FDA label 15ea875e-d5b6-45d6-a7eb-ca370ef9eed6

5 WARNINGS AND PRECAUTIONS Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics ( 5.1 , 6.1 , 6.11 ) Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter ( 5.2 ) Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated ( 5.3 ) Severe hepatotoxicity including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction ( 5.4 ) Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST ( 5.5 ) Gastrointestinal perforations, some fatal, have been reported ( 5.6 ) Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Gleevec in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM) ( 5.7 ) Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Gleevec ( 5.8 ) Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients ( 5.9 ). Consider potential toxicities, specifically, liver, kidney, and cardiac toxicity, and immunosuppression from long-term use ( 5.10 ) Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus ( 5.11 , 8.1 ) Growth retardation occurring in children and pre-adolescents receiving Gleevec has been reported. Close monitoring of growth in children under Gleevec treatment is recommended ( 5.12 , 6.13 ) Tumor lysis syndrome. Close monitoring is recommended ( 5.13 ) Reports of motor vehicle accidents have been received in patients receiving Gleevec. Caution patients about driving a car or operating machinery ( 5.14 ) 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [ see Adverse Reactions (6.1) ]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [ see Adverse Reactions (6.11) ] . 5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [ see Dosage and Administration (2. 12 ) ] . 5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [ see Adverse Reactions (6.3) ] . Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [ see Dosage and Administration (2. 11 ) ] . When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. 5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. Patients should therefore be monitored for gastrointestinal symptoms at the start of therapy. 5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. 5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy. 5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. 5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients. 5.1 0 Toxicities from Long -Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression . Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. 5.11 Use in Pregnancy Pregnancy Category D Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Sexually active female patients of reproductive potential taking Gleevec should use highly effective contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)] . 5.12 Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended [see Adverse Reactions (6.13)] . 5.13 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Gleevec. 5.14 Driving and Using Machinery Reports of motor vehicle accidents have been received in patients receiving Gleevec. While most of these reports are not suspected to be caused by Gleevec, patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Gleevec. Therefore, caution should be recommended when driving a car or operating machinery.

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The most frequently reported adverse reactions ( > 30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain ( 6.1 , 6.11 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Chronic Myeloid Leukemia The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% 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 for newly diagnosed CML, Table 3 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 Gleevec [ see Dosage and Administration (2. 11 ) ] . 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 Gleevec treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec treated patients are shown in Tables 2 and 3. Table 2 Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial (≥10% of Gleevec Treated Patients) (1) All Grades CTC Grades 3/4 Gleevec IFN+Ara−C Gleevec IFN+Ara−C Preferred Term N=551 (%) N=533 (%) N=551 (%) 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 2 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 (1) All adverse reactions occurring in ≥10% of Gleevec treated patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Table 3 Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (≥10% of All Patients in any Trial) (1) 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 (2) 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 (1) All adverse reactions occurring in ≥10% of patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. 6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥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 4 and 5). 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 Gleevec, but in rare cases require permanent discontinuation of treatment. Table 4 Lab Abnormalities in Newly Diagnosed CML Clinical Trial Gleevec N=551 IFN+Ara−C N=533 % % CTC Grades Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters* − 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 /SGPT 4.7 0.5 7.1 0.4 *p<0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups) Table 5 Lab Abnormalities in Other CML Clinical Trials Myeloid Blast Crisis (n=260) Accelerated Phase (n=235) Chronic Phase, IFN Failure (n=532) 600 mg n=223 400 mg n=37 600 mg n=158 400 mg n=77 400 mg % % % CTC Grades 1 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 1 CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 10 9 /L, Grade 4 <0.5 x 10 9 /L), thrombocytopenia (Grade 3 ≥10-50 x 10 9 /L, Grade 4 <10 x 10 9 /L), anemia (hemoglobin ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN) 6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) 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. 6.4 Adverse Reactions in Pediatric Population The overall safety profile of pediatric patients treated with Gleevec 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. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low. 6.5 Adverse Reactions in Other Subpopulations In older patients (≥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. 6.6 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, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec. 6.7 Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the phase 2 study, are shown in Table 6. Table 6 Adverse Reactions Regardless of Relationship to Study Drug Reported (More than One Patient) in MPD Patients in the Phase 2 Study (≥10% All Patients) All Grades 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) 6.8 Aggressive Systemic Mastocytosis All 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 Gleevec due to drug-related adverse reactions or abnormal laboratory values. 6.9 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 Gleevec observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia and anemia. 6.10 Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the phase 2 study are shown in Table 7. Table 7 Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (≥10% All Patients) All Grades 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) Edema Peripheral 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 Gleevec for DFSP in the phase 2 study are presented in Table 8. Table 8 Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study N=12 CTC Grades 1 Grade 3 Grade 4 Hematology Parameters - Anemia 17 % 0 % - Thrombocytopenia 17 % 0 % - Neutropenia 0 % 8 % Biochemistry Parameters - Elevated Creatinine 0 % 8 % 1 CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 10 9 /L, Grade 4 <0.5 x 10 9 /L), thrombocytopenia (Grade 3 ≥10 - 50 x 10 9 /L, Grade 4 <10 x 10 9 /L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), 6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-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 Gleevec [ see Dosage and Administration (2. 11 ) ]. 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 Gleevec are shown in Table 9. 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 9 Number (%) of Patients with Adverse Reactions Regardless of Relationship to Study Drug where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Reported or Specified Term Imatinib 400 mg N=818 Imatinib 800 mg N=822 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 10. Table 10 Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n=73) 600 mg (n=74) % % CTC Grades 1 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 1 CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 10 9 /L, Grade 4 <0.5 x 10 9 /L), thrombocytopenia (Grade 3 ≥10 - 50 x 10 9 /L, Grade 4 <10 x 10 9 /L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L) Adjuvant Treatment of GIST In Study 1, the majority of both Gleevec 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 Gleevec and placebo treated patients respectively. Edema, gastrointestinal 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 Gleevec 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 Gleevec are shown in Table 11 (Study 1) and Table 12 (Study 2). There were no deaths attributable to Gleevec treatment in either trial. Table 11: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (≥5% of Gleevec Treated Patients) (1) All CTC Grades CTC Grade 3 and above Gleevec (n=337) Placebo (n=345) Gleevec (n=337) Placebo (n=345) Preferred Term % % % % 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 (1) All adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Table 12: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (≥5% of Gleevec Treated Patients) Study 2 (1) Preferred Term All CTC Grades CTC Grades 3 and above Gleevec 12 Months (N=194) % Gleevec 36 Months (N=198) % Gleevec 12 Months (N=194) % Gleevec 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 Edema peripheral 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 (1) All adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. 6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec. Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema, Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, Clinical Laboratory Tests : Estimated 0.1%-1%: blood CPK increased, blood LDH increased, Estimated 0.01%-0.1%: blood amylase increased Dermatologic : Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae 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, erythema multiforme, leucocytoclastic vasculitis Digestive: 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 Hematologic : Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary : Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis 1 Hypersensitivity : Estimated 0.01%-0.1%: angioedema Infections : Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal : Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis Nervous System/Psychiatric : 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 pressure 1 , confusional state, convulsions, optic neuritis Renal : Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive : Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory : 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 Special Senses : Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema 1 , glaucoma, cataract 1 Including some fatalities 6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec. 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. Nervous system disorders : cerebral edema 1 Eye disorders : vitreous hemorrhage Cardiac disorders : pericarditis, cardiac tamponade 1 Vascular disorders : thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders : acute respiratory failure 1 , interstitial lung disease Gastrointestinal disorders : ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation 1 [ see Warnings and Precautions (5.6) ], diverticulitis Skin and subcutaneous tissue disorders : lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome Musculoskeletal and connective tissue disorders : avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children Reproduction disorders : hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1 Including some fatalities

17.3 Adverse Reactions Patients should be advised to tell their doctor if they experience side effects during Gleevec therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure.

<table ID="i78c3993d-541a-425b-8f60-dac93445d339"> <caption>Table 2 Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial (&#x2265;10% of Gleevec Treated Patients)⁽¹⁾ </caption> <col width="211"/> <col width="120"/> <col width="125"/> <col width="139"/> <col width="139"/> <tbody> <tr> <td align="center"/> <td colspan="2" align="center"> <content styleCode="bold">All Grades</content> </td> <td colspan="2" align="center"> <content styleCode="bold">CTC Grades 3/4</content> </td> </tr> <tr> <td align="center"/> <td align="center"> <content styleCode="bold">Gleevec</content> </td> <td align="center"> <content styleCode="bold">IFN+Ara&#x2212;C</content> </td> <td align="center"> <content styleCode="bold">Gleevec</content> </td> <td align="center"> <content styleCode="bold">IFN+Ara&#x2212;C</content> </td> </tr> <tr> <td> <content styleCode="bold">Preferred Term</content> </td> <td align="center"> <content styleCode="bold">N=551 (%)</content> </td> <td align="center"> <content styleCode="bold">N=533 (%)</content> </td> <td align="center"> <content styleCode="bold">N=551 (%)</content> </td> <td align="center"> <content styleCode="bold">N=533 (%)</content> </td> </tr> <tr> <td styleCode="Toprule ">Fluid Retention</td> <td styleCode="Toprule " align="center">61.7</td> <td styleCode="Toprule " align="center">11.1</td> <td styleCode="Toprule " align="center">2.5</td> <td styleCode="Toprule " align="center">0.9</td> </tr> <tr> <td>&#x2212; Superficial Edema</td> <td align="center">59.9</td> <td align="center">9.6</td> <td align="center">1.5</td> <td align="center">0.4</td> </tr> <tr> <td>&#x2212; Other Fluid Retention Reactions² </td> <td align="center">6.9</td> <td align="center">1.9</td> <td align="center">1.3</td> <td align="center">0.6</td> </tr> <tr> <td>Nausea</td> <td align="center">49.5</td> <td align="center">61.5</td> <td align="center">1.3</td> <td align="center">5.1</td> </tr> <tr> <td>Muscle Cramps</td> <td align="center">49.2</td> <td align="center">11.8</td> <td align="center">2.2</td> <td align="center">0.2</td> </tr> <tr> <td>Musculoskeletal Pain</td> <td align="center">47.0</td> <td align="center">44.8</td> <td align="center">5.4</td> <td align="center">8.6</td> </tr> <tr> <td>Diarrhea</td> <td align="center">45.4</td> <td align="center">43.3</td> <td align="center">3.3</td> <td align="center">3.2</td> </tr> <tr> <td>Rash and Related Terms</td> <td align="center">40.1</td> <td align="center">26.1</td> <td align="center">2.9</td> <td align="center">2.4</td> </tr> <tr> <td>Fatigue</td> <td align="center">38.8</td> <td align="center">67.0</td> <td align="center">1.8</td> <td align="center">25.1</td> </tr> <tr> <td>Headache</td> <td align="center">37.0</td> <td align="center">43.3</td> <td align="center">0.5</td> <td align="center">3.8</td> </tr> <tr> <td>Joint Pain</td> <td align="center">31.4</td> <td align="center">38.1</td> <td align="center">2.5</td> <td align="center">7.7</td> </tr> <tr> <td>Abdominal Pain</td> <td align="center">36.5</td> <td align="center">25.9</td> <td align="center">4.2</td> <td align="center">3.9</td> </tr> <tr> <td>Nasopharyngitis</td> <td align="center">30.5</td> <td align="center">8.8</td> <td align="center">0</td> <td align="center">0.4</td> </tr> <tr> <td>Hemorrhage</td> <td align="center">28.9</td> <td align="center">21.2</td> <td align="center">1.8</td> <td align="center">1.7</td> </tr> <tr> <td>- GI Hemorrhage</td> <td align="center">1.6</td> <td align="center">1.1</td> <td align="center">0.5</td> <td align="center">0.2</td> </tr> <tr> <td>- CNS Hemorrhage</td> <td align="center">0.2</td> <td align="center">0.4</td> <td align="center">0</td> <td align="center">0.4</td> </tr> <tr> <td>Myalgia</td> <td align="center">24.1</td> <td align="center">38.8</td> <td align="center">1.5</td> <td align="center">8.3</td> </tr> <tr> <td>Vomiting</td> <td align="center">22.5</td> <td align="center">27.8</td> <td align="center">2.0</td> <td align="center">3.4</td> </tr> <tr> <td>Dyspepsia</td> <td align="center">18.9</td> <td align="center">8.3</td> <td align="center">0</td> <td align="center">0.8</td> </tr> <tr> <td>Cough</td> <td align="center">20.0</td> <td align="center">23.1</td> <td align="center">0.2</td> <td align="center">0.6</td> </tr> <tr> <td>Pharyngolaryngeal Pain</td> <td align="center">18.1</td> <td align="center">11.4</td> <td align="center">0.2</td> <td align="center">0</td> </tr> <tr> <td>Upper Respiratory Tract Infection</td> <td align="center">21.2</td> <td align="center">8.4</td> <td align="center">0.2</td> <td align="center">0.4</td> </tr> <tr> <td>Dizziness</td> <td align="center">19.4</td> <td align="center">24.4</td> <td align="center">0.9</td> <td align="center">3.8</td> </tr> <tr> <td>Pyrexia</td> <td align="center">17.8</td> <td align="center">42.6</td> <td align="center">0.9</td> <td align="center">3.0</td> </tr> <tr> <td>Weight Increased</td> <td align="center">15.6</td> <td align="center">2.6</td> <td align="center">2.0</td> <td align="center">0.4</td> </tr> <tr> <td>Insomnia</td> <td align="center">14.7</td> <td align="center">18.6</td> <td align="center">0</td> <td align="center">2.3</td> </tr> <tr> <td>Depression</td> <td align="center">14.9</td> <td align="center">35.8</td> <td align="center">0.5</td> <td align="center">13.1</td> </tr> <tr> <td>Influenza</td> <td align="center">13.8</td> <td align="center">6.2</td> <td align="center">0.2</td> <td align="center">0.2</td> </tr> <tr> <td>Bone Pain</td> <td align="center">11.3</td> <td align="center">15.6</td> <td align="center">1.6</td> <td align="center">3.4</td> </tr> <tr> <td>Constipation</td> <td align="center">11.4</td> <td align="center">14.4</td> <td align="center">0.7</td> <td align="center">0.2</td> </tr> <tr> <td>Sinusitis</td> <td align="center">11.4</td> <td align="center">6.0</td> <td align="center">0.2</td> <td align="center">0.2</td> </tr> <tr> <td styleCode="Toprule " colspan="5"> ⁽¹⁾All adverse reactions occurring in &#x2265;10% of Gleevec treated patients are listed regardless of suspected relationship to treatment. ⁽²⁾Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.</td> </tr> </tbody> </table>

<table ID="i318f2952-074f-4371-87ca-126185ebbce1"> <caption>Table 3 Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (&#x2265;10% of All Patients in any Trial)⁽¹⁾ </caption> <col width="187"/> <col width="84"/> <col width="86"/> <col width="87"/> <col width="88"/> <col width="82"/> <col width="77"/> <tbody> <tr> <td valign="bottom"/> <td colspan="2" align="center"> <content styleCode="bold">Myeloid Blast Crisis</content> <content styleCode="bold">(n= 260)</content> </td> <td colspan="2" align="center"> <content styleCode="bold">Accelerated Phase</content> <content styleCode="bold">(n=235)</content> </td> <td colspan="2" align="center"> <content styleCode="bold">Chronic Phase, IFN Failure</content> <content styleCode="bold">(n=532)</content> </td> </tr> <tr> <td valign="bottom"/> <td colspan="2" valign="bottom" align="center"> <content styleCode="bold">%</content> </td> <td colspan="2" valign="bottom" align="center"> <content styleCode="bold">%</content> </td> <td colspan="2" valign="bottom" align="center"> <content styleCode="bold">%</content> </td> </tr> <tr> <td valign="bottom"> <content styleCode="bold">Preferred Term</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">All Grades</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">Grade 3/4</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">All Grades</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">Grade 3/4</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">All Grades</content> </td> <td valign="bottom" align="center"> <content styleCode="bold">Grade 3/4</content> </td> </tr> <tr> <td styleCode="Toprule " valign="bottom">Fluid Retention</td> <td styleCode="Toprule " valign="bottom" align="center">72</td> <td styleCode="Toprule " valign="bottom" align="center">11</td> <td styleCode="Toprule " valign="bottom" align="center">76</td> <td styleCode="Toprule " valign="bottom" align="center">6</td> <td styleCode="Toprule " valign="bottom" align="center">69</td> <td styleCode="Toprule " valign="bottom" align="center">4</td> </tr> <tr> <td valign="bottom"> -Superficial Edema</td> <td valign="bottom" align="center">66</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">74</td> <td valign="bottom" align="center">3</td> <td valign="bottom" align="center">67</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom"> -Other Fluid Retention Reactions ⁽²⁾ </td> <td valign="bottom" align="center">22</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">15</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom">Nausea</td> <td valign="bottom" align="center">71</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">73</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">63</td> <td valign="bottom" align="center">3</td> </tr> <tr> <td valign="bottom">Muscle Cramps</td> <td valign="bottom" align="center">28</td> <td valign="bottom" align="center">1</td> <td valign="bottom" align="center">47</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">62</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom">Vomiting</td> <td valign="bottom" align="center">54</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">58</td> <td valign="bottom" align="center">3</td> <td valign="bottom" align="center">36</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom">Diarrhea</td> <td valign="bottom" align="center">43</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">57</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">48</td> <td valign="bottom" align="center">3</td> </tr> <tr> <td valign="bottom">Hemorrhage</td> <td valign="bottom" align="center">53</td> <td valign="bottom" align="center">19</td> <td valign="bottom" align="center">49</td> <td valign="bottom" align="center">11</td> <td valign="bottom" align="center">30</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom"> - CNS Hemorrhage</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">3</td> <td valign="bottom" align="center">3</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">1</td> </tr> <tr> <td valign="bottom"> - GI Hemorrhage</td> <td valign="bottom" align="center">8</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">0.4</td> </tr> <tr> <td valign="bottom">Musculoskeletal Pain</td> <td valign="bottom" align="center">42</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">49</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">38</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom">Fatigue</td> <td valign="bottom" align="center">30</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">46</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">48</td> <td valign="bottom" align="center">1</td> </tr> <tr> <td valign="bottom">Skin Rash</td> <td valign="bottom" align="center">36</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">47</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">47</td> <td valign="bottom" align="center">3</td> </tr> <tr> <td valign="bottom">Pyrexia</td> <td valign="bottom" align="center">41</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">41</td> <td valign="bottom" align="center">8</td> <td valign="bottom" align="center">21</td> <td valign="bottom" align="center">2</td> </tr> <tr> <td valign="bottom">Arthralgia</td> <td valign="bottom" align="center">25</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">34</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">40</td> <td valign="bottom" align="center">1</td> </tr> <tr> <td valign="bottom">Headache</td> <td valign="bottom" align="center">27</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">32</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">36</td> <td valign="bottom" align="center">0.6</td> </tr> <tr> <td valign="bottom">Abdominal Pain</td> <td valign="bottom" align="center">30</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">33</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">32</td> <td valign="bottom" align="center">1</td> </tr> <tr> <td valign="bottom">Weight Increased</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">1</td> <td valign="bottom" align="center">17</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">32</td> <td valign="bottom" align="center">7</td> </tr> <tr> <td valign="bottom">Cough</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0.8</td> <td valign="bottom" align="center">27</td> <td valign="bottom" align="center">0.9</td> <td valign="bottom" align="center">20</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Dyspepsia</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">22</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">27</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Myalgia</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">24</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">27</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Nasopharyngitis</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">17</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">22</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Asthenia</td> <td valign="bottom" align="center">18</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">21</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">15</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Dyspnea</td> <td valign="bottom" align="center">15</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">21</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0.9</td> </tr> <tr> <td valign="bottom">Upper Respiratory Tract Infection</td> <td valign="bottom" align="center">3</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">19</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Anorexia</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">17</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Night Sweats</td> <td valign="bottom" align="center">13</td> <td valign="bottom" align="center">0.8</td> <td valign="bottom" align="center">17</td> <td valign="bottom" align="center">1</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Constipation</td> <td valign="bottom" align="center">16</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">16</td> <td valign="bottom" align="center">0.9</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">0.4</td> </tr> <tr> <td valign="bottom">Dizziness</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">13</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">16</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Pharyngitis</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">15</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Insomnia</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Pruritus</td> <td valign="bottom" align="center">8</td> <td valign="bottom" align="center">1</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0.9</td> <td valign="bottom" align="center">14</td> <td valign="bottom" align="center">0.8</td> </tr> <tr> <td valign="bottom">Hypokalemia</td> <td valign="bottom" align="center">13</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">0.8</td> </tr> <tr> <td valign="bottom">Pneumonia</td> <td valign="bottom" align="center">13</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">1</td> </tr> <tr> <td valign="bottom">Anxiety</td> <td valign="bottom" align="center">8</td> <td valign="bottom" align="center">0.8</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">8</td> <td valign="bottom" align="center">0.4</td> </tr> <tr> <td valign="bottom">Liver Toxicity</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">5</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">3</td> </tr> <tr> <td valign="bottom">Rigors</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">12</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0</td> </tr> <tr> <td valign="bottom">Chest Pain</td> <td valign="bottom" align="center">7</td> <td valign="bottom" align="center">2</td> <td valign="bottom" align="center">10</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">11</td> <td valign="bottom" align="center">0.8</td> </tr> <tr> <td valign="bottom">Influenza</td> <td valign="bottom" align="center">0.8</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">6</td> <td valign="bottom" align="center">0</td> <td valign="bottom" align="center">11</td> <td valign="bottom" align="center">0.2</td> </tr> <tr> <td valign="bottom">Sinusitis</td> <td valign="bottom" align="center">4</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">11</td> <td valign="bottom" align="center">0.4</td> <td valign="bottom" align="center">9</td> <td valign="bottom" align="center">0.4</td> </tr> <tr> <td styleCode="Toprule " colspan="7" valign="bottom"> ⁽¹⁾ All adverse reactions occurring in &#x2265;10% of patients are listed regardless of suspected relationship to treatment. ⁽²⁾ Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.</td> </tr> </tbody> </table>