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)]

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/m2 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/m2 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