Imatinib Oral

1 INDICATIONS AND USAGE Imkeldi is 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.

2 DOSAGE AND ADMINISTRATION Adults with Ph+ CML CP ( 2.2 ): 400 mg/day Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day Adults with Ph+ ALL ( 2.4 ): 600 mg/day Pediatrics with Ph+ ALL ( 2.5 ): 340 mg/m 2 /day Adults with MDS/MPD ( 2.6 ): 400 mg/day Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day Adults with DFSP ( 2.9 ): 800 mg/day Adults with metastatic and/or unresectable GIST ( 2.10 ): 400 mg/day Adjuvant treatment of adults with GIST ( 2.11 ): 400 mg/day Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device. A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. ( 2.1 , 5.15 ) 2.1 Important Administration Instructions All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, and a dose of 800 mg should be administered as 400 mg twice a day. If a dose is missed, the patient should wait until the next scheduled dose and not take two doses at the same time. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device [see Warnings and Precautions (5.15) , Instructions for Use ]. A household teaspoon is not an accurate measuring device. A pharmacist can provide a press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. Recommendations for Dose Rounding Round each dose to the nearest measurable graduation mark on the oral syringe, if necessary [see Instructions for Use ] . Continue treatment until disease progression or unacceptable toxicity. Imkeldi is a hazardous drug. Follow applicable special handling and disposal procedures 1 . 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dosage of Imkeldi is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dosage of Imkeldi for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose or the daily dose may be split into two–one portion doses in the morning and one portion in the evening. There is no experience with Imkeldi treatment in children under 1 year of age. Follow recommendations for dose rounding [see Dosage and Administration (2.1) ]. 2.4 Adult Patients With Ph+ ALL The recommended dosage of Imkeldi is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dosage of Imkeldi to be given in combination with chemotherapy to pediatric patients with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose. Follow recommendations for dose rounding [see Dosage and Administration (2.1) ]. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dosage of Imkeldi is 400 mg/day for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dosage of Imkeldi is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c- Kit mutational status is not known or unavailable, treatment with Imkeldi 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.8 Adult Patients With HES/CEL The recommended dosage of Imkeldi is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.9 Adult Patients With DFSP The recommended dosage of Imkeldi is 800 mg/day for adult patients with DFSP. 2.10 Adult Patients With Metastatic and/or Unresectable GIST The recommended dosage of Imkeldi is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 2.11 Adult Patients With Adjuvant GIST The recommended dosage of Imkeldi is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib and three years of imatinib were studied. In the patient population defined in Study 2, three years of Imkeldi is recommended [see Clinical Studies (14.8) ] . The optimal treatment duration with Imkeldi is not known. 2.12 Dosage Modifications for Drug Interactions, Hepatic Impairment, and Renal Impairment Drug Interactions Concomitant Strong CYP3A4 inducers Avoid concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital) with Imkeldi. If concomitant use with a strong CYP3A4 inducer cannot be avoided the Imkeldi dosage should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1) ]. Hepatic Impairment A 25% decrease in the approved recommended Imkeldi dosage should be used for patients with severe hepatic impairment (total bilirubin ˃3 to 10 times upper limit of normal [ULN] and any value for AST) [see Use in Specific Populations (8.6) ] . Patients with mild hepatic impairment (total bilirubin ≤ ULN and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) do not require a dose adjustment and should be treated per the approved recommended dosage. Renal Impairment Imkeldi should be used with caution in patients with severe renal impairment [see Warnings and Precautions (5.3) , Use in Specific Populations (8.7) ] . Patients with moderate renal impairment (creatinine clearance [CLcr] = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CLcr = 40-59 mL/min). Doses greater than 400 mg are not recommended for patients with moderate renal impairment. 2.13 Dosage Modifications for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Imkeldi should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with Imkeldi may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m 2 /day to 260 mg/m 2 /day. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imkeldi should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the reaction. 2.14 Dosage Modifications for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1. Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Imkeldi until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Imkeldi until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Imkeldi until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Imkeldi at the original starting dose of 400 mg If recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Imkeldi at a reduced dose of 300 mg Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) ANC less than 0.5 x 10 9 /L and/or platelets less than 10 x 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of Imkeldi to 400 mg If cytopenia persists 2 weeks, reduce further to 300 mg If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Imkeldi until ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Imkeldi until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Imkeldi at 600 mg In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Imkeldi at reduced dose of 400 mg Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2 ) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Imkeldi until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Imkeldi at reduced dose of 260 mg/m 2 Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.

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 (≥30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shorla Oncology at 844-9-SHORLA 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-treated patients experienced adverse reactions at some time. Imatinib was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib versus IFN+Ara-C, and in 12.5% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib and nilotinib. Imatinib 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 [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 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-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 Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib-Treated Patients) All adverse reactions occurring in greater than or equal to 10% of imatinib-treated patients are listed regardless of suspected relationship to treatment. All Grades CTC Grades NCI Common Terminology Criteria for Adverse Events, version 3.0. 3/4 Preferred term Imatinib N = 551 (%) IFN+Ara-C N = 533 (%) Imatinib 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 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. 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 Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysis Excluding laboratory abnormalities. Patients with newly diagnosed Ph+ CML-CP Imatinib 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Imatinib 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Body system and preferred term 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 Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. 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. 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 Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha. 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, but may require permanent discontinuation of treatment. Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Imatinib Versus IFN+Ara-C) Imatinib 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 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). 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 Versus Nilotinib) Imatinib 400 mg once daily Nilotinib 300 mg twice daily N = 280 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 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). Table 7: Laboratory Abnormalities in Other CML Clinical Trials Myeloid blast crisis Accelerated phase Chronic phase, IFN failure (n = 260) (n = 235) (n = 532) 600 mg n = 223 600 mg n = 158 400 mg n = 37 400 mg n = 77 400 mg % % % CTC Grades CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 10 9 /L, Grade 4 less than 10 x 10 9 /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 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). 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 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 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 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. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib, and 647 without imatinib. 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 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%) Adverse event Per patient incidence Ph+ ALL with Imatinib N = 92 n (%) Per patient incidence Ph- ALL no Imatinib N = 65 n (%) Per patient per cycle incidence with Imatinib Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib (includes patients with Ph+ ALL that received cycles with imatinib). N = 778 n (%) Per patient per cycle incidence no Imatinib Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib (includes patients with Ph+ ALL that received cycles without imatinib as well as all patients with Ph- ALL who did not receive imatinib in any treatment cycle). N = 647 n (%) Grade 3 and 4 adverse events 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) Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia. 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. Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib 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 N = 7 Preferred term 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) Abbreviation: MPD, myeloproliferative disease. 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 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 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 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 N = 12 Preferred term 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) Abbreviation: DFSP, dermatofibrosarcoma protuberans. Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib 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 N = 12 CTC Grades CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 10 9 /L, Grade 4 less than 10 x 10 9 /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). Grade 3 % Grade 4 % Hematology parameters - Anemia 17 0 - Thrombocytopenia 17 0 - Neutropenia 0 8 Biochemistry parameters - Elevated creatinine 0 8 Abbreviation: CTC, common terminology criteria. Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials, the majority of imatinib-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 [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 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 Imatinib 400 mg N = 818 Imatinib 800 mg N = 822 All Grades Grades 3/4/5 All Grades Grades 3/4/5 Reported or specified term % % % % 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 Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors. 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 400 mg (n = 73) % 600 mg (n = 74) % CTC Grades CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5-1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10-50 x 10 9 /L, Grade 4 less than 10 x 10 9 /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). 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 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). Adjuvant Treatment of GIST In Study 1, the majority of both imatinib 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 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 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 are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib 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-Treated Patients) All adverse reactions occurring in greater than or equal to 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. All CTC Grades CTC Grade 3 NCI Common Terminology Criteria for Adverse Events, version 3.0. and Above Imatinib Placebo Imatinib Placebo (n = 337) (n = 345) (n = 337) (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 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). 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-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. 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 12 Months Imatinib 36 Months Imatinib 12 Months Imatinib 36 Months (N = 194) (N = 198) (N = 194) (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 Dry skin 6.7 6.1 0.5 Nasopharyngitis 1.0 6.1 0 0.5 Palpitations 5.2 5.1 0 0 Abbreviations: AE, adverse event; CTC, common terminology criteria. 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 pressure 1 , 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%: papilledema 1 , glaucoma 1 Including some fatalities. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of imatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : thrombotic microangiopathy Cardiac Disorders : pericarditis, cardiac tamponade 1 Eye Disorders : vitreous hemorrhage Gastrointestinal Disorders : ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation 1 [see Warnings and Precautions (5.6) ] , diverticulitis, gastric antral vascular ectasia Infections : hepatitis B virus reactivation 1 Musculoskeletal and Connective Tissue Disorders : osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthralgia, bone pain) Nervous System Disorders : cerebral edema 1 Reproduction Disorders : hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders : acute respiratory failure 1 , interstitial lung disease Skin and Subcutaneous Tissue Disorders : lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus Vascular Disorders : thrombosis/embolism, anaphylactic shock 1 Including some fatalities.

12.3 Pharmacokinetics The pharmacokinetics of imatinib have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. No clinically significant difference in imatinib pharmacokinetics were observed between CML and GIST patients. Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1000 mg (0.06 to 1.25 times the approved recommended dosage of 400 mg). Imatinib accumulation is 1.5- to 2.5- fold at steady state when imatinib is dosed once daily. Absorption Imatinib mean absolute bioavailability is 98%. Imatinib is well absorbed after oral administration with maximum concentration (C max ) achieved within 2-4 hours post-dose. Distribution Imatinib and the N-demethylated metabolite (CGP74588) plasma protein binding is approximately 95% in vitro, mostly to albumin and α1-acid glycoprotein. Elimination The elimination half-life is approximately 18 hours for imatinib and 40 hours for the N-demethyl derivative metabolite (CGP74588), following oral administration in healthy volunteers. Typical imatinib clearance in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity. Metabolism CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative (CGP74588), formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. Excretion Imatinib elimination is predominately in the feces, mostly as metabolites. Following an oral radio-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Specific Populations 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 and varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN) and moderately (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) hepatically-impaired groups and the normal group. Patients with severe hepatic impairment (Total bilirubin ˃ 3 to 10 times ULN and any value for AST) tend to have higher exposure to both imatinib and CGP74588 than patients with normal hepatic function. At steady state, the mean C max /dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean C max /dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (AUC/dose) in patients with mild (CLcr = 40-59 mL/min) and moderate (CLcr = 20-39 mL/min) renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment (CLcr = less than 20 mL/min) were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Pediatric Use Dosing in a limited number of children at both 260 mg/m 2 and 340 mg/m 2 (0.76 and 1 times the approved recommended dosage) achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs Day 1 at 260 mg/m 2 and 340 mg/m 2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose. Another analysis suggested that exposure of imatinib in pediatric patients receiving 260 mg/m 2 once daily (not exceeding 400 mg once daily) or 340 mg/m 2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily. Imatinib time to C max is 2-4 hours in pediatric patients which is similar to adult patients. Apparent oral clearance was also similar to adult values (11.0 L/hr/m 2 in children vs 10.0 L/hr/m 2 in adults), as was the half-life (14.8 hours in children vs 17.1 hours in adults). Imatinib clearance increases with increasing BSA in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib). After correcting for this BSA effect, other demographics, such as age, body weight, and body mass index did not have clinically significant effects on the exposure of imatinib. Drug Interactions Clinical Studies Agents Inducing CYP3A Metabolism Imatinib oral-dose clearance increased by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC, following pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib. Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib 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 and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Agents Inhibiting CYP3A Metabolism There was a significant increase in imatinib exposure (mean C max increased by 26% and mean AUC increased by 40%) in healthy subjects following concomitant use of imatinib with a single dose of ketoconazole (CYP3A4 inhibitor). Interactions with Drugs Metabolized by CYP3A4 Simvastatin (CYP3A4 substrate) mean C max increased 2-fold and AUC 3.5-fold, following concomitant use with imatinib. Interactions with Drugs Metabolized by CYP2D6 Metoprolol (CYP2D6 substrate) mean C max and AUC increased by approximately 23% following concomitant use with imatinib. Interactions with Acetaminophen Imatinib inhibits the acetaminophen O-glucuronidate pathway in vitro. No clinically significant differences in the pharmacokinetics of acetaminophen or imatinib were observed when acetaminophen (1,000 mg single dose on Day 8) was used concomitantly with imatinib (400 mg/day for 8 days) in patients with CML. There is no pharmacokinetic or safety data on the concomitant use of imatinib at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib. In vitro Studies CYP450 Metabolism: Imatinib is a substrate of CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Imatinib is a competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5.