Neulasta

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, lung infiltrates, or respiratory distress. Discontinue Neulasta in patients with ARDS. ( 5.2 ) Serious hypersensitivity reactions, including anaphylaxis: Permanently discontinue Neulasta in patients with serious hypersensitivity reactions. ( 5.3 ) The on-body injector for Neulasta uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. ( 5.4 ) Fatal sickle cell crises: Discontinue Neulasta if sickle cell crisis occurs. ( 5.5 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of Neulasta if causality is likely. ( 5.6 ) Thrombocytopenia: Monitor platelet counts. ( 5.8 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Neulasta in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.11 ) Potential device failures: Instruct patients to notify their healthcare provider if they suspect the on-body injector may not have performed as intended. ( 5.12 ) Large and Medium Vessel Arteritis: Discontinue Neulasta if arteritis is suspected. ( 5.13 ) 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. 5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. 5.3 Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Hypersensitivity reactions, including anaphylaxis, can recur within days after the discontinuation of initial therapies to manage the reaction. Permanently discontinue Neulasta in patients with serious hypersensitivity reactions. Neulasta is contraindicated in patients with a history of a serious hypersensitivity reaction to pegfilgrastim or filgrastim. 5.4 Allergies to Acrylics The on-body injector (OBI) for Neulasta uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. 5.5 Use in Patients with Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Discontinue Neulasta if sickle cell crisis occurs. 5.6 Glomerulonephritis Glomerulonephritis has occurred in patients receiving Neulasta. 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 Neulasta. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Neulasta. 5.7 Leukocytosis White blood cell (WBC) counts of 100 × 10 9 /L or greater have been observed in patients receiving Neulasta. Monitoring of complete blood count (CBC) during Neulasta therapy is recommended. 5.8 Thrombocytopenia Neulasta can cause thrombocytopenia. Monitor platelet counts during Neulasta therapy. 5.9 Capillary Leak Syndrome Capillary leak syndrome has been reported after G-CSF administration, including Neulasta, 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. 5.10 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that Neulasta acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. 5.11 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer MDS and AML have been associated with the use of Neulasta 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. 5.12 Potential Device Failures Missed or partial doses have been reported in patients receiving Neulasta via the on-body injector (OBI) due to the device not performing as intended. In the event of a missed or partial dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered. Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of Neulasta if they suspect that the device may not have performed as intended. 5.13 Large and Medium Vessel Arteritis Serious large and medium vessel arteritis, including aortitis, has been reported in patients receiving Neulasta. 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, headache, neck pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider arteritis in patients who develop these signs and symptoms without known etiology. Consider appropriate clinical management and discontinue Neulasta as needed if arteritis is suspected. 5.14 Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy, including Neulasta, has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

6 ADVERSE REACTIONS The following clinically significant 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 Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Allergies to Acrylics [see Warnings and Precautions (5.4) ] Use in Patients with Sickle Cell Disorders [see Warnings and Precautions (5.5) ] Glomerulonephritis [see Warnings and Precautions (5.6) ] Leukocytosis [see Warnings and Precautions (5.7) ] Thrombocytopenia [see Warnings and Precautions (5.8) ] Capillary Leak Syndrome [see Warnings and Precautions (5.9) ] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.10) ] Myelodysplastic syndrome [see Warnings and Precautions (5.11) ] Acute myeloid leukemia [see Warnings and Precautions (5.11) ] Large and Medium Vessel Arteritis [see Warnings and Precautions (5.13) ] Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) 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. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 2 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American, or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity. Table 2. Adverse Reactions with ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) Neulasta 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 × 10 9 /L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. 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 (5.1) ] Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2) ] Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3) ] Sickle cell crisis [see Warnings and Precautions (5.5) ] Glomerulonephritis [see Warnings and Precautions (5.6) ] Leukocytosis [see Warnings and Precautions (5.7) ] Thrombocytopenia [see Warnings and Precautions (5.8) ] Capillary Leak Syndrome [see Warnings and Precautions (5.9) ] Injection site reactions Sweet's syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis Application site reactions (including events such as application site hemorrhage, application site pain, application site discomfort, application site bruise, and application site erythema) have been reported with the use of the on-body injector for Neulasta. Contact dermatitis and local skin reactions such as rash, pruritus, and urticaria have been reported with the use of the on-body injector for Neulasta, possibly indicating a hypersensitivity reaction to the adhesive. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.11) ] Large and medium vessel arteritis, including aortitis [see Warnings and Precautions (5.13) ] Alveolar hemorrhage

<table width="90%" ID="Table2"><caption>Table 2. Adverse Reactions with &#x2265; 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3</caption><col width="55%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule Toprule Botrule" align="center" valign="middle">Body System Adverse Reaction</th><th styleCode="Lrule Rrule Toprule Botrule" valign="bottom">Placebo (N = 461)</th><th styleCode="Lrule Rrule Toprule Botrule" valign="bottom">Neulasta 6 mg SC on Day 2 (N = 467)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule Toprule Botrule" colspan="3" align="left">Musculoskeletal and connective tissue disorders</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule">Bone pain</td><td styleCode="Lrule Rrule Toprule Botrule">26%</td><td styleCode="Lrule Rrule Toprule Botrule">31%</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule">Pain in extremity</td><td styleCode="Lrule Rrule Toprule Botrule">4%</td><td styleCode="Lrule Rrule Toprule Botrule">9%</td></tr></tbody></table>