FDA label 063f36a7-6f99-40fa-af02-8a5183c51e99

5 WARNINGS AND PRECAUTIONS 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): Monitor for and manage immediately. Discontinue GRANIX if suspected ( 5.2 ) Serious Allergic Reactions Including Anaphylaxis: Permanently discontinue GRANIX in patients with serious allergic reactions ( 5.3 ) Sickle Cell Disorders: Severe and sometimes fatal crisis can occur. Discontinue GRANIX if suspected ( 5.4 ) Glomerulonephritis: Evaluate and consider dose reduction or interruption of GRANIX if causality is likely ( 5.5 ) Capillary Leak Syndrome: Monitor if symptoms develop and administer standard symptomatic treatment ( 5.6 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using GRANIX in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.8 ) 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of filgrastim products. Evaluate patients who report upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Discontinue GRANIX if splenic rupture is suspected or confirmed. 5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving GRANIX. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue GRANIX if sickle cell crisis occurs. 5.5 Glomerulonephritis Glomerulonephritis can occur in patients receiving filgrastim products. The diagnoses were based on azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of the filgrastim product. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose reduction or interruption of GRANIX. 5.6 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving 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. 5.7 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G‑CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 5.8 Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Breast and Lung Cancer Patients with Severe Chronic Neutropenia Confirm the diagnosis of SCN before initiating GRANIX 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 GRANIX 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 GRANIX on the development of abnormal cytogenetics and the effect of continued GRANIX 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 GRANIX should be carefully considered. Patients with Breast and Lung Cancer MDS and AML have been associated with the use of GRANIX 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 Leukocytosis White blood cell counts of 100‚000/mm 3 or greater were observed in approximately 2% of patients receiving filgrastim products at dosages above 5 mcg/kg/day. In patients with cancer receiving GRANIX as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that GRANIX 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. Dosages of GRANIX that increase the ANC beyond 10‚000/mm 3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of filgrastim products therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days. 5.10 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of filgrastim products, including GRANIX, given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use GRANIX in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration ( 2.2 )] . The safety and efficacy of GRANIX have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of GRANIX with chemotherapy and radiation therapy. 5.11 Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. Consider this when interpreting bone-imaging results. 5.12 Aortitis Aortitis has been reported in patients receiving another filgrastim product. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c‑reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue GRANIX if aortitis is suspected. 5.13 Alveolar Hemorrhage Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell (PBPC) collection treated with another filgrastim product. Hemoptysis resolved with discontinuation of filgrastim. The use of GRANIX for PBPC mobilization in healthy donors is not an approved indication.

6 ADVERSE REACTIONS The following potential 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) ] Capillary Leak Syndrome [see Warnings and Precautions (5.6) ] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.7) ] Myelodysplastic Syndrome and Acute Myeloid Leukemia [see Warnings and Precautions (5.8) ] Leukocytosis [ see Warnings and Precautions ( 5.9 ) ] Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended [see Warnings and Precautions ( 5.10 ) ] Aortitis [see Warnings and Precautions ( 5.12 ) ] Alveolar Hemorrhage [see Warnings and Precautions (5.13) ] Most common adverse reaction (≥1%) to GRANIX is bone pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1 ‑ 866-832-8537 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adult Patients GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-U.S.-approved filgrastim product were used as controls. Both GRANIX and the non-U.S.-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 10 6 /L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-U.S.-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 10 6 /L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of filgrastim products include myalgia, headache, vomiting, cutaneous vasculitis and thrombocytopenia. Adverse Reactions in Pediatric Patients GRANIX clinical trials safety data in pediatric patients are based upon the results of one single-arm clinical trial in 50 pediatric patients who received myelosuppressive chemotherapy for treatment of solid tumors without marrow involvement [see Use in Special Populations ( 8.4 )] . In this study, GRANIX was administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy. The most common (>5%) adverse reactions included thrombocytopenia (34%), pyrexia (8%), pain in extremity (6%), headache (6%) and diarrhea (6%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of GRANIX. 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. Sweet’s syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue