IMATINIB MESYLATE- imatinib mesylate_tablet, film coated

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 In vivo In vitro, The pharmacokinetics of imatinib mesylate have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of imatinib mesylate are similar in CML and GIST patients. Absorption and Distribution Imatinib is well absorbed after oral administration with C max in vitro Elimination 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, formed predominantly by CYP3A4. It shows in vitro i Excretion Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14 Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. Typically, clearance of imatinib 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. 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 [see Use in Specific Populations (8. 6) max max [see Dosage and Administration (2. 12) Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment [see Use in Specific Populations (8. 7) [see Dosage and Administration (2. 12) Pediatric Use As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a C max 2 2 2 2 2 2 Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing BSA. After correcting for the BSA effect, other demographics, such as age, body weight, and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m 2 2 Drug Interactions Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate, increased imatinib mesylate oral-dose clearance by 3. 8-fold, which significantly (p less than 0. 05) decreased mean C max Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib mesylate concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e. , carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of imatinib mesylate and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib mesylate doses up to 1,200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2. 12) Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean C max Interactions with Drugs Metabolized by CYP3A4 Imatinib mesylate increases the mean C max Imatinib mesylate will increase plasma concentration of other CYP3A4 metabolized drugs (e. , triazolo-‑benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc. Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin. Interactions with Drugs Metabolized by CYP2D6 Imatinib mesylate increased the mean C max Interactions with Acetaminophen In vitro, i.

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) 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. 2 Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 3) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 4 Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 5) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. 6) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRalpha 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-PDGFRalpha fusion kinase negative or unknown. 7) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). 8) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). 9 Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. 10 Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRalpha 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-PDGFRalpha fusion kinase negative or unknown. Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Adults with Ph+ CML CP ( 2. 2 Adults with Ph+ CML AP or BC ( 2. 2 Pediatrics with Ph+ CML CP ( 2. 3 2 Adults with Ph+ ALL ( 2. 4 Pediatrics with Ph+ ALL ( 2. 5 2 Adults with MDS/MPD ( 2. 6 Adults with ASM ( 2. 7 Adults with HES/CEL ( 2. 8 Adults with DFSP ( 2. 9 Adults with metastatic and/or unresectable GIST ( 2. 10 Adjuvant treatment of adults with GIST ( 2. 11 Patients with mild to moderate hepatic impairment ( 2. 12 Patients with severe hepatic impairment ( 2. 12 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 tablets 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. The prescribed dose should be administered orally, with a meal and a large glass of water. 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. The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 The recommended dose of imatinib mesylate tablets are 600 mg/day for adult patients with relapsed/refractory 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 Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients with MDS/MPD. Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dose of imatinib mesylate tablets are 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 tablets 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-PDGFRalpha, 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. The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRalpha fusion kinase, a starting dose of 100 mg/day is recommended. The recommended dose of imatinib mesylate tablets are 800 mg/day for adult patients with DFSP. The recommended dose of imatinib mesylate tablets are 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. The recommended dose of imatinib mesylate tablets are 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib mesylate tablets and three years of imatinib mesylate tablets were studied. In the patient population defined in Study 2, three years of imatinib mesylate tablets are recommended [see Clinical Studies (14. 8) Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e. , 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 tablets 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 (creatinine clearance [CrCL] = 20 to 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 (CrCL = 40 to 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) 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 tablets 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 tablets may then be continued at a reduced daily dose (i. , 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 2 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 ANC less than 1 x 10 9 9 Stop imatinib mesylate tablets until ANC greater than or equal to 1. 5 x 10 9 9 Resume treatment with imatinib mesylate tablets at previous dose (i. , dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRalpha fusion kinase (starting dose 100 mg) ANC less than 1 x 10 9 9 Stop imatinib mesylate tablets until ANC greater than or equal to 1. , dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) ANC less than 1 x 10 9 9 Stop imatinib mesylate tablets until ANC greater than or equal to 1. 5 x 10 9 9 Resume treatment with imatinib mesylate tablets at the original starting dose of 400 mg If recurrence of ANC less than 1 x 10 9 9 Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) ANC less than 0. 5 x 10 9 9 Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate tablets 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 tablets until ANC greater than or equal to 1 x 10 9 9 DFSP ANC less than 1 x 10 9 9 Stop imatinib mesylate tablets until ANC greater than or equal to 1. 5 x 10 9 9 Resume treatment with imatinib mesylate tablets at 600 mg In the event of recurrence of ANC less than 1 x 10 9 9 Pediatric newly diagnosed chronic phase CML 2 ANC less than 1 x 10 9 9 Stop imatinib mesylate tablets until ANC greater than or equal to 1. , dose before severe adverse reaction) In the event of recurrence of ANC less than 1 x 10 9 9 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.

The following serious adverse reactions are described elsewhere in the labeling: Fluid Retention and Edema [see Warnings and Precautions (5. 1) Hematologic Toxicity [see Warnings and Precautions (5. 2) Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5. 3) Hepatotoxicity [see Warnings and Precautions (5. 4) Hemorrhage [see Warnings and Precautions (5. 5) Gastrointestinal Disorders [see Warnings and Precautions (5. 6) Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5. 7) Dermatologic Toxicities [see Warnings and Precautions (5. 8) Hypothyroidism [see Warnings and Precautions (5. 9) Growth Retardation in Children and Adolescents [see Warnings and Precautions (5. 11) Tumor Lysis Syndrome [see Warnings and Precautions (5. 12) Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5. 13) Renal Toxicity [see Warnings and Precautions (5. 14) The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. 1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 [see Dosage and Administration (2. 13) 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 * Imatinib Mesylate IFN+Ara−C Imatinib Mesylate IFN+Ara−C Preferred term N = 551 (%) N = 533 (%) N = 551 (%) N = 533 (%) Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. (1) (2) Fluid retention 61. 9 − Superficial edema 59. 4 − Other fluid retention reactions 2 6. 6 Nausea 49. 1 Muscle cramps 49. 2 Musculoskeletal pain 47. 6 Diarrhea 45. 2 Rash and related terms 40. 4 Fatigue 38. 1 Headache 37. 8 Joint pain 31. 7 Abdominal pain 36. 9 Nasopharyngitis 30. 4 Hemorrhage 28. 7 - GI hemorrhage 1. 2 - CNS hemorrhage 0. 4 Myalgia 24. 3 Vomiting 22. 4 Dyspepsia 18. 6 Pharyngolaryngeal pain 18. 2 0 Upper respiratory tract infection 21. 4 Dizziness 19. 8 Pyrexia 17. 0 Weight increased 15. 4 Insomnia 14. 3 Depression 14. 1 Influenza 13. 2 Bone pain 11. 4 Constipation 11. 2 Sinusitis 11. 2 Table 3: Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Imatinib Mesylate Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib Mesylate 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysis a Patients with newly diagnosed Ph+ CML-CP Imatinib Mesylate 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Imatinib Mesylate 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Body system and preferred term All Grades (%) CTC Grades b Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. a b Skin and subcutaneous tissue disorders Rash 19 38 2 < 1 Pruritus 7 21 0 < 1 Alopecia 7 13 0 0 Dry skin 6 12 0 0 Gastrointestinal disorders Nausea 41 22 2 2 Constipation 8 20 0 < 1 Diarrhea 46 19 4 1 Vomiting 27 15 < 1 < 1 Abdominal pain upper 14 18 < 1 1 Abdominal pain 12 15 0 2 Dyspepsia 12 10 0 0 Nervous system disorders Headache 23 32 < 1 3 Dizziness 11 12 < 1 < 1 General disorders and administration-site conditions Fatigue 20 23 1 1 Pyrexia 13 14 0 < 1 Asthenia 12 14 0 < 1 Peripheral edema 20 9 0 < 1 Face edema 14 < 1 < 1 0 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 17 22 < 1 < 1 Muscle spasms 34 12 1 0 Pain in extremity 16 15 < 1 < 1 Back pain 17 19 1 1 Respiratory, thoracic and mediastinal disorders Cough 13 17 0 0 Oropharyngeal pain 6 12 0 0 Dyspnea 6 11 < 1 2 Infections and infestations Nasopharyngitis 21 27 0 0 Upper respiratory tract infection 14 17 0 < 1 Influenza 9 13 0 0 Gastroenteritis 10 7 < 1 0 Eye disorders Eyelid edema 19 1 < 1 0 Periorbital edema 15 < 1 0 0 Psychiatric disorders Insomnia 9 11 0 0 Vascular disorder Hypertension 4 10 < 1 1 Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (Greater Than or Equal to 10% of All Patients in Any Trial) (1) Myeloid blast Crisis (n = 260) % Accelerated phase (n = 235) % Chronic phase, IFN failure (n = 532) % Preferred term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 (1) (2) 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. 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. 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. 8 Hypokalemia 13 4 9 2 6 0. 8 Pneumonia 13 7 10 7 4 1 Anxiety 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. 8 Influenza 0. 2 Sinusitis 4 0. 4 Hematologic and Biochemistry Laboratory Abnormalities Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3‑fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively. These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib mesylate, but may require permanent discontinuation of treatment. Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus IFN+Ara-C) Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). Imatinib Mesylate N = 551 % IFN+Ara−C N = 533 % CTC Grades Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters* − Neutropenia* 13. 5 − Thrombocytopenia* 8. 6 − Anemia 3. 2 Biochemistry parameters − Elevated creatinine 0 0 0. 4 0 − Elevated bilirubin 0. 2 0 − Elevated alkaline phosphatase 0. 8 0 − Elevated SGOT 4. 4 Table 6: Percent Incidence of Clinically Relevant Grade 3/4 * Imatinib Mesylate 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 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 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). (1) 9 9 9 9 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. 2 0 − Elevated bilirubin 3. 6 0 − Elevated alkaline phosphatase 4. 2 0 − Elevated SGOT (AST) 1. 3 0 − Elevated SGPT (ALT) 2. 1 0 Hepatotoxicity Adverse Reactions in Pediatric Population Single-Agent Therapy In Combination with Multi-Agent Chemotherapy Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive imatinib mesylate and treated in 5 successive cohorts. Imatinib mesylate exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration. The safety of imatinib mesylate given in combination with intensive chemotherapy was evaluated by comparing the incidence of Grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive imatinib mesylate. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib mesylate, and 647 without imatinib mesylate. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included imatinib mesylate are presented in Table 8. Table 8: Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (Greater Than 5%) or in Cycles With Study Drug (Greater Than 1%) Adverse event Grade 3 and 4 adverse events Per patient incidence Ph+ ALL with imatinib mesylate N = 92 n (%) Per patient incidence Ph- ALL no imatinib mesylate N = 65 n (%) Per patient per cycle incidence with imatinib mesylate * N = 778 n (%) Per patient per cycle incidence no imatinib mesylate ** N = 647 n (%) Nausea and/or vomiting 15 (16) 6 (9) 28 (4) 8 (1) Hypokalemia 31 (34) 16 (25) 72 (9) 32 (5) Pneumonitis 7 (8) 1 (1) 7 (1) 1 (< 1) Pleural effusion 6 (7) 0 6 (1) 0 Abdominal pain 8 (9) 2 (3) 9 (1) 3 (< 1) Anorexia 10 (11) 3 (5) 19 (2) 4 (1) Hemorrhage 11 (12) 4 (6) 17 (2) 8 (1) Hypoxia 8 (9) 2 (3) 12 (2) 2 (< 1) Myalgia 5 (5) 0 4 (1) 1 (< 1) Stomatitis 15 (16) 8 (12) 22 (3) 14 (2) Diarrhea 8 (9) 3 (5) 12 (2) 3 (< 1) Rash/Skin disorder 4 (4) 0 5 (1) 0 Infection 49 (53) 32 (49) 131 (17) 92 (14) Hepatic (transaminase and/or bilirubin) 52 (57) 38 (58) 172 (22) 113 (17) Hypotension 10 (11) 5 (8) 16 (2) 6 (1) Myelosuppression Neutropenia (< 750/mcL) 92 (100) 63 (97) 556 (71) 218 (34) Thrombocytopenia (< 75,000/mcL) 90 (92) 63 (97) 431 (55) 329 (51) Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia. Adverse Reactions in Other Subpopulations Acute Lymphoblastic Leukemia Myelodysplastic/Myeloproliferative Diseases Table 9: Adverse Reactions Regardless of Relationship to Study Drug Reported (More Than One Patient) in MPD Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades Abbreviation: MPD, myeloproliferative disease. Preferred term N = 7 n (%) Nausea 4 (57. 1) Diarrhea 3 (42. 9) Anemia 2 (28. 6) Fatigue 2 (28. 6) Muscle cramp 3 (42. 9) Arthralgia 2 (28. 6) Periorbital edema 2 (28. 6) Aggressive Systemic Mastocytosis Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia Dermatofibrosarcoma Protuberans Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades Abbreviation: DFSP, dermatofibrosarcoma protuberans. Preferred term N = 12 n (%) Nausea 5 (41. 7) Diarrhea 3 (25. 0) Vomiting 3 (25. 0) Periorbital edema 4 (33. 3) Face edema 2 (16. 7) Rash 3 (25. 0) Fatigue 5 (41. 7) Peripheral edema 4 (33. 3) Pyrexia 2 (16. 7) Eye edema 4 (33. 3) Lacrimation increased 3 (25. 0) Dyspnea exertional 2 (16. 7) Anemia 3 (25. 0) Rhinitis 2 (16. 7) Anorexia 2 (16. 7) Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are presented in Table 11. Table 11: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study Abbreviation: CTC, common terminology criteria. (1) 9 9 9 9 CTC Grades (1) N = 12 Grade 3% Grade 4% Hematology parameters - Anemia 17 0 - Thrombocytopenia 17 0 - Neutropenia 0 8 Biochemistry parameters - Elevated creatinine 0 8 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST [see Dosage and Administration (2. 13)] Table 12: Number (%) of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors. Reported or specified term Imatinib 400 mg N = 818 Imatinib 800 mg N = 822 All Grades % Grades 3/4/5 % All Grades % Grades 3/4/5 % Edema 76. 1 Fatigue/lethargy, malaise, asthenia 69. 2 Nausea 58. 8 Abdominal pain/cramping 57. 8 Diarrhea 56. 6 Rash/desquamation 38. 9 Vomiting 37. 5 Myalgia 32. 8 Anemia 32. 4 Anorexia 31. 7 Other GI toxicity 25. 6 Headache 22. 6 Other pain (excluding tumor related pain) 20. 0 Other dermatology/skin toxicity 17. 7 Leukopenia 17. 6 Other constitutional symptoms 16. 2 Infection (without neutropenia) 15. 6 Pruritus 15. 3 Other neurological toxicity 15. 9 Constipation 14. 1 Other renal/genitourinary toxicity 14. 2 Arthralgia (joint pain) 13. 0 Dyspnea (shortness of breath) 13. 6 Fever in absence of neutropenia (ANC < 1. 0 x 10 9 13. 4 Sweating 12. 8 Other hemorrhage 12. 1 Weight gain 12. 6 Alopecia 11. 2 Dyspepsia/heartburn 11. 5 Neutropenia/granulocytopenia 11. 1 Rigors/chills 11. 0 Dizziness/lightheadedness 11. 8 Creatinine increase 10. 6 Flatulence 10. 1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9. 3 Lymphopenia 6. 9 Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13. Table 13: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamicoxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). 1 9 9 9 9 CTC Grades 1 400 mg (n = 73) % 600 mg (n = 74) % Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters − Anemia 3 0 8 1 − Thrombocytopenia 0 0 1 0 − Neutropenia 7 3 8 3 Biochemistry parameters − Elevated creatinine 0 0 3 0 − Reduced albumin 3 0 4 0 − Elevated bilirubin 1 0 1 3 − Elevated alkaline phosphatase 0 0 3 0 − Elevated SGOT (AST) 4 0 3 3 − Elevated SGPT (ALT) 6 0 7 1 Adjuvant Treatment of GIST Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (Greater Than or Equal to 5% of Imatinib mesylate-Treated Patients) (1) Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamicoxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). (1) Preferred term All CTC Grades CTC Grade 3* and Above Imatinib mesylate (n = 337) % Placebo (n = 345) % Imatinib mesylate (n = 337) % Placebo (n = 345) % Diarrhea 59. 4 Fatigue 57. 2 Nausea 53. 2 Periorbital edema 47. 2 0 Hemoglobin decreased 46. 6 0 Peripheral edema 26. 3 0 Rash (Exfoliative) 26. 7 0 Vomiting 25. 6 Abdominal pain 21. 4 Headache 19. 6 0 Dyspepsia 17. 9 0 Anorexia 16. 3 0 Weight increased 16. 3 0 Liver enzymes (ALT) increased 16. 7 0 Muscle spasms 16. 3 0 0 Neutrophil count decreased 16. 9 Arthralgia 15. 3 White blood cell count decreased 14. 3 Constipation 12. 3 Dizziness 12. 3 Liver enzymes (AST) increased 12. 1 0 Myalgia 12. 3 Blood creatinine increased 11. 3 0 0 Pruritus 11. 9 0 Weight decreased 10. 2 0 0 Hyperglycemia 9. 7 Insomnia 9. 9 0 Lacrimation increased 9. 8 0 0 Alopecia 9. 7 0 0 Flatulence 8. 6 0 0 Rash 8. 9 0 Abdominal distension 7. 3 Back pain 7. 6 0 Pain in extremity 7. 3 0 Hypokalemia 7. 6 Depression 6. 6 Facial edema 6. 3 0 Blood alkaline phosphatase increased 6. 5 0 0 Dry skin 6. 2 0 0 Dysgeusia 6. 9 0 0 Abdominal pain upper 6. 3 0 Neuropathy peripheral 5. 4 0 0 Hypocalcemia 5. 3 0 Leukopenia 5. 3 0 Platelet count decreased 5. 5 0 0 Stomatitis 5. 6 0 Upper respiratory tract infection 5. 5 0 0 Vision blurred 5. 3 0 0 Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (Greater Than or Equal to 5% of Imatinib mesylate-Treated Patients) Study 2 (1) Abbreviations: AE, adverse event; CTC, common terminology criteria. (1) Preferred term All CTC Grades CTC Grades 3 and above Imatinib mesylate 12 Months (N = 194) % Imatinib mesylate 36 Months (N = 198) % Imatinib mesylate 12 Months (N = 194) % Imatinib mesylate 36 Months (N = 198) % Patients with at least one AE 99. 8 Hemoglobin decreased 72. 5 Periorbital edema 59. 0 Blood lactate dehydrogenase increased 43. 1 0 0 Diarrhea 43. 0 Nausea 44. 5 Muscle spasms 30. 0 Fatigue 48. 5 White blood cell count decreased 34. 0 Blood creatinine increased 30. 4 0 0 Peripheral edema 33. 0 Dermatitis 29. 5 Aspartate aminotransferase increased 30. 0 Alanine aminotransferase increased 28. 0 Neutrophil count decreased 24. 1 Hypoproteinemia 23. 8 0 0 Infection 13. 5 Weight increased 13. 5 Pruritus 12. 8 0 0 Flatulence 19. 5 Vomiting 10. 0 Dyspepsia 17. 0 Hypoalbuminemia 11. 2 0 0 Edema 10. 5 Abdominal distension 11. 5 0 Headache 8. 2 0 0 Lacrimation increased 18. 7 0 0 Arthralgia 8. 0 Blood alkaline phosphatase increased 10. 5 Dyspnea 6. 5 Myalgia 9. 0 Platelet count decreased 11. 1 0 0 Blood bilirubin increased 11. 1 0 0 Dysgeusia 9. 6 0 0 Paresthesia 5. 5 Vision blurred 10. 5 Alopecia 11. 6 0 0 Decreased appetite 9. 1 0 0 Constipation 8. 6 0 0 Pyrexia 6. 6 0 0 Depression 3. 1 0 0 Abdominal pain 2. 6 0 0 Conjunctivitis 5. 6 0 0 Photosensitivity reaction 3. 1 0 0 Dizziness 4. 5 0 Hemorrhage 3. 6 0 0 Dry skin 6. 5 0 Nasopharyngitis 1. 5 Palpitations 5. 1 0 0 Adverse Reactions from Multiple Clinical Trials Cardiac Disorders: Vascular Disorders: Investigations: Skin and Subcutaneous Tissue Disorders: Estimated 0. 1% to 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. 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% to 10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0. 1% to 1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0. 1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration-Site Conditions Estimated 1% to 10%: weakness, anasarca, chills Estimated 0. 1% to 1%: malaise Blood and Lymphatic System Disorders Estimated 1% to 10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia Estimated 0. 1% to 1%: thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0. 1%: hemolytic anemia, aplastic anemia Hepatobiliary Disorders Estimated 0. 1% to 1%: hepatitis, jaundice Estimated 0. 1%: hepatic failure and hepatic necrosis 1 Immune System Disorders Estimated 0. 1%: angioedema Infections and Infestations Estimated 0. 1% to 1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0. 1%: fungal infection Metabolism and Nutrition Disorders Estimated 1% to 10%: weight decreased, decreased appetite Estimated 0. 1% to 1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia Musculoskeletal and Connective Tissue Disorders Estimated 1% to 10%: joint swelling Estimated 0. 1% to 1%: joint and muscle stiffness, muscular weakness, arthritis Nervous System/Psychiatric Disorders Estimated 1% to 10%: paresthesia, hypesthesia Estimated 0. 1% to 1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0. 1%: increased intracranial pressure 1 Renal and Urinary Disorders Estimated 0. 1% to 1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive System and Breast Disorders Estimated 0. 1% to 1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory, Thoracic and Mediastinal Disorders Estimated 1% to 10%: epistaxis Estimated 0. 1% to 1%: pleural effusion Estimated 0. 1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Endocrine Disorders Estimated 0. 1% to 1%: hypothyroidism, hyperthyroidism Eye, Ear, and Labyrinth Disorders Estimated 1% to 10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye Estimated 0. 1% to 1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract Estimated 0. 1%: papilledema1, glaucoma 1 The following additional adverse reactions have been identified during post approval use of imatinib mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Cardiac Disorders: 1 Eye Disorders: Gastrointestinal Disorders: 1 [see Warnings and Precautions (5. 6) Infections: 1 Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: 1 Reproduction Disorders: Respiratory, Thoracic and Mediastinal Disorders: 1 Skin and Subcutaneous Tissue Disorders: Vascular Disorders: 1.

Risk Summary Data Animal Data Risk Summary Human Data Human postmarketing reports and animal studies have shown imatinib mesylate to be harmful to the developing fetus [see Use in Specific Populations (8. 1) Pregnancy Testing Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib mesylate. Contraception Females Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate during treatment and for fourteen days after stopping treatment with imatinib mesylate [see Use in Specific Populations (8. 1) Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13) The safety and effectiveness of imatinib mesylate have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14. 4) In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5. 1) In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of imatinib mesylate was similar in patients older than 65 years and younger patients. The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, the imatinib C max max [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 12) Table 16: Liver Function Classification Abbreviation: SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); ULN, upper limit of normal for the institution. Liver function test Normal (n = 14) Mild (n = 30) Moderate (n = 20) Severe (n = 20) Total bilirubin less than or equal to ULN greater than 1. 5 times the ULN greater than 1. 5 to 3 times the ULN greater than 3 to 10 times the ULN SGOT less than or equal greater than ULN (can be normal if Total Bilirubin is Any Any The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1. 5- to 2-fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment [see Clinical Pharmacology (12. 12) Table 17: Renal Function Classification Renal dysfunction Renal function tests Mild CrCL = 40 to 59 mL/min Moderate CrCL = 20 to 39 mL/min Severe CrCL = less than 20 mL/min Abbreviation: CrCL, creatinine clearance.

CYP3A4 inducers may decrease imatinib mesylate C max (2. 3 CYP3A4 inhibitors may increase imatinib mesylate C max 7. 3) Imatinib mesylate is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max 7. 3 Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. 3) Concomitant administration of imatinib mesylate and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12. 3) Concomitant administration of imatinib mesylate 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) Imatinib mesylate will increase plasma concentration of CYP3A4 metabolized drugs (e. , triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc. Use caution when administering imatinib mesylate with CYP3A4 substrates that have a narrow therapeutic window. [see Clinical Pharmacology (12. 3) Use caution when administering imatinib mesylate with CYP2D6 substrates that have a narrow therapeutic window.

OVERDOSAGE
Experience with doses greater than 800 mg is limited. Isolated cases of imatinib mesylate overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): 6,400 mg (single dose): 8 to 10 g (single dose): A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of imatinib mesylate on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.
NONCLINICAL TOXICOLOGY
In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0. 5 to 4 or 0. 4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0. 0 times the daily exposure in children (based on AUC) at 340 mg/m 2 in vitro in vitro in vitro in vivo Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression.
CLINICAL STUDIES
Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (Imatinib Mesylate versus IFN+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent imatinib mesylate or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the imatinib mesylate arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m 2 2 A total of 1106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range, 18 to 70 years), with 21. 9% of patients greater than or equal to 60 years of age. There were 59% males and 41% females; 89. 9% Caucasian and 4. 7% black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the imatinib mesylate and IFN arm, respectively. The median duration of second-line treatment with imatinib mesylate was 64 months. Sixty percent of patients randomized to imatinib mesylate are still receiving first-line treatment. In these patients, the average dose of imatinib mesylate was 403 mg +/- 57 mg. Overall, in patients receiving first line imatinib mesylate, the average daily dose delivered was 406 mg +/- 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the imatinib mesylate arm was severe intolerance to treatment (26%) and progression (14%). The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive imatinib mesylate were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81. 2% [95% CI: 78, 85] in the imatinib mesylate arm and 60. 6% [56, 65] in the IFN arm (p less than 0. 0001, log-rank test), (Figure 1). With 7 years follow up there were 93 (16. 8%) progression events in the imatinib mesylate arm: 37 (6. 7%) progression to AP/BC, 31 (5. 6%) loss of MCyR, 15 (2. 7%) loss of CHR or increase in WBC and 10 (1. 8%) CML unrelated deaths. In contrast, there were 165 (29. 8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C. The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92. 5% [90, 95] in the imatinib mesylate arm compared to the 85. 1%, [82, 89] (p less than or equal to 0. 001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0. th th Table 18: Response in Newly Diagnosed CML Study (84-Month Data) *p less than 0. 001, Fischer’s exact test. 1 9 9 2 3 Best response rate Imatinib Mesylate n = 553 IFN+Ara−C n = 553 Hematologic response 1 CHR rate n (%) 534 (96. 6%)* 313 (56. 6%)* [95% CI] [94. 8%] Cytogenetic response 2 Major cytogenetic response n (%) 472 (85. 4%)* 93 (16. 8%)* [95% CI] [82. 2%] Unconfirmed 3 88. 3%* Complete cytogenetic response n (%) 413 (74. 5%)* [95% CI] [70. 9] Unconfirmed 3 82. 6%* Molecular response was defined as follows: Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to 6 months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity. There was no apparent change from baseline in median index for patients treated with imatinib mesylate. An open-label, multicenter, randomized trial (Imatinib Mesylate versus nilotinib) was conducted to determine the efficacy of imatinib mesylate versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib mesylate 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group. Median age was 46 years in the imatinib mesylate group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in imatinib mesylate 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib mesylate 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice-daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian. The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier. Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment or discontinued earlier. The median time on treatment was approximately 61 months in all three treatment groups. The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as less than or equal to 0. 1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 19. Twelve patients in the imatinib mesylate arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment). Table 19: Efficacy (MMR and CCyR) of Imatinib Mesylate Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; Ph+ CML-CP, Philadelphia a b Imatinib Mesylate 400 mg once daily Nilotinib 300 mg twice daily N = 283 N = 282 MMR at 12 months (95% CI) 22% (17. 3) P-Value a < 0. 0001 CCyR b 65% (59. 6) MMR at 24 months (95% CI) 38% (31. 4) CCyR b 77% (71. 6) By 60 months, MMR was achieved by 60% of patients on imatinib mesylate and 77% of patients on nilotinib. Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 91. 7% for patients on imatinib mesylate and 93. 7% for patients on nilotinib. Late Chronic Phase CML and Advanced Stage CML: Chronic Phase, Prior Interferon-Alpha Treatment: 6 Accelerated Phase: 9 Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i. , clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months). Efficacy results are reported in Table 20. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs 64%), confirmed and unconfirmed major cytogenetic response (31% vs 19%). Myeloid Blast Crisis: Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months). The hematologic response rate was higher in untreated patients than in treated patients (36% vs 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs 8%). Table 10: Response in Chronic Myeloid Leukemia Studies Abbreviations: BM, bone marrow; PB, peripheral blood. 1 Hematologic response criteria 9 9 9 9 9 9 2 3 4 Chronic phase IFN failure (n = 532) 400 mg Accelerated phase (n = 235) 600 mg n = 158 400 mg n = 77 Myeloid blast crisis (n = 260) 600 mg n = 223 400 mg n = 37 % of patients [CI 95% Hematologic response 1 95% [92. 8] Complete hematologic response (CHR) 95% 38% 7% No evidence of leukemia (NEL) Not applicable 13% 5% Return to chronic phase (RTC) Not applicable 20% 18% Major cytogenetic response 2 60% [55. 2] (Unconfirmed 3 (65%) (27%) (15%) Complete 4 3 39% (47%) 16% (20%) 2% (7%) The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87. 8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85. 4% of patients were free of progression to AP or BC, and estimated overall survival was 90. In accelerated phase, median duration of hematologic response was 28. 8 months for patients with an initial dose of 600 mg (16. 5 months for 400 mg). An estimated 63. 8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20. 4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0. An estimated 46. 3] of patients were still alive after 2 years of treatment in the 400 mg vs 600 mg dose groups, respectively. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27. 7] of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6. 6] months, and an estimated 18. 3] of all patients with blast crisis were alive 2 years after start of study. Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in black patients, but there were too few black patients to allow a quantitative comparison. imatinib-fig1 imatinib-fig2 A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial. Patients were treated with imatinib mesylate 340 mg/m 2 2 2 2 2 2 A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended imatinib mesylate dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received imatinib mesylate 600 mg/day in a Phase 1 study. Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ ALL Phase 2 study patients and for the 2 Phase 1 patients are shown in Table 21. The median duration of hematologic response was 3. 4 months and the median duration of MCyR was 2. Table 21: Effect of Imatinib Mesylate on Relapsed/Refractory Ph+ ALL Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; NEL, no evidence of leukemia; PCyR, partial cytogenic response; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; PHR, partial hematologic response; RTC, return to chronic phase. Phase 2 study (N = 43) n(%) Phase 1 study (N = 2) n(%) CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) 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 safety and effectiveness of imatinib mesylate (340 mg/m 2 There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received imatinib mesylate plus chemotherapy; 30 were treated exclusively with chemotherapy and imatinib mesylate and 20 received chemotherapy plus imatinib mesylate and then underwent hematopoietic stem cell transplant, followed by further imatinib mesylate treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to imatinib mesylate beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12, imatinib mesylate was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of imatinib mesylate prior to HSCT, and 28 weeks (196 days) of imatinib mesylate after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40. An open-label, multicenter, Phase 2 clinical trial was conducted testing imatinib mesylate in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with imatinib mesylate 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received imatinib mesylate at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a CCyR). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12. 9 months (0. 7) in the 7 patients treated within the Phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 22. Response durations of Phase 2 study patients ranged from 141+ days to 457+ days. Table 22: Response in MDS/MPD Abbreviations: NE, not evaluable; MDS/MPD, myelodysplastic/myeloproliferative disease. Number of patients N Complete hematologic response N (%) Major cytogenetic response N (%) Overall population 31 14 (45) 12 (39) Chromosome 5 translocation 14 11 (79) 11 (79) Chromosome 4 translocation 2 2 (100) 1 (50) Others/no translocation 14 1 (7) 0 Molecular relapse 1 NE NE One open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with ASM treated with 100 mg to 400 mg of imatinib mesylate daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of imatinib mesylate in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of imatinib mesylate daily. Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with imatinib mesylate from the published reports and in the Phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRalpha fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to imatinib mesylate), one with concomitant CML. Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (PHR) (61% overall response rate). Median duration of imatinib mesylate therapy for the 5 ASM patients in the Phase 2 study was 13 months (range, 1. 3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to imatinib mesylate in ASM is provided in Table 23. Response durations of literature patients ranged from 1+ to 30+ months. Table 23: Response in ASM Cytogenetic abnormality Number of patients N Complete hematologic response N (%) Partial hematologic response N (%) FIP1L1-PDGFRalpha fusion kinase (or CHIC2 deletion) 7 7 (100) 0 Juxtamembrane mutation 2 0 2 (100) Unknown or no cytogenetic abnormality detected 15 0 7 (44) D816V mutation 4 1* (25) 0 Total 28 8 (29) 9 (32) Abbreviations: ASM, aggressive systemic mastocytosis; PDGFR, platelet-derived growth factor receptor. Imatinib mesylate has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). imatinib mesylate is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to imatinib mesylate and should not receive imatinib mesylate. One open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1,000 mg of imatinib mesylate daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received imatinib mesylate at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months. Table 24: Response in HES/CEL Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor. Cytogenetic abnormality Number of patients Complete hematological response N (%) Partial hematological response N (%) Positive FIP1L1-PDGFRalpha fusion kinase 61 61 (100) 0 Negative FIP1L1-PDGFRalpha fusion kinase 56 12 (21) 9 (16) Unknown cytogenetic abnormality 59 34 (58) 7 (12) Total 176 107 (61) 23 (13) Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene. 2 2 Table 25: Response in DFSP Number of patients (n = 18) % Complete response 7 39 Partial response* 8 44 Total responders 15 83 *5 patients made disease free by surgery. Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses. The median duration of response in the Phase 2 study was 6. 2 months, with a maximum duration of 24. 3 months, while in the published literature it ranged between 4 weeks and more than 20 months. Unresectable and/or Malignant Metastatic GIST Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant GIST. The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST. The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26. Table 26: Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials Abbreviation: GIST, gastrointestinal stromal tumors. Imatinib mesylate 400 mg N = 818 Imatinib mesylate 800 mg N = 822 Progression-free survival (months) Median 18. 2 95% CI 17. 9 Overall survival (months) 49. 7 95% CI 45. 6 Best overall tumor response Complete response 43 (5. 0%) Partial response 377 (46. 1%) 402 (48. 9%) Median follow up for the combined studies was 37. There were no observed differences in overall survival between the treatment groups (p = 0. Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n = 347) had a 3. 4 month median and a 7. 7 month mean exposure to imatinib mesylate following crossover. One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally every day for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68. 5% for the 400 mg group and 67. 6% for the 600 mg group. The median time to response was 12 weeks (range was 3 to 98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached). Adjuvant Treatment of GIST In the adjuvant setting, imatinib mesylate was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to imatinib mesylate at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration. Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month imatinib mesylate arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0. 398 (95% CI: 0. 610), p less than 0. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month imatinib mesylate arm. Seventy-two of these 79 patients subsequently crossed over to imatinib mesylate therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month imatinib mesylate arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0. 718 (95% CI: 0. 971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month imatinib mesylate and placebo arms, respectively with a hazard ratio of 0. 816 (95% CI: 0. RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of imatinib mesylate treatment significantly prolonged RFS compared to 12 months of imatinib mesylate treatment with a hazard ratio of 0. 46 (95% CI: 0. 65), p less than 0. 0001 (Figure 4). The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of imatinib mesylate treatment significantly prolonged OS compared to 12 months of imatinib mesylate treatment with a hazard ratio of 0. 45 (95% CI: 0. 0187 (Figure 5). figure figure figure.
REFERENCES
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