irradiated non-human primates: 21% mortality (5/24) in the filgrastim group compared to 59% mortality (13/22) in the control group.
PATIENT INFORMATION
RELEUKO registered (filgrastim-ayow) What is RELEUKO? Acute Radiation Syndrome: The effectiveness of filgrastim for this use was only studied in animals, because it could not be studied in people. Do not take RELEUKO Before you take RELEUKO, tell your healthcare provider about all of your medical conditions, including if you: have a sickle cell disorder. have kidney problems. are receiving radiation therapy. are pregnant or plan to become pregnant. It is not known if RELEUKO will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if RELEUKO passes into your breast milk. Tell your healthcare provider about all the medicines you take, How will I receive RELEUKO? RELEUKO injections can be given by a healthcare provider by intravenous (IV) infusion or under your skin (subcutaneous injection). Your healthcare provider may decide subcutaneous injections can be given at home by you or your caregiver. If RELEUKO is given at home, see the detailed “Instructions for Use” that comes with your RELEUKO for information on how to prepare and inject a dose of RELEUKO. You and your caregiver should be shown how to prepare and inject RELEUKO before you use it, by your healthcare provider. Your healthcare provider will tell you how much RELEUKO to inject and when to inject it. Do not change your dose or stop RELEUKO unless your healthcare provider tells you to. You should not inject a dose of RELEUKO less than 0.3 mL (180 mcg) from a RELEUKO prefilled syringe. A dose less than 0.3 mL cannot be accurately measured using the RELEUKO prefilled syringe. If you are receiving RELEUKO because you are also receiving chemotherapy, your dose of RELEUKO should be injected at least 24 hours before 24 hours after If you are receiving RELEUKO because you have been suddenly (acutely) exposed to an amount of radiation that can affect your bone marrow (Acute Radiation Syndrome), you will need to have blood tests about every 3 days during treatment with RELEUKO to check your white blood cell count. If you miss a dose of RELEUKO, talk to your healthcare provider about when you should give your next dose. What are the possible side effects of RELEUKO? RELEUKO may cause serious side effects, including: Spleen rupture A serious lung problem called acute respiratory distress syndrome (ARDS). Serious allergic reactions. Sickle cell crises. Kidney injury (glomerulonephritis) swelling of your face or ankles blood in your urine or dark colored urine you urinate less than usual Capillary leak syndrome. swelling or puffiness and are urinating less than usual trouble breathing swelling of your stomach area (abdomen) and feeling of fullness dizziness or feeling faint a general feeling of tiredness Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) RELEUKO may increase the risk of developing a precancerous condition called MDS or a type of blood cancer called AML in people who were born with low white blood cell counts (congenital neutropenia). If you have breast cancer or lung cancer, when RELEUKO is used with chemotherapy and radiation therapy, or with radiation therapy only, you may have an increased risk of developing MDS or AML. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Call your healthcare provider if you develop any of these symptoms during treatment with RELEUKO. Decreased platelet count (thrombocytopenia). Increased white blood cell count (leukocytosis). Inflammation of your blood vessels (cutaneous vasculitis). Inflammation of the aorta (aortitis). Patients with cancer receiving chemotherapy: fever, pain, rash, cough, and shortness of breath Patients with acute myeloid leukemia receiving chemotherapy: pain, nose bleed, and rash Patients with cancer receiving chemotherapy followed by bone marrow transplant: rash Patients who are having their own blood cells collected: bone pain, fever, and headache Patients with severe chronic neutropenia: pain, decreased red blood cells, nose bleed, diarrhea, reduced sensation, and hair loss How should I store RELEUKO? Store RELEUKO in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not Keep RELEUKO in the original pack to protect from light or physical damage. Do not leave RELEUKO in direct sunlight. Do not Take RELEUKO out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. Throw away (dispose of) any RELEUKO that has been left at room temperature for longer than 24 hours. After you inject your dose, throw away (dispose of) any unused RELEUKO left in the vials or prefilled syringes. Do not Keep RELEUKO and all medicines out of the reach of children. General information about the safe and effective use of RELEUKO. What are the ingredients in RELEUKO? Active ingredient: Inactive ingredients: Kashiv BioSciences, LLC Amneal Pharmaceuticals LLC This Patient Information has been approved by the U.S. Food and Drug Administration . Rev. 04-2025-03

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