Imatinib

12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo , imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

1 INDICATIONS AND 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 ) • 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

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 imatinib mesylate tablets should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg (imatinib as free base) should be administered once daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg (imatinib as free base) and above should be accomplished using the 400 mg tablet (imatinib as free base) 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 (imatinib as free base) should be administered once daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) 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 (imatinib as free base) and above, dosing should be accomplished using the 400-mg (imatinib as free base) 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 tablets is 400 mg/day (imatinib as free base) for adult patients in chronic phase CML and 600 mg/day (imatinib as free base) for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg (imatinib as free base) in adult patients with chronic phase disease, or from 600 mg to 800 mg (imatinib as free base) (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 tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (imatinib as free base) (not to exceed 600 mg). Imatinib mesylate tablets 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 treatment in children under 1 year of age. 2.4 Adult Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets is 600 mg/day (imatinib as free base) for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) 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 tablets 400 mg/day (imatinib as free base) 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 (i

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 ( 5.1 4 ) ] 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 Apotex Corp. at 1-800-706-5575 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 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 [ see Dosage and Administration ( 2.13 ) ]. The frequency of severe superficial edema was 1.5% to 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 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 1.8 25.1 Headache 37 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 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20 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 Weight increased 15.6 2.6 2 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 0.2 0.2 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CT

7 DRUG INTERACTIONS 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 ) Imatinib mesylate tablets delay the clearance of methotrexate when methotrexate is used at high doses (> 500 mg/m 2 ). ( 7.5 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology ( 12.3 )] . 7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology ( 12.3 )] . 7.3 Interactions With Drugs Metabolized by CYP3A4 Imatinib mesylate will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology ( 12.3 )] . 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering imatinib mesylate with CYP2D6 substrates that have a narrow therapeutic window. 7.5 Interactions With Methotrexate Imatinib mesylate tablets delay the clearance of methotrexate and result in sustained methotrexate concentrations when methotrexate is used at high doses (>500 mg/m 2 ). Refer to the prescribing information for methotrexate injection for recommendations on management of methotrexate concentrations.