ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

Fluid Retention and Edema [see Warnings and Precautions (5.1) ]
Hematologic Toxicity [see Warnings and Precautions (5.2) ]
Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3) ]
Hepatotoxicity [see Warnings and Precautions (5.4) ]
Hemorrhage [see Warnings and Precautions (5.5) ]
Gastrointestinal Disorders [see Warnings and Precautions (5.6) ]
Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7) ]
Dermatologic Toxicities [see Warnings and Precautions (5.8) ]
Hypothyroidism [see Warnings and Precautions (5.9) ]
Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11) ]
Tumor Lysis Syndrome [see Warnings and Precautions (5.12) ]
Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13) ]
Renal Toxicity [see Warnings and Precautions (5.14) ]

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 practice.

Chronic Myeloid Leukemia

The majority of imatinib mesylate-treated patients experienced adverse reactions at some time. Imatinib mesylate was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus IFN+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis.

The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13) ] . The frequency of severe superficial edema was 1.5%-6%.

A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib mesylate treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib mesylate-treated patients are shown in Tables 2, 3, and 4.

Table 2: Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Mesylate Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib Mesylate-Treated Patients)( All adverse reactions occurring in greater than or equal to 10% of imatinib mesylate-treated patients are listed regardless of suspected relationship to treatment. )
Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha.
Preferred term	All Grades		CTC Grades NCI Common Terminology Criteria for Adverse Events, version 3.0. 3/4
Preferred term	Imatinib Mesylate N = 551 (%)	IFN+Ara-C N = 533 (%)	Imatinib Mesylate N = 551 (%)	IFN+Ara-C N = 533 (%)
Fluid retention	61.7	11.1	2.5	0.9
-- Superficial edema	59.9	9.6	1.5	0.4
-- Other fluid retention reactions ⁽ Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. ⁾	6.9	1.9	1.3	0.6
Nausea	49.5	61.5	1.3	5.1
Muscle cramps	49.2	11.8	2.2	0.2
Musculoskeletal pain	47.0	44.8	5.4	8.6
Diarrhea	45.4	43.3	3.3	3.2
Rash and related terms	40.1	26.1	2.9	2.4
Fatigue	38.8	67.0	1.8	25.1
Headache	37.0	43.3	0.5	3.8
Joint pain	31.4	38.1	2.5	7.7
Abdominal pain	36.5	25.9	4.2	3.9
Nasopharyngitis	30.5	8.8	0	0.4
Hemorrhage	28.9	21.2	1.8	1.7
-- GI hemorrhage	1.6	1.1	0.5	0.2
-- CNS hemorrhage	0.2	0.4	0	0.4
Myalgia	24.1	38.8	1.5	8.3
Vomiting	22.5	27.8	2.0	3.4
Dyspepsia	18.9	8.3	0	0.8
Cough	20.0	23.1	0.2	0.6
Pharyngolaryngeal pain	18.1	11.4	0.2	0
Upper respiratory tract infection	21.2	8.4	0.2	0.4
Dizziness	19.4	24.4	0.9	3.8
Pyrexia	17.8	42.6	0.9	3.0
Weight increased	15.6	2.6	2.0	0.4
Insomnia	14.7	18.6	0	2.3
Depression	14.9	35.8	0.5	13.1
Influenza	13.8	6.2	0.2	0.2
Bone pain	11.3	15.6	1.6	3.4
Constipation	11.4	14.4	0.7	0.2
Sinusitis	11.4	6.0	0.2	0.2

Table 3: Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Imatinib Mesylate Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib Mesylate Tablets 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysis Excluding laboratory abnormalities.
Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase.
Body system and preferred term		Patients with newly diagnosed Ph+ CML-CP
		Imatinib Mesylate Tablets 400 mg once daily N = 280	Nilotinib 300 mg twice daily N = 279	Imatinib Mesylate Tablets 400 mg once daily N = 280	Nilotinib 300 mg twice daily N = 279
		All Grades (%)		CTC Grades NCI Common Terminology Criteria for Adverse Events, version 3.0. 3/4 (%)
Skin and subcutaneous tissue disorders	Rash	19	38	2	< 1
	Pruritus	7	21	0	< 1
	Alopecia	7	13	0	0
	Dry skin	6	12	0	0
Gastrointestinal disorders	Nausea	41	22	2	2
	Constipation	8	20	0	< 1
	Diarrhea	46	19	4	1
	Vomiting	27	15	< 1	< 1
	Abdominal pain upper	14	18	< 1	1
	Abdominal pain	12	15	0	2
	Dyspepsia	12	10	0	0
Nervous system disorders	Headache	23	32	< 1	3
Nervous system disorders	Dizziness	11	12	< 1	< 1
General disorders and administration-site conditions	Fatigue	20	23	1	1
	Pyrexia	13	14	0	< 1
	Asthenia	12	14	0	< 1
	Peripheral edema	20	9	0	< 1
	Face edema	14	< 1	< 1	0
Musculoskeletal and connective tissue disorders	Myalgia	19	19	< 1	< 1
	Arthralgia	17	22	< 1	< 1
	Muscle spasms	34	12	1	0
	Pain in extremity	16	15	< 1	< 1
	Back pain	17	19	1	1
Respiratory, thoracic and mediastinal disorders	Cough	13	17	0	0
	Oropharyngeal pain	6	12	0	0
	Dyspnea	6	11	< 1	2
Infections and infestations	Nasopharyngitis	21	27	0	0
	Upper respiratory tract infection	14	17	0	< 1
	Influenza	9	13	0	0
	Gastroenteritis	10	7	< 1	0
Eye disorders	Eyelid edema	19	1	< 1	0
Eye disorders	Periorbital edema	15	< 1	0	0
Psychiatric disorders	Insomnia	9	11	0	0
Vascular disorder	Hypertension	4	10	< 1	1

Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (Greater Than or Equal to 10% of All Patients in Any Trial) ⁽ All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment. ⁾
Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha.
Myeloid blast crisis (n = 260) %		Accelerated phase (n = 235) %		Chronic phase, IFN failure (n = 532) %
Preferred term	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
Fluid retention	72	11	76	6	69	4
-- Superficial edema	66	6	74	3	67	2
-- Other fluid retention reactions ⁽ Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. ⁾	22	6	15	4	7	2
Nausea	71	5	73	5	63	3
Muscle cramps	28	1	47	0.4	62	2
Vomiting	54	4	58	3	36	2
Diarrhea	43	4	57	5	48	3
Hemorrhage	53	19	49	11	30	2
-- CNS hemorrhage	9	7	3	3	2	1
-- GI hemorrhage	8	4	6	5	2	0.4
Musculoskeletal pain	42	9	49	9	38	2
Fatigue	30	4	46	4	48	1
Skin rash	36	5	47	5	47	3
Pyrexia	41	7	41	8	21	2
Arthralgia	25	5	34	6	40	1
Headache	27	5	32	2	36	0.6
Abdominal pain	30	6	33	4	32	1
Weight increased	5	1	17	5	32	7
Cough	14	0.8	27	0.9	20	0
Dyspepsia	12	0	22	0	27	0
Myalgia	9	0	24	2	27	0.2
Nasopharyngitis	10	0	17	0	22	0.2
Asthenia	18	5	21	5	15	0.2
Dyspnea	15	4	21	7	12	0.9
Upper respiratory tract infection	3	0	12	0.4	19	0
Anorexia	14	2	17	2	7	0
Night sweats	13	0.8	17	1	14	0.2
Constipation	16	2	16	0.9	9	0.4
Dizziness	12	0.4	13	0	16	0.2
Pharyngitis	10	0	12	0	15	0
Insomnia	10	0	14	0	14	0.2
Pruritus	8	1	14	0.9	14	0.8
Hypokalemia	13	4	9	2	6	0.8
Pneumonia	13	7	10	7	4	1
Anxiety	8	0.8	12	0	8	0.4
Liver toxicity	10	5	12	6	6	3
Rigors	10	0	12	0.4	10	0
Chest pain	7	2	10	0.4	11	0.8
Influenza	0.8	0.4	6	0	11	0.2
Sinusitis	4	0.4	11	0.4	9	0.4

Hematologic and Biochemistry Laboratory Abnormalities

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib mesylate, but may require permanent discontinuation of treatment.

Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus IFN+Ara-C)
Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
Imatinib Mesylate N = 551 %		IFN+Ara-C N = 533 %
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4
Hematology parameters p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups).
-- Neutropenia	13.1	3.6	20.8	4.5
-- Thrombocytopenia	8.5	0.4	15.9	0.6
-- Anemia	3.3	1.1	4.1	0.2
Biochemistry parameters
-- Elevated creatinine	0	0	0.4	0
-- Elevated bilirubin	0.9	0.2	0.2	0
-- Elevated alkaline phosphatase	0.2	0	0.8	0
-- Elevated SGOT (AST)/SGPT (ALT)	4.7	0.5	7.1	0.4

Table 6: Percent Incidence of Clinically Relevant Grade 3/4 NCI Common Terminology Criteria for Adverse Events, version 3.0. Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus Nilotinib)
Abbreviations: CML, chronic myeloid leukemia; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
Imatinib Mesylate Tablets 400 mg once daily N = 280 (%)	Nilotinib 300 mg twice daily N = 279 (%)
Hematologic parameters
Thrombocytopenia	9	10
Neutropenia	22	12
Anemia	6	4
Biochemistry parameters
Elevated lipase	4	9
Hyperglycemia	< 1	7
Hypophosphatemia	10	8
Elevated bilirubin (total)	< 1	4
Elevated SGPT (ALT)	3	4
Hyperkalemia	1	2
Hyponatremia	< 1	1
Hypokalemia	2	< 1
Elevated SGOT (AST)	1	1
Decreased albumin	< 1	0
Hypocalcemia	< 1	< 1
Elevated alkaline phosphatase	< 1	0
Elevated creatinine	< 1	0

Table 7: Laboratory Abnormalities in Other CML Clinical Trials
Abbreviations: CML, chronic myeloid leukemia; CTC, common terminology criteria; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
Myeloid blast crisis (n = 260) 600 mg n = 223 400 mg n = 37 %		Accelerated phase (n = 235) 600 mg n = 158 400 mg n = 77 %		Chronic phase, IFN failure (n = 532) 400 mg %
CTC Grades ⁽ CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 109/L, Grade 4 less than 10 x 109/L), anemia (hemoglobin greater than or equal to 65-80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3-6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3-10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5-20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5-20 x ULN, Grade 4 greater than 20 x ULN). ⁾	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4
Hematology parameters
-- Neutropenia	16	48	23	36	27	9
-- Thrombocytopenia	30	33	31	13	21	< 1
-- Anemia	42	11	34	7	6	1
Biochemistry parameters
-- Elevated creatinine	1.5	0	1.3	0	0.2	0
-- Elevated bilirubin	3.8	0	2.1	0	0.6	0
-- Elevated alkaline phosphatase	4.6	0	5.5	0.4	0.2	0
-- Elevated SGOT (AST)	1.9	0	3.0	0	2.3	0
-- Elevated SGPT (ALT)	2.3	0.4	4.3	0	2.1	0

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Adverse Reactions in Pediatric Population

Single-Agent Therapy

The overall safety profile of pediatric patients treated with imatinib mesylate in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression.

In Combination with Multi-Agent Chemotherapy

Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive imatinib mesylate and treated in 5 successive cohorts. Imatinib exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of imatinib mesylate given in combination with intensive chemotherapy was evaluated by comparing the incidence of Grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive imatinib mesylate. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib mesylate, and 647 without imatinib mesylate. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included imatinib mesylate are presented in Table 8.

Table 8: Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (Greater Than 5%) or in Cycles With Study Drug (Greater Than 1%)
Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia.
Adverse event Grade 3 and 4 adverse events	Per patient incidence Ph+ ALL with imatinib mesylate N = 92 n (%)	Per patient incidence Ph- ALL no imatinib mesylate N = 65 n (%)	Per patient per cycle incidence with imatinib mesylate Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib mesylate (includes patients with Ph+ ALL that received cycles with imatinib mesylate). N = 778 n (%)	Per patient per cycle incidence no imatinib mesylate Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib mesylate (includes patients with Ph+ ALL that received cycles without imatinib mesylate as well as all patients with Ph- ALL who did not receive imatinib mesylate in any treatment cycle). N = 647 n (%)
Nausea and/or vomiting	15 (16)	6 (9)	28 (4)	8 (1)
Hypokalemia	31 (34)	16 (25)	72 (9)	32 (5)
Pneumonitis	7 (8)	1 (1)	7 (1)	1 (< 1)
Pleural effusion	6 (7)	0	6 (1)	0
Abdominal pain	8 (9)	2 (3)	9 (1)	3 (< 1)
Anorexia	10 (11)	3 (5)	19 (2)	4 (1)
Hemorrhage	11 (12)	4 (6)	17 (2)	8 (1)
Hypoxia	8 (9)	2 (3)	12 (2)	2 (< 1)
Myalgia	5 (5)	0	4 (1)	1 (< 1)
Stomatitis	15 (16)	8 (12)	22 (3)	14 (2)
Diarrhea	8 (9)	3 (5)	12 (2)	3 (< 1)
Rash/Skin disorder	4 (4)	0	5 (1)	0
Infection	49 (53)	32 (49)	131 (17)	92 (14)
Hepatic (transaminase and/or bilirubin)	52 (57)	38 (58)	172 (22)	113 (17)
Hypotension	10 (11)	5 (8)	16 (2)	6 (1)
Myelosuppression
Neutropenia (< 750/mcL)	92 (100)	63 (97)	556 (71)	218 (34)
Thrombocytopenia (< 75,000/mcL)	90 (92)	63 (97)	431 (55)	329 (51)

Adverse Reactions in Other Subpopulations

In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

Acute Lymphoblastic Leukemia

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of imatinib mesylate.

Myelodysplastic/Myeloproliferative Diseases

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate for MDS/MPD in the Phase 2 study, are shown in Table 9.

Table 9: Adverse Reactions Regardless of Relationship to Study Drug Reported (More Than One Patient) in MPD Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades
Abbreviation: MPD, myeloproliferative disease.
Preferred term	N = 7 n (%)
Nausea	4 (57.1)
Diarrhea	3 (42.9)
Anemia	2 (28.6)
Fatigue	2 (28.6)
Muscle cramp	3 (42.9)
Arthralgia	2 (28.6)
Periorbital edema	2 (28.6)

Aggressive Systemic Mastocytosis

All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued imatinib mesylate due to drug-related adverse reactions or abnormal laboratory values.

Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib mesylate observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.

Dermatofibrosarcoma Protuberans

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are shown in Table 10.

Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades
Abbreviation: DFSP, dermatofibrosarcoma protuberans.
Preferred term	N = 12 n (%)
Nausea	5 (41.7)
Diarrhea	3 (25.0)
Vomiting	3 (25.0)
Periorbital edema	4 (33.3)
Face edema	2 (16.7)
Rash	3 (25.0)
Fatigue	5 (41.7)
Peripheral edema	4 (33.3)
Pyrexia	2 (16.7)
Eye edema	4 (33.3)
Lacrimation increased	3 (25.0)
Dyspnea exertional	2 (16.7)
Anemia	3 (25.0)
Rhinitis	2 (16.7)
Anorexia	2 (16.7)

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are presented in Table 11.

Table 11: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study
Abbreviation: CTC, common terminology criteria.
CTC Grades ⁽ CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65-80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3-6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN). ⁾	N = 12
	Grade 3 %	Grade 4 %
Hematology parameters
-- Anemia	17	0
-- Thrombocytopenia	17	0
-- Neutropenia	0	8
Biochemistry parameters
-- Elevated creatinine	0	8

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

In the Phase 3 trials, the majority of imatinib mesylate-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13) ] . Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate are shown in Table 12.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 12: Number (%) of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials
Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors.
Reported or specified term	Imatinib 400 mg N = 818		Imatinib 800 mg N = 822
Reported or specified term	All Grades %	Grades 3/4/5 %	All Grades %	Grades 3/4/5 %
Edema	76.7	9.0	86.1	13.1
Fatigue/lethargy, malaise, asthenia	69.3	11.7	74.9	12.2
Nausea	58.1	9.0	64.5	7.8
Abdominal pain/cramping	57.2	13.8	55.2	11.8
Diarrhea	56.2	8.1	58.2	8.6
Rash/desquamation	38.1	7.6	49.8	8.9
Vomiting	37.4	9.2	40.6	7.5
Myalgia	32.2	5.6	30.2	3.8
Anemia	32.0	4.9	34.8	6.4
Anorexia	31.1	6.6	35.8	4.7
Other GI toxicity	25.2	8.1	28.1	6.6
Headache	22.0	5.7	19.7	3.6
Other pain (excluding tumor related pain)	20.4	5.9	20.8	5.0
Other dermatology/skin toxicity	17.6	5.9	20.1	5.7
Leukopenia	17.0	0.7	19.6	1.6
Other constitutional symptoms	16.7	6.4	15.2	4.4
Cough	16.1	4.5	14.5	3.2
Infection (without neutropenia)	15.5	6.6	16.5	5.6
Pruritus	15.4	5.4	18.9	4.3
Other neurological toxicity	15.0	6.4	15.2	4.9
Constipation	14.8	5.1	14.4	4.1
Other renal/genitourinary toxicity	14.2	6.5	13.6	5.2
Arthralgia (joint pain)	13.6	4.8	12.3	3.0
Dyspnea (shortness of breath)	13.6	6.8	14.2	5.6
Fever in absence of neutropenia (ANC < 1.0 x 10 ⁹/L)	13.2	4.9	12.9	3.4
Sweating	12.7	4.6	8.5	2.8
Other hemorrhage	12.3	6.7	13.3	6.1
Weight gain	12.0	1.0	10.6	0.6
Alopecia	11.9	4.3	14.8	3.2
Dyspepsia/heartburn	11.5	0.6	10.9	0.5
Neutropenia/granulocytopenia	11.5	3.1	16.1	4.1
Rigors/chills	11.0	4.6	10.2	3.0
Dizziness/lightheadedness	11.0	4.8	10.0	2.8
Creatinine increase	10.8	0.4	10.1	0.6
Flatulence	10.0	0.2	10.1	0.1
Stomatitis/pharyngitis (oral/pharyngeal mucositis)	9.2	5.4	10.0	4.3
Lymphopenia	6.0	0.7	10.1	1.9

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.

Table 13: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial
Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
CTC Grades CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65-80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3-6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3-10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5-20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L).	400 mg (n = 73) %		600 mg (n = 74) %
	Grade 3	Grade 4	Grade 3	Grade 4
Hematology parameters
− Anemia	3	0	8	1
− Thrombocytopenia	0	0	1	0
− Neutropenia	7	3	8	3
Biochemistry parameters
− Elevated creatinine	0	0	3	0
− Reduced albumin	3	0	4	0
− Elevated bilirubin	1	0	1	3
− Elevated alkaline phosphatase	0	0	3	0
− Elevated SGOT (AST)	4	0	3	3
− Elevated SGPT (ALT)	6	0	7	1

Adjuvant Treatment of GIST

In Study 1, the majority of both imatinib mesylate and placebo-treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST-treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the imatinib mesylate and placebo-treated patients, respectively. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.

In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the imatinib mesylate 12-month and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with imatinib mesylate are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib mesylate treatment in either trial.

Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (Greater Than or Equal to 5% of Imatinib Mesylate-Treated Patients) ⁽ All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. ⁾
Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
Preferred term	All CTC Grades		CTC Grade 3 NCI Common Terminology Criteria for Adverse Events, version 3.0. and Above
Preferred term	Imatinib Mesylate (n = 337) %	Placebo (n = 345) %	Imatinib Mesylate (n = 337) %	Placebo (n = 345) %
Diarrhea	59.3	29.3	3.0	1.4
Fatigue	57.0	40.9	2.1	1.2
Nausea	53.1	27.8	2.4	1.2
Periorbital edema	47.2	14.5	1.2	0
Hemoglobin decreased	46.9	27.0	0.6	0
Peripheral edema	26.7	14.8	0.3	0
Rash (Exfoliative)	26.1	12.8	2.7	0
Vomiting	25.5	13.9	2.4	0.6
Abdominal pain	21.1	22.3	3.0	1.4
Headache	19.3	20.3	0.6	0
Dyspepsia	17.2	13.0	0.9	0
Anorexia	16.9	8.7	0.3	0
Weight increased	16.9	11.6	0.3	0
Liver enzymes (ALT) increased	16.6	13.0	2.7	0
Muscle spasms	16.3	3.3	0	0
Neutrophil count decreased	16.0	6.1	3.3	0.9
Arthralgia	15.1	14.5	0	0.3
White blood cell count decreased	14.5	4.3	0.6	0.3
Constipation	12.8	17.7	0	0.3
Dizziness	12.5	10.7	0	0.3
Liver enzymes (AST) increased	12.2	7.5	2.1	0
Myalgia	12.2	11.6	0	0.3
Blood creatinine increased	11.6	5.8	0	0.3
Cough	11.0	11.3	0	0
Pruritus	11.0	7.8	0.9	0
Weight decreased	10.1	5.2	0	0
Hyperglycemia	9.8	11.3	0.6	1.7
Insomnia	9.8	7.2	0.9	0
Lacrimation increased	9.8	3.8	0	0
Alopecia	9.5	6.7	0	0
Flatulence	8.9	9.6	0	0
Rash	8.9	5.2	0.9	0
Abdominal distension	7.4	6.4	0.3	0.3
Back pain	7.4	8.1	0.6	0
Pain in extremity	7.4	7.2	0.3	0
Hypokalemia	7.1	2.0	0.9	0.6
Depression	6.8	6.4	0.9	0.6
Facial edema	6.8	1.2	0.3	0
Blood alkaline phosphatase increased	6.5	7.5	0	0
Dry skin	6.5	5.2	0	0
Dysgeusia	6.5	2.9	0	0
Abdominal pain upper	6.2	6.4	0.3	0
Neuropathy peripheral	5.9	6.4	0	0
Hypocalcemia	5.6	1.7	0.3	0
Leukopenia	5.0	2.6	0.3	0
Platelet count decreased	5.0	3.5	0	0
Stomatitis	5.0	1.7	0.6	0
Upper respiratory tract infection	5.0	3.5	0	0
Vision blurred	5.0	2.3	0	0

A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (Greater Than or Equal to 5% of Imatinib Mesylate-Treated Patients) Study 2 ⁽ All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. ⁾
Abbreviations: AE, adverse event; CTC, common terminology criteria.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.
Preferred term	All CTC Grades		CTC Grades 3 and above
Preferred term	Imatinib Mesylate 12 Months (N = 194) %	Imatinib Mesylate 36 Months (N = 198) %	Imatinib Mesylate 12 Months (N = 194) %	Imatinib Mesylate 36 Months (N = 198) %
Patients with at least one AE	99.0	100.0	20.1	32.8
Hemoglobin decreased	72.2	80.3	0.5	0.5
Periorbital edema	59.3	74.2	0.5	1.0
Blood lactate dehydrogenase increased	43.3	60.1	0	0
Diarrhea	43.8	54.0	0.5	2.0
Nausea	44.8	51.0	1.5	0.5
Muscle spasms	30.9	49.0	0.5	1.0
Fatigue	48.5	48.5	1.0	0.5
White blood cell count decreased	34.5	47.0	2.1	3.0
Pain	25.8	45.5	1.0	3.0
Blood creatinine increased	30.4	44.4	0	0
Peripheral edema	33.0	40.9	0.5	1.0
Dermatitis	29.4	38.9	2.1	1.5
Aspartate aminotransferase increased	30.9	37.9	1.5	3.0
Alanine aminotransferase increased	28.9	34.3	2.1	3.0
Neutrophil count decreased	24.2	33.3	4.6	5.1
Hypoproteinemia	23.7	31.8	0	0
Infection	13.9	27.8	1.5	2.5
Weight increased	13.4	26.8	0	0.5
Pruritus	12.9	25.8	0	0
Flatulence	19.1	24.7	1.0	0.5
Vomiting	10.8	22.2	0.5	1.0
Dyspepsia	17.5	21.7	0.5	1.0
Hypoalbuminemia	11.9	21.2	0	0
Edema	10.8	19.7	0	0.5
Abdominal distension	11.9	19.2	0.5	0
Headache	8.2	18.2	0	0
Lacrimation increased	18.0	17.7	0	0
Arthralgia	8.8	17.2	0	1.0
Blood alkaline phosphatase increased	10.8	16.7	0	0.5
Dyspnea	6.2	16.2	0.5	1.5
Myalgia	9.3	15.2	0	1.0
Platelet count decreased	11.3	14.1	0	0
Blood bilirubin increased	11.3	13.1	0	0
Dysgeusia	9.3	12.6	0	0
Paresthesia	5.2	12.1	0	0.5
Vision blurred	10.8	11.1	1.0	0.5
Alopecia	11.3	10.6	0	0
Decreased appetite	9.8	10.1	0	0
Constipation	8.8	9.6	0	0
Pyrexia	6.2	9.6	0	0
Depression	3.1	8.1	0	0
Abdominal pain	2.6	7.6	0	0
Conjunctivitis	5.2	7.6	0	0
Photosensitivity reaction	3.6	7.1	0	0
Dizziness	4.6	6.6	0.5	0
Hemorrhage	3.1	6.6	0	0
Dry skin	6.7	6.1	0.5	0
Nasopharyngitis	1.0	6.1	0	0.5
Palpitations	5.2	5.1	0	0

Adverse Reactions from Multiple Clinical Trials

Cardiac Disorders:
Estimated 1%-10%: palpitations, pericardial effusion
Estimated 0.1%-1%: congestive cardiac failure, tachycardia, pulmonary edema
Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris

Vascular Disorders:
Estimated 1%-10%: flushing, hemorrhage
Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma

Investigations:
Estimated 1%-10%: blood creatine phosphokinase (CPK) increased, blood amylase increased
Estimated 0.1%-1%: blood lactate dehydrogenase (LDH) increased

Skin and Subcutaneous Tissue Disorders:
Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura
Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme, panniculitis (including erythema nodosum)
Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis

Gastrointestinal Disorders:
Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis
Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis
Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease

General Disorders and Administration-Site Conditions:
Estimated 1%-10%: weakness, anasarca, chills
Estimated 0.1%-1%: malaise

Blood and Lymphatic System Disorders:
Estimated 1%-10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia
Estimated 0.1%-1%: thrombocythemia, bone marrow depression, lymphadenopathy
Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia

Hepatobiliary Disorders:
Estimated 0.1%-1%: hepatitis, jaundice
Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis ¹

Immune System Disorders:
Estimated 0.01%-0.1%: angioedema

Infections and Infestations:
Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
Estimated 0.01%-0.1%: fungal infection

Metabolism and Nutrition Disorders:
Estimated 1%-10%: weight decreased, decreased appetite
Estimated 0.1%-1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia

Musculoskeletal and Connective Tissue Disorders:
Estimated 1%-10%: joint swelling
Estimated 0.1%-1%: joint and muscle stiffness, muscular weakness, arthritis

Nervous System/Psychiatric Disorders:
Estimated 1%-10%: paresthesia, hypesthesia
Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor
Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis

Renal and Urinary Disorders:
Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain

Reproductive System and Breast Disorders:
Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema

Respiratory, Thoracic and Mediastinal Disorders:
Estimated 1%-10%: epistaxis
Estimated 0.1%-1%: pleural effusion
Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage

Endocrine Disorders:
Estimated 0.1%-1%: hypothyroidism, hyperthyroidism

Eye, Ear, and Labyrinth Disorders:
Estimated 1%-10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye
Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract
Estimated 0.01%-0.1%: papilledema1, glaucoma

¹Including some fatalities.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of imatinib mesylate. 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.

Blood and Lymphatic System Disorders: thrombotic microangiopathy

Cardiac Disorders: pericarditis, cardiac tamponade ¹

Eye Disorders: vitreous hemorrhage

Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation ¹ [see Warnings and Precautions (5.6) ] , diverticulitis, gastric antral vascular ectasia

Infections: hepatitis B virus reactivation ¹

Musculoskeletal and Connective Tissue Disorders: osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthralgia, bone pain)

Nervous System Disorders: cerebral edema ¹

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure ¹, interstitial lung disease

Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus

Vascular Disorders: thrombosis/embolism, anaphylactic shock

¹Including some fatalities.

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