1 INDICATIONS AND USAGE LEUKINE is a leukocyte growth factor indicated: To shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).

( 1.1 ) For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients.

( 1.2 ) For the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older.

( 1.3 ) For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older.

( 1.4 ) For treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older.

( 1.5 ) To increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).

( 1.6 ) 1.1 Acute Myeloid Leukemia Following Induction Chemotherapy LEUKINE is indicated to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).

1.2 Autologous Peripheral Blood Progenitor Cell Mobilization and Collection LEUKINE is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.

1.3 Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation LEUKINE is indicated for the acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).

1.4 Allogeneic Bone Marrow Transplantation LEUKINE is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic bone marrow transplantation from HLA-matched related donors.

1.5 Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure LEUKINE is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous bone marrow transplantation in whom neutrophil recovery is delayed or failed.

1.6 Acute Exposure to Myelosuppressive Doses of Radiation (H-ARS) LEUKINE is indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Infusion Related Reactions [see Warnings and Precautions ( 5.2 )] Risk of Severe Myelosuppression when LEUKINE Administered within 24 Hours of Chemotherapy or Radiotherapy [see Warnings and Precautions ( 5.3 )] Effusions and Capillary Leak Syndrome [see Warnings and Precautions ( 5.4 )] Supraventricular Arrhythmias [see Warnings and Precautions ( 5.5 )] Leukocytosis [see Warnings and Precautions ( 5.6 )] Potential Effect on Malignant Cells [see Warnings and Precautions ( 5.7 )] Immunogenicity [see Warnings and Precautions ( 5.8 )] Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions ( 5.9 )] The most common adverse reactions (incidence >30%) were ( 6.1 ): In recipients of autologous BMT: fever, nausea, diarrhea, vomiting, mucous membrane disorder, alopecia, asthenia, malaise, anorexia, rash, gastrointestinal disorder and edema.

In recipients of allogeneic BMT: diarrhea, fever, nausea, rash, vomiting, stomatitis, anorexia, high glucose, alopecia, abdominal pain, low albumin, headache and hypertension.

In patients with AML: fever, liver toxicity, skin reactions, infections, metabolic laboratory abnormalities, nausea, diarrhea, genitourinary abnormalities, pulmonary toxicity, vomiting, neurotoxicity, stomatitis, alopecia and weight loss.

To report SUSPECTED ADVERSE REACTIONS, contact Partner Therapeutics, Inc., at 1-888-4RX-LEUKINE 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.

Autologous Peripheral Blood Progenitor Cell (PBPC) and Bone Marrow Transplantation Studies 301, 302 and 303 enrolled a total of 156 patients after autologous or allogeneic marrow or PBPC transplantation.

In these placebo-controlled studies, pediatric and adult patients received once-daily intravenous infusions of LEUKINE 250 mcg/m 2 or placebo for 21 days.

In Studies 301, 302, and 303, there was no difference in relapse rate between the LEUKINE and placebo-treated patients.

Adverse reactions reported in at least 10% of patients who received intravenous LEUKINE or at a rate that was at least 5% higher than the placebo arm are shown in Table 1 .

Table 1: Adverse Reactions after Autologous Marrow or PBPC Transplantation in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm Adverse Reactions by Body System LEUKINE (n=79) % Placebo (n=77) % Adverse Reactions by Body System LEUKINE (n=79) % Placebo (n=77) % Body, General Metabolic, Nutritional Disorder Fever 95 96 Edema 34 35 Mucous membrane disorder 75 78 Peripheral edema 11 7 Asthenia 66 51 Respiratory System Malaise 57 51 Dyspnea 28 31 Sepsis 11 14 Lung disorder 20 23 Digestive System Blood and Lymphatic System Nausea 90 96 Blood dyscrasia 25 27 Diarrhea 89 82 Cardiovascular Vascular System Vomiting 85 90 Hemorrhage 23 30 Anorexia 54 58 Urogenital System GI disorder 37 47 Urinary tract disorder 14 13 GI hemorrhage 27 33 Nervous System Stomatitis 24 29 CNS disorder 11 16 Liver damage 13 14 Skin and Appendages Alopecia 73 74 Rash 44 38 Additional Clinically Significant Adverse Reactions Occurring in Less than 10% Incidence Investigations : Elevated creatinine, elevated bilirubin, elevate transaminases Allogeneic Bone Marrow Transplantation In the placebo-controlled trial of 109 patients after allogeneic BMT (Study 9002), acute graft-vs-host disease occurred in 55% on the LEUKINE arm and in 59% on the placebo arm.

Adverse reactions reported in at least 10% of patients who received IV LEUKINE or at a rate at least 5% higher than the placebo arm are shown in Table 2 .

Table 2: Adverse Reactions after Allogeneic Marrow Transplantation in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm * Grade 3 and 4 laboratory abnormalities only.

Denominators may vary due to missing laboratory measures.

Adverse Reactions by Body System LEUKINE (n=53) % Placebo (n=56) % Adverse Reactions by Body System LEUKINE (n=53) % Placebo (n=56) % Body, General Eye hemorrhage 11 0 Fever 77 80 Cardiovascular Vascular System Abdominal pain 38 23 Hypertension 34 32 Headache 36 36 Tachycardia 11 9 Chills 25 20 Metabolic / Nutritional Disorders Pain 17 36 Bilirubinemia 30 27 Asthenia 17 20 Hyperglycemia 25 23 Chest pain 15 9 Peripheral edema 15 21 Digestive System Increased creatinine 15 14 Diarrhea 81 66 Hypomagnesemia 15 9 Nausea 70 66 Increased SGPT 13 11 Vomiting 70 57 Edema 13 11 Stomatitis 62 63 Respiratory System Anorexia 51 57 Pharyngitis 23 13 Dyspepsia 17 20 Epistaxis 17 16 Hematemesis 13 7 Dyspnea 15 14 Dysphagia 11 7 Rhinitis 11 14 GI hemorrhage 11 5 Blood and Lymphatic System Skin and Appendages Thrombocytopenia 19 34 Rash 70 73 Leukopenia 17 29 Alopecia 45 45 Nervous System Pruritus 23 13 Paresthesia 11 13 Musculoskeletal System Insomnia 11 9 Bone pain 21 5 Anxiety 11 2 Arthralgia 11 4 Laboratory Abnormalities* Special Senses High glucose 49 41 Low albumin 36 27 High BUN 17 23 Acute Myeloid Leukemia Following Induction Chemotherapy Nearly all patients in both arms developed leukopenia, thrombocytopenia, and anemia.

Adverse reactions reported in at least 10% of patients who received LEUKINE or at least 5% higher than the placebo arm are reported in Table 3 .

Table 3: Adverse Reactions after Treatment of AML in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm Adverse Reactions by Body System LEUKINE (n=52) % Placebo (n=47) % Adverse Reactions by Body System LEUKINE (n=52) % Placebo (n=47) % Body, General Metabolic, Nutritional Disorder Fever (no infection) 81 74 Metabolic Laboratory Abnormalities 58 49 Infection 65 68 Edema 25 23 Weight loss 37 28 Respiratory System Chills 19 26 Pulmonary toxicity 48 64 Allergy 12 15 Blood and Lymphatic System Digestive System Coagulation 19 21 Nausea 58 55 Cardiovascular System Liver toxicity 77 83 Hemorrhage 29 43 Diarrhea 52 3 Hypertension 25 32 Vomiting 46 34 Cardiac 23 32 Stomatitis 42 43 Hypotension 13 26 Anorexia 13 11 Urogenital System Skin and Appendages GU abnormalities 50 57 Skin Reactions 77 45 Nervous System Alopecia 37 51 Neuro-clinical 42 53 Neuro-motor 25 26 Neuro-psych 15 26 There was no significant difference between the arms in the proportion of patients achieving complete remission (CR; 69% in the LEUKINE group and 55% in the placebo group).

There was also no significant difference in relapse rates; 12 of 36 patients who received LEUKINE and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26).

The study was not sized to assess the impact of LEUKINE treatment on response.

Graft Failure In a historically controlled study of 86 patients with AML, the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins, and prolonged prothrombin time (p=0.02) when compared to the control group.

Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow, which reversed when LEUKINE was discontinued.

The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).

Headache (26%), pericardial effusion (25%), arthralgia (21%), and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study.

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity with LEUKINE.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, duration of treatment, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to sargramostim in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

In 214 patients with a variety of underlying diseases, neutralizing anti-sargramostim antibodies were detected in 5 patients (2.3%) after receiving LEUKINE by continuous IV infusion (3 patients) or SC injection (2 patients) for 28 to 84 days in multiple courses (as assessed by GM-CSF dependent human cell-line proliferation assay).

All 5 patients had impaired hematopoiesis before the administration of LEUKINE, and consequently the effect of the development of anti-sargramostim antibodies on normal hematopoiesis could not be assessed.

Antibody studies of 75 patients with Crohn's disease (a disease for which LEUKINE is not indicated), with normal hematopoiesis and no other immunosuppressive drugs, receiving LEUKINE daily for 8 weeks by SC injection, showed 1 patient (1.3%) with detectable neutralizing anti-sargramostim antibodies (as assessed by GM-CSF dependent human cell-line proliferation assay).

In an experimental use trial where LEUKINE was given for an extended period, 53 patients with melanoma in complete remission (a disease for which LEUKINE is not indicated) received adjuvant therapy with LEUKINE 125 mcg/m 2 once daily (maximum dose 250 mcg) from day 1 to 14 every 28 days for 1 year.

Serum samples from patients assessed at day 0, 2 weeks, 1 month, and 5 and/or 12 months were tested retrospectively for the presence of anti-sargramostim antibodies.

Of 43 evaluable patients (having at least 3 timepoint samples post treatment), 42 (97.7%) developed anti-sargramostim binding antibody as assessed by ELISA and confirmed using an immunoprecipitation assay.

Of these 42 patients, 41 had sufficient sample and were further tested: 34 patients (82.9%) developed anti-sargramostim neutralizing antibodies (as determined by a cell based luciferase reporter gene neutralizing antibody assay); 17 (50%) of these patients did not have a sustained pharmacodynamic effect of LEUKINE by day 155 as assessed by WBC counts.

This study provided limited assessment of the impact of antibody formation on the safety and efficacy of LEUKINE.

Serious allergic and anaphylactoid reactions have been reported with LEUKINE, but the rate of occurrence of antibodies in such patients has not been assessed.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of LEUKINE in clinical trials and/or postmarketing surveillance.

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.

Infusion related reactions including dyspnea, hypoxia, flushing, hypotension, syncope and/or tachycardia [see Warnings and Precautions [see Warnings and Precautions ( 5.1 )] Serious allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions ( 5.2 )] Effusions and capillary leak syndrome [see Warnings and Precautions ( 5.3 )] Supraventricular arrhythmias [see Warnings and Precautions ( 5.4 )] Leukocytosis including eosinophilia [see Warnings and Precautions ( 5.6 )] Thromboembolic events Pain, including chest, abdominal, back, and joint pain Injection site reactions