Imatinib

1 INDICATIONS AND USAGE Imatinib mesylate tablets are a kinase inhibitor indicated for the treatment of: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy. ( 1.2 ) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ( 1.3 ) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. ( 1.4 ) Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. ( 1.5 ) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. ( 1.6 ) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. ( 1.7 ) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). ( 1.8 ) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). ( 1.9 ) Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. ( 1.10 ) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

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 ) Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or 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. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. ( 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 (GI) perforations, some fatal, have been reported. ( 5.6 ) Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of imatinib mesylate tablets 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 imatinib mesylate tablets. ( 5.8 ) Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients. ( 5.9 ) Fetal harm can occur when administered to a pregnant woman. Apprise women of the potential harm to the fetus, and to use effective contraception. ( 5.10 , 8.1 ) Growth retardation occurring in children and pre-adolescents receiving imatinib mesylate tablets has been reported. Close monitoring of growth in children under imatinib mesylate tablets treatment is recommended. ( 5.11 , 6.2 ) Tumor Lysis Syndrome. Close monitoring is recommended. ( 5.12 ) Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate tablets. Caution patients about driving a car or operating machinery. ( 5.13 ) Renal Toxicity. A decline in renal function may occur in patients receiving imatinib mesylate tablets. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction. ( 5.14 ) 5.1 Fluid Retention and Edema Imatinib mesylate is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) ] . Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib mesylate dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. 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 imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate for GIST [see Adverse Reactions (6.1) ] . In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib mesylate arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm. 5.2 Hematologic Toxicity Treatment with imatinib mesylate is associated with anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 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 (2.14) ] . 5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib mesylate. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib mesylate compared to 0.9% of patients taking IFN+Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib mesylate arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with imatinib mesylate [see Adverse Reactions (6.1) ] . Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib mesylate. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with imatinib mesylate interruption and/or dose reduction [see Dosage and Administration (2.13) ] . When imatinib mesylate 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 a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 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. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib mesylate arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience. 5.6 Gastrointestinal Disorders Imatinib mesylate is sometimes associated with GI irritation. Imatinib mesylate tablets should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation. 5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with imatinib mesylate 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 imatinib mesylate. 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 rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate therapy after resolution or improvement of the bullous reaction. In these instances, imatinib mesylate 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 imatinib mesylate. Monitor TSH levels in such patients. 5.10 Embryo-Fetal Toxicity Imatinib mesylate 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 (BSA). 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 BSA. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate and for 14 days after stopping imatinib mesylate. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . 5.11 Growth Retardation in Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate. The long-term effects of prolonged treatment with imatinib mesylate on growth in children are unknown. Therefore, monitor growth in children under imatinib mesylate treatment [see Adverse Reactions (6.1) ] . 5.12 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 imatinib mesylate. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate. 5.13 Impairments Related to Driving and Using Machinery Motor vehicle accidents have been reported in patients receiving imatinib mesylate. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate. Recommend caution when driving a car or operating machinery. 5.14 Renal Toxicity A decline in renal function may occur in patients receiving imatinib mesylate. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib mesylate tablets 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m2 (N = 1190) to 75 mL/min/1.73 m 2 at 12 months (N = 1082) and 69 mL/min/1.73 m 2 at 60 months (N = 549). Evaluate renal function prior to initiating imatinib mesylate and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

6 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) ] The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 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 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 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 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 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 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 1 Including some fatalities. 6.2 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 perforation1 [see Warnings and Precautions (5.6) ] , diverticulitis, gastric antral vascular ectasia Infections: hepatitis B virus reactivation1 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 edema1 Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure1, 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 1 Including some fatalities.

7 DRUG INTERACTIONS CYP3A4 inducers may decrease imatinib mesylate tablets Cmax and area under curve (AUC). ( 2.12 , 7.1 , 12.3 ) CYP3A4 inhibitors may increase imatinib mesylate tablets Cmax and AUC. ( 7.2 , 12.3 ) Imatinib mesylate tablets are an inhibitor of CYP3A4 and CYP2D6 which may increase the Cmax and AUC of other drugs. ( 7.3 , 7.4 , 12.3 ) Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. ( 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3) ] . 7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3) ] . 7.3 Interactions With Drugs Metabolized by CYP3A4 Imatinib mesylate tablets will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology (12.3) ] . 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window.

Drug Interactions Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate tablets, increased imatinib mesylate tablets oral-dose clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC. Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib mesylate tablets concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of imatinib mesylate tablets and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib mesylate tablets doses up to 1,200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.12) ] . Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean C max and AUC increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate tablets were coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Interactions with Drugs Metabolized by CYP3A4 Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate tablets. Particular caution is recommended when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus). Imatinib mesylate tablets will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin. Interactions with Drugs Metabolized by CYP2D6 Imatinib mesylate tablets increased the mean C max and AUC of metoprolol by approximately 23% suggesting that imatinib mesylate tablets have a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window. Interactions with Acetaminophen In vitro , imatinib mesylate tablets inhibit the acetaminophen O-glucuronidate pathway (K i 58.5 μM). Coadministration of imatinib mesylate tablets (400 mg/day for 8 days) with acetaminophen (1,000 mg single dose on Day 8) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Imatinib mesylate tablets pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of imatinib mesylate tablets at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate tablets.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day. 8.2 Lactation Risk Summary Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from imatinib mesylate, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose. Human Data Based on data from 3 breastfeeding women taking imatinib mesylate tablets, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. 8.3 Females and Males of Reproductive Potential Human postmarketing reports and animal studies have shown imatinib mesylate to be harmful to the developing fetus [see Use in Specific Populations (8.1) ] . Pregnancy Testing Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib mesylate tablets. Contraception Females Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate tablets during treatment and for fourteen days after stopping treatment with imatinib mesylate tablets [see Use in Specific Populations (8.1) ] . Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13) ] . 8.4 Pediatric Use The safety and effectiveness of imatinib mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2 , 14.4) ] . There are no data in children under 1 year of age. 8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1) ] . The efficacy of imatinib mesylate tablets was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of imatinib mesylate tablets was similar in patients older than 65 years and younger patients. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, the imatinib Cmax and area under curve (AUC) increased by 63% and 45% and the CGP74588 Cmax and AUC increased by 56% and 55%, relative to patients with normal hepatic function [see Clinical Pharmacology (12.3) ] . Reduce the dose by 25% for patients with severe hepatic impairment [see Dosage and Administration (2.12) ] . Table 16: Liver Function Classification Abbreviation: SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); ULN, upper limit of normal for the institution. Liver Function Test Normal (n = 14) Mild (n = 30) Moderate (n = 20) Severe (n = 20) Total Bilirubin less than or equal to ULN greater than 1.0-1.5 times the ULN greater than 1.5-3 times the ULN greater than 3-10 times the ULN SGOT less than or equal to ULN greater than ULN (can be normal if Total Bilirubin is greater than ULN) Any Any 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment [see Clinical Pharmacology (12.3) ] . Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2.12) ] . Table 17: Renal Function Classification Abbreviation: CrCL, creatinine clearance. Renal Dysfunction Renal Function Tests Mild CrCL = 40-59 mL/min Moderate CrCL = 20-39 mL/min Severe CrCL = less than 20 mL/min

8.1 Pregnancy Risk Summary Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

10 OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of imatinib mesylate tablets overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment. Adult Overdose: 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate tablets daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate tablets daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of imatinib mesylate tablets on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose: One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.