Leukine

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]).

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for dosage adjustments and timing of administration ( 2.1 - 2.6 ). AML, Neutrophil recovery following chemotherapy: 250 mcg/m 2 /day administered intravenously over a 4-hour period. ( 2.1 ) Mobilization of peripheral blood progenitor cells: 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneous injection once daily. ( 2.2 ) Post peripheral blood progenitor cell transplantation: 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneous injection once daily. ( 2.3 ) Myeloid reconstitution after autologous or allogeneic BMT: 250 mcg/m 2 /day administered intravenously over a 2-hour period. ( 2.4 ) BMT failure or engraftment delayed: 250 mcg/m 2 /day for 14 days as a 2-hour intravenous infusion. ( 2.5 ) Patients acutely exposed to myelosuppressive doses of radiation, administer once daily as subcutaneous injection: Adults and pediatric patients weighing >40 kg: 7 mcg/kg Pediatric patients 15 kg to 40 kg: 10 mcg/kg Pediatric patients <15 kg: 12 mcg/kg ( 2.6 ) 2.1 Neutrophil Recovery Following Induction Chemotherapy for Acute Myeloid Leukemia The recommended dose is 250 mcg/m 2 /day administered intravenously over a 4-hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with less than 5% blasts. If a second cycle of induction chemotherapy is necessary, administer LEUKINE approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Continue LEUKINE until an absolute neutrophil count (ANC) greater than 1500 cells/mm 3 for 3 consecutive days or a maximum of 42 days. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ( 5.3 )] . Dose Modifications Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose for the following: Leukemic regrowth: Discontinue LEUKINE immediately Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or interrupt dosing until the reaction abates ANC greater than 20,000 cells/mm 3 : Interrupt LEUKINE treatment or reduce the dose by 50% 2.2 Autologous Peripheral Blood Progenitor Cell Mobilization and Collection The recommended dose is 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneously once daily. Continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun after 5 days of LEUKINE and performed daily until protocol specified targets were achieved [see Clinical Studies ( 14 )] . If WBC greater than 50,000 cells/mm 3 , reduce the LEUKINE dose by 50%. Consider other mobilization therapy if adequate numbers of progenitor cells are not collected. 2.3 Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation Autologous Peripheral Blood Progenitor Cell Transplantation The recommended dose is 250 mcg/m 2 /day administered intravenously over 24 hours or subcutaneously once daily beginning immediately following infusion of progenitor cells and continuing until an ANC greater than 1500 cells/mm 3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy. Autologous Bone Marrow Transplantation The recommended dose is 250 mcg/m 2 /day administered intravenously over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Do not administer LEUKINE until the post marrow infusion ANC is less than 500 cells/mm 3 . Continue LEUKINE until an ANC greater than 1500 cells/mm 3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ( 5.3 )] . 2.4 Allogeneic Bone Marrow Transplantation The recommended dose is 250 mcg/m 2 /day administered intravenously over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Do not administer LEUKINE until the post marrow infusion ANC is less than 500 cells/mm 3 . Continue LEUKINE until an ANC greater than 1500 cells/mm 3 for three consecutive days is attained. Do not administer LEUKINE within 24 hours preceding or following receipt of chemotherapy or radiotherapy [see Warnings and Precautions ( 5.3 )] . Dose Modifications Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose as for the following: Disease progression or blast cell appearance: Discontinue LEUKINE immediately Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or temporarily discontinue until the reaction abates WBC greater than 50,000 cells/mm 3 or ANC greater than 20,000 cells/mm 3 : Interrupt LEUKINE treatment or reduce the dose by 50% 2.5 Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure The recommended dose is 250 mcg/m 2 /day for 14 days as a 2-hour intravenous infusion. The dose can be repeated after 7 days off therapy if neutrophil recovery has not occurred. If neutrophil recovery still has not occurred, a third course of 500 mcg/m 2 /day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. Dose Modifications Obtain a CBC with differential twice per week during LEUKINE therapy and modify the dose as for the following: Disease progression or blast cell appearance: Discontinue LEUKINE immediately Grade 3 or 4 adverse reactions: Reduce the dose of LEUKINE by 50% or temporarily discontinue until the reaction abates WBC greater than 50,000 cells/mm 3 or ANC greater than 20,000 cells/mm 3 : Interrupt LEUKINE treatment or reduce the dose by 50% 2.6 Acute Exposure to Myelosuppressive Doses of Radiation (H-ARS) For patients with H-ARS, the recommended dose of LEUKINE is a subcutaneous injection administered once daily as follows: 7 mcg/kg in adult and pediatric patients weighing greater than 40 kg 10 mcg/kg in pediatric patients weighing 15 kg to 40 kg 12 mcg/kg in pediatric patients weighing less than 15 kg Administer LEUKINE 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.e., 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 with differential and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm 3 for three consecutive CBCs. Do not delay administration of LEUKINE if a CBC is not readily available. Continue administration of LEUKINE until the ANC remains greater than 1,000/mm 3 for three consecutive CBCs or exceeds 10,000/mm3 after a radiation-induced nadir. 2.7 Preparation and Administration of LEUKINE Do not administer LEUKINE simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy [see Warnings and Precautions ( 5.3 )] . LEUKINE for injection is a sterile, preservative-free lyophilized powder that requires reconstitution with 1 mL Sterile Water for Injection (without preservative), USP, to yield a clear, colorless single-dose solution or 1 mL Bacteriostatic Water for Injection, USP (with 0.9% benzyl alcohol as preservative) to yield a clear, colorless single-dose solution. Use only LEUKINE for injection (lyophilized powder) reconstituted with Sterile Water for Injection without preservatives when administering LEUKINE to neonates or infants to avoid benzyl alcohol exposure [see Warnings and Precautions ( 5.9 )] . Do NOT use an in-line membrane filter for intravenous infusion of LEUKINE. Store reconstituted solution under refrigeration at 2°C to 8°C (36°F to 46°F); DO NOT FREEZE. In the absence of compatibility and stability information, do not add other medication to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare intravenous infusion solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used. LEUKINE for Injection Preparation Reconstitute the lyophilized powder with 1 mL of diluent. Do not mix the contents of vials reconstituted with different diluents together . Reconstitute with either Sterile Water for Injection, USP (without preservative) or Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) for intravenous or subcutaneous administration. Discard any unused portions. When reconstituted with Sterile Water for Injection, USP (without preservative) , may store the reconstituted solution refrigerated at 2°C to 8°C and must use within 24 hours following reconstitution. When reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) , may store the reconstituted solution refrigerated at 2°C to 8°C and must use within 20 days following reconstitution. LEUKINE for Intravenous Administration Dilute reconstituted LEUKINE in 0.9% Sodium Chloride Injection, USP. If the final concentration of LEUKINE is less than 10 mcg/mL, add Albumin (Human) to a final concentration of 0.1% [1 mL 5% Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP] to prevent adsorption of LEUKINE to the drug delivery system. LEUKINE for intravenous administration must be used immediately after dilution with 0.9 % Sodium Chloride Injection, USP.

4 CONTRAINDICATIONS Do not administer LEUKINE to patients with a history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony-stimulating factor such as sargramostim, yeast-derived products, or any component of the product. Anaphylactic reactions have been reported with LEUKINE [see Warnings and Precautions ( 5.1 )] . Do not administer LEUKINE to patients with a history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Permanently discontinue LEUKINE in patients with serious allergic reactions. ( 5.1 ) Infusion Related Reactions: Manage using infusion rate reductions or discontinuations. ( 5.2 ) Effusions and Capillary Leak Syndrome: Manage with dose-reduction, discontinuation, or diuretics. Monitor body weight and hydration status during therapy. ( 5.4 ) Supraventricular Arrhythmias: Risk may be increased in patients with history of cardiac arrhythmias. Manage medically and discontinue LEUKINE. ( 5.5 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. Parenteral administration of LEUKINE should be attended by appropriate precautions in case an allergic or untoward reaction occurs. If any serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy and institute medical management. Discontinue LEUKINE permanently for patients with serious allergic reactions. 5.2 Infusion Related Reactions LEUKINE can cause infusion-related reactions. Infusion-related reactions may be characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment. Observe closely during infusion for symptoms, particularly in patients with pre-existing lung disease. If patients display dyspnea or other acute symptoms, reduce the rate of infusion by 50%. If symptoms persist or worsen despite rate reduction, discontinue the LEUKINE infusion. If patient experiences infusion-related reaction, subsequent intravenous infusions may be administered following the standard dose schedule with careful monitoring. 5.3 Risk of Severe Myelosuppression when LEUKINE Administered within 24 hours of Chemotherapy or Radiotherapy Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse reactions, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia. 5.4 Effusions and Capillary Leak Syndrome Edema, capillary leak syndrome, and pleural and/or pericardial effusion, have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m 2 /day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure. Body weight and hydration status should be carefully monitored during LEUKINE administration. 5.5 Supraventricular Arrhythmias Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. These arrhythmias have been reversible after discontinuation of LEUKINE. Use LEUKINE with caution in patients with preexisting cardiac disease. 5.6 Leukocytosis White blood cell counts of ≥ 50,000/mm 3 were observed in patients receiving LEUKINE. Monitor complete blood counts (CBC) with differential twice per week. Base the decision whether to reduce the dose or interrupt treatment on the clinical condition of the patient [see Dosage and Administration ( 2.1 , 2.4 , 2.5 , 2.6 )] . Following cessation of LEUKINE therapy, excessive blood counts have returned to normal or baseline levels within 3 to 7 days. 5.7 Potential Effect on Malignant Cells LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics. Discontinue LEUKINE therapy if disease progression is detected during LEUKINE treatment. 5.8 Immunogenicity Treatment with LEUKINE may induce neutralizing anti-drug antibodies. The incidence of anti-sargramostim neutralizing antibodies may be related to duration of exposure to LEUKINE. In a study of patients with normal neutrophil count and a solid tumor in complete response (an unapproved use) treated with LEUKINE for up to 12 months, 82.9% of 41 evaluable patients developed anti-sargramostim neutralizing antibodies and the myelostimulatory effect of LEUKINE was not sustained by day 155 as assessed by WBC count. Use LEUKINE for the shortest duration required [see Adverse Reactions ( 6.2 )] . 5.9 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol). The “gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Avoid administration of solutions containing benzyl alcohol (including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP [0.9% benzyl alcohol]) to neonates and low birth weight infants. Instead, administer lyophilized LEUKINE reconstituted with Sterile Water for Injection, USP [see Dosage and Administration ( 2.7 )] . If LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) must be used in neonates and low birth weight infants, consider the combined daily metabolic load of benzyl alcohol from all sources including LEUKINE (LEUKINE for injection reconstituted with Bacteriostatic Water contains 9 mg of benzyl alcohol per mL). The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations ( 8.4 ) and Dosage and Administration ( 2.7 )] .

7 DRUG INTERACTIONS Use with caution in patients receiving drugs that may potentiate LEUKINE's myeloproliferative effects, such as lithium and corticosteroids. ( 7.1 ) 7.1 Concomitant Use with Products that Induce Myeloproliferation Avoid the concomitant use of LEUKINE and products that induce myeloproliferation (such as lithium and corticosteroids). Such products may increase the myeloproliferative effects of LEUKINE. Monitor patients receiving both LEUKINE and products that induce myeloproliferation frequently for clinical and laboratory signs of excess myeloproliferative effects.

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

8.1 Pregnancy Risk Summary LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP contain 0.9% benzyl alcohol, which has been associated with gasping syndrome in neonates and infants. The preservative benzyl alcohol can cause serious adverse reactions and death when administered intravenously to neonates and infants. If LEUKINE is needed during pregnancy, reconstitute LEUKINE for injection only with Sterile Water for injection without preservatives [see Dosage and Administration ( 2.7 ) and Use in Specific Populations ( 8.4 )] . The limited available data on LEUKINE use in pregnant women are insufficient to inform the drug-associated risk of adverse developmental outcomes. Based on animal studies LEUKINE may cause embryofetal harm. In animal reproduction studies, administration of LEUKINE to pregnant rabbits during organogenesis resulted in adverse developmental outcomes including increased spontaneous abortion at systemic exposures ≥1.3 times the human exposure expected at the recommended human dose [see Data ] . Advise pregnant women of the potential risk to a fetus. 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 are 2%-4% and 15%-20%, respectively. Data Animal data In an embryofetal developmental study and a prenatal and postnatal study, pregnant rabbits were administered SC doses of LEUKINE during the period of gestation day (GD) 6 to GD19, GD19 to GD28, or GD19 to parturition at 25, 70, and 200 mcg/kg/day. An increase in spontaneous abortions, late resorptions, and post implantation loss, and a reduction in viable fetuses, mean live litter size, and offspring body weight were evident in rabbits treated with LEUKINE at 200 mcg/kg/day. No adverse effects were observed at ≤70 mcg/kg/day. After the first administration in rabbits, the dose of 200 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 11-25.3 times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m 2 ; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC in rabbits was reduced to 1.3-5.5 times the clinical exposure by the end of the dosing periods. Similarly, after the first administration in rabbits, the dose of 70 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 7 to 11 times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m 2 ; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC in rabbits was reduced to 1.0-1.2 times the clinical exposure by the end of the dosing periods.