IMATINIB MESYLATE 400 MG

Imatinib is a small molecule kinase inhibitor. Imatinib mesylate film-coated tablets contain Imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl­1-piperazinyl) methy1]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate and Its structural formula is Imatinib mesylate is a off white to pale yellow crystalline powder. Its molecular formula is C 29 H 31 N 7 O·CH 4 SO 3 and its molecular weight is 589.7. Imatinib mesylate is soluble in water, slightly soluble in methanol and Dimethyl sulphoxide. Inactive Ingredients: Povidone (USP) and Magnesium Stearate (NF). Tablet coating: Hypromellose (USP), yellow iron oxide (NF), poly ethylene glycol (NF), talc (USP), titanium dioxide (USP), and red iron oxide (NF). image description

INDICATIONS & USAGE Imatinib mesylate 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 ) Adult patients with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements as determined with an FDA-approved test ( 1.5 ) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation as determined with an FDA-approved test 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 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 ) 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). 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/ myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements as determined with an FDA-approved test [see Dosage and Administration ( 2.6 )] 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test [see Dosage and Administration ( 2.7 )] 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 FIP1L1­PDGFRα fusion kinase (mutational analysis or 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.

DOSAGE & 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 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 Patients with mild to moderate hepatic impairment ( 2.12 ): 400mg/day Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of Imatinib mesylate tablets 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. Imatinib mesylate tablet can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400 mg tablet to reduce exposure to iron. 2.1 Drug Administration The prescribed dose should be administered orally, 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. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. 2.2 Adult Patients with Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate 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 dose of imatinib mesylate tablet for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg).Imatinib mesylate treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening. There is no experience with imatinib mesylate tablet treatment in children under 1 year of age 2.4 Adults Patients with Ph+ ALL The recommended dose of Imatinib mesylate tablet is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.6 Adult Patients with MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. Information on FDA approved tests for the detection of PDGFRb rearrangements is available at http://www.fda.gov/companiondiagnostics. The recommended dose of imatinib mesylate 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. Information on FDA-approved test for the detection of D816V c-Kit mutation is available at http://www.fda.gov/companiondiagnostics. The recommended dose of imatinib mesylate 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 imatinib mesylate 400mg/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 dose of imatinib mesylate 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 dose of imatinib mesylate is 800 mg/day for adult patients with DFSP. 2.12 Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided(e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of imatinib mesylate should be increased by at least 50%, and clinical response should be carefully monitored [ see Drug Interactions ( 7.1 ) ]. Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [ see Use in Specific Populations ( 8.6 ) ]. Renal Impairment: Patients with moderate renal impairment (CrCL = 20 - 39 mL/min) should be 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 (CrCL = 40 - 59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment [ See Warnings and Precautions (5.3) , Use in Specific Populations ( 8.7 ) ]. 2.13 Dose Adjustment 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, imatinib mesylate 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 imatinib mesylate 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), imatinib mesylate should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. 2.14 Dose Adjustment 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 1 less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate 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 Imatinib mesylate tablet at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1.0 x 10 9 /L and/or platelets less than 50x 10 9 /L Stop imatinib mesylate 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 imatinib mesylate 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) ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x10 9 /L Stop imatinib mesylate 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 imatinib mesylate at the original starting dose of 400 mg If recurrence of ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate 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 x10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate 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 imatinib mesylate 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

None None (4)

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%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-557 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) (1) All Grades CTC Grades 3/4 Imatinib mesylate IFN+Ara−C Imatinib mesylate IFN+Ara−C Preferred Term N = 551 (%) N = 533 (%) N = 551 (%) N = 533 (%) Fluid Retention 61.7 11.1 2.5 0.9 − Superficial Edema 59.9 9.6 1.5 0.4 − Other Fluid Retention Reactions 2 6.9 1.9 1.3 0.6 Nausea 49.5 61.5 1.3 5.1 Muscle Cramps 49.2 11.8 2.2 0.2 Musculoskeletal Pain 47.0 44.8 5.4 8.6 Diarrhea 45.4 43.3 3.3 3.2 Rash and Related Terms 40.1 26.1 2.9 2.4 Fatigue 38.8 67.0 1.8 25.1 Headache 37.0 43.3 0.5 3.8 Joint Pain 31.4 38.1 2.5 7.7 Abdominal Pain 36.5 25.9 4.2 3.9 Nasopharyngitis 30.5 8.8 0 0.4 Hemorrhage 28.9 21.2 1.8 1.7 - GI Hemorrhage 1.6 1.1 0.5 0.2 - CNS Hemorrhage 0.2 0.4 0 0.4 Myalgia 24.1 38.8 1.5 8.3 Vomiting 22.5 27.8 2.0 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20.0 23.1 0.2 0.6 Pharyngolaryngeal Pain 18.1 11.4 0.2 0 Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4 Dizziness 19.4 24.4 0.9 3.8 Pyrexia 17.8 42.6 0.9 3.0 Weight Increased 15.6 2.6 2.0 0.4 Insomnia 14.7 18.6 0 2.3 Depression 14.9 35.8 0.5 13.1 Influenza 13.8 6.2 0.2 0.2 Bone Pain 11.3 15.6 1.6 3.4 Constipation 11.4 14.4 0.7 0.2 Sinusitis 11.4 6.0 0.2 0.2 (1) All adverse reactions occurring in greater than or equal to 10% of imatinib mesylate treated patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Table 3: 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 a Patients with Newly Diagnosed Ph+ CML-CP imatinib mesylate tablet 400 mg once-daily N=280 nilotinib 300 mg twice-daily N=279 imatinib mesylate tablet 400 mg once-daily N=280 nilotinib 300 mg twice-daily N=279 Body System and Preferred Term All Grades (%) CTC Grades b 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 a Excluding laboratory abnormalities b NCI Common Terminology Criteria for Adverse Events, Version 3.0 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) (1) Myeloid Blast Crisis Accelerated Phase Chronic Phase, IFN Failure (n = 260) (n = 235) (n = 532) % % % Preferred Term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Fluid Retention 72 11 76 6 69 4 -Superficial Edema 66 6 74 3 67 2 -Other Fluid Retention Reactions (2) 22 6 15 4 7 2 Nausea 71 5 73 5 63 3 Muscle Cramps 28 1 47 0.4 62 2 Vomiting 54 4 58 3 36 2 Diarrhea 43 4 57 5 48 3 Hemorrhage 53 19 49 11 30 2 - CNS Hemorrhage 9 7 3 3 2 1 - GI Hemorrhage 8 4 6 5 2 0.4 Musculoskeletal Pain 42 9 49 9 38 2 Fatigue 30 4 46 4 48 1 Skin Rash 36 5 47 5 47 3 Pyrexia 41 7 41 8 21 2 Arthralgia 25 5 34 6 40 1 Headache 27 5 32 2 36 0.6 Abdominal Pain 30 6 33 4 32 1 Weight Increased 5 1 17 5 32 7 Cough 14 0.8 27 0.9 20 0 Dyspepsia 12 0 22 0 27 0 Myalgia 9 0 24 2 27 0.2 Nasopharyngitis 10 0 17 0 22 0.2 Asthenia 18 5 21 5 15 0.2 Dyspnea 15 4 21 7 12 0.9 Upper Respiratory Tract Infection 3 0 12 0.4 19 0 Anorexia 14 2 17 2 7 0 Night Sweats 13 0.8 17 1 14 0.2 Constipation 16 2 16 0.9 9 0.4 Dizziness 12 0.4 13 0 16 0.2 Pharyngitis 10 0 12 0 15 0 Insomnia 10 0 14 0 14 0.2 Pruritus 8 1 14 0.9 14 0.8 Hypokalemia 13 4 9 2 6 0.8 Pneumonia 13 7 10 7 4 1 Anxiety 8 0.8 12 0 8 0.4 Liver Toxicity 10 5 12 6 6 3 Rigors 10 0 12 0.4 10 0 Chest Pain 7 2 10 0.4 11 0.8 Influenza 0.8 0.4 6 0 11 0.2 Sinusitis 4 0.4 11 0.4 9 0.4 (1) All adverse reactions occurring in ≥ 10% of patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. 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) Imatinib mesylate N = 551 % IFN+Ara-C N = 533 % CTC Grades Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters* − Neutropenia* 13.1 3.6 20.8 4.5 − Thrombocytopenia* 8.5 0.4 15.9 0.6 − Anemia 3.3 1.1 4.1 0.2 Biochemistry Parameters − Elevated Creatinine 0 0 0.4 0 − Elevated Bilirubin 0.9 0.2 0.2 0 − Elevated Alkaline Phosphatase 0.2 0 0.8 0 − Elevated SGOT /SGPT 4.7 0.5 7.1 0.4 *p < 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups) Table 6: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib Mesylate versus nilotinib). Imatinib mesylate tablet 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 *NCI Common Terminology Criteria for Adverse Events, version 3.0 Table 7: Laboratory Abnormalities in Other CML Clinical Trials 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 1 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters − Neutropenia 16 48 23 36 27 9 − Thrombocytopenia 30 33 31 13 21 < 1 − Anemia 42 11 34 7 6 1 Biochemistry Parameters − Elevated Creatinine 1.5 0 1.3 0 0.2 0 − Elevated Bilirubin 3.8 0 2.1 0 0.6 0 − Elevated Alkaline Phosphatase 4.6 0 5.5 0.4 0.2 0 − Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0 − Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0 1 CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 to 1.0 x 10 9 /L, Grade 4 < 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) 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. 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. 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 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 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 gastrointestinal, 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 Preferred term N = 12 n (%) Nausea 5 (41.7) Diarrhea 3 (25.0) Vomiting 3 (25.0) Periorbital Edema 4 (33.3) Face Edema 2 (16.7) Rash 3 (25.0) Fatigue 5 (41.7) Edema Peripheral 4 (33.3) Pyrexia 2 (16.7) Eye Edema 4 (33.3) Lacrimation Increased 3 (25.0) Dyspnea Exertional 2 (16.7) Anemia 3 (25.0) Rhinitis 2 (16.7) Anorexia 2 (16.7) Clinically relevant or severe laboratory abnormalities in the 12 patients treated with 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 N = 12 CTC Grades 1 Grade 3 (%) Grade 4 (%) Hematology Parameters - Anemia 17 0 - Thrombocytopenia 17 0 - Neutropenia 0 8 Biochemistry Parameters - Elevated Creatinine 0 8 1 CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 – 1 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) 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 CPK increased, blood amylase increased Estimated 0.1%–1%: blood 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 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 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 mesylate tablets. 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. Infections: hepatitis B virus reactivation 1 Nervous System Disorders : cerebral edema 1 Eye Disorders: vitreous hemorrhage Cardiac Disorders : pericarditis, cardiac tamponade 1 Vascular Disorders : thrombosis/embolism, anaphylactic shock Respiratory, Thoracic and Mediastinal Disorders : acute respiratory failure 1 , interstitial lung disease Gastrointestinal Disorders : ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation 1 [ see Warnings and Precautions (5.6) ], diverticulitis, gastric antral vascular ectasia 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. Musculoskeletal and Connective Tissue Disorders : avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain) Reproduction Disorders : hemorrhagic corpus luteum/hemorrhagic ovarian cyst Blood and Lymphatic System Disorder s : thrombotic microangiopathy 1 Including some fatalities

CYP3A4 inducers may decrease imatinib mesylate C max and area under curve (AUC). ( 2.12 , 7.1 , 12.3 ) CYP3A4 inhibitors may increase imatinib mesylate C max and AUC. ( 7.2 , 12.3 ) Imatinib mesylate is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max 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 tablet 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 tablet 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 tablet 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 tablet 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 tablet with CYP2D6 substrates that have a narrow therapeutic window.