Imatinib Drug Information

    Generic name: IMATINIB MESYLATE

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    Uses of Imatinib

    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.

    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.

    Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)

    Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

    Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

    Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

    Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

    Aggressive Systemic Mastocytosis (ASM)

    Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

    Hypereosinophilic Syndrome

    (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

    Dermatofibrosarcoma Protuberans (DFSP)

    Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

    Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

    Adjuvant Treatment of GIST

    Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

    Dosage & Administration of Imatinib

    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.

    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.

    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.

    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.

    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).

    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.

    Adult Patients With ASM Determine

    D816V c-Kit mutation status prior to initiating treatment. 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 (imatinib as free base) is recommended.

    Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

    Adult Patients With HES/CEL

    For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day (imatinib as free base) is recommended.

    A dose increase up to 800 mg daily (imatinib as free base) (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.

    Adult Patients With Adjuvant GIST

    The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) 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 is recommended.

    The optimal treatment duration with imatinib mesylate tablets is not known.

    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 tablets should be increased by at least 50%, and clinical response should be carefully monitored.
    • 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.
    • Renal Impairment: Patients with moderate renal impairment (creatinine clearance = 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 (imatinib as free base) 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 (imatinib as free base) 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.

    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 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. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), imatinib mesylate tablets should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

    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 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.

    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
    ASM associated with eosinophilia (starting dose 100 mg)ANC 1 less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L1. 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 2. Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction)
    HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg)ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L1. 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 2. Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction)
    Chronic Phase CML (starting dose 400 mg)ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L1. 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
    MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg)2. Resume treatment with imatinib mesylate at the original starting dose of 400 mg 3. If recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume 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 x 10 9 /L1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy) 2. If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate to 400 mg 3. If cytopenia persists 2 weeks, reduce further to 300 mg 4. 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
    DFSP (starting dose 800 mg)ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L1. 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. 2. Resume treatment with imatinib mesylate at 600 mg 3. In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate at reduced dose of 400 mg.
    Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2 )ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L1. Stop imatinib mesylate until ANC greater than or equal to 1.5 x10 9 /L and platelets greater than or equal to 75 x 10 9 /L. 2. Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) 3. In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate at reduced dose of 260 mg/m 2

    Side Effects of Imatinib

    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.

    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. 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 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. *NCI Common Terminology Criteria for Adverse Events, version 3.0.

    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 1 Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. 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 Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha. All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment.

    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).

    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 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). *p less than 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 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). *NCI Common Terminology Criteria for Adverse Events, version 3.0.

    Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure.

    Bilirubin elevation was observed in 2.7% of patients. Adverse Reactions in Pediatric Population Single-Agent Therapy The overall safety profile of pediatric patients treated with imatinib mesylate in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients.

    Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression. In Combination with Multi-Agent Chemotherapy Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.

    Patients with Ph+ ALL (n = 92) were assigned to receive imatinib mesylate tablets and treated in 5 successive cohorts. Imatinib mesylate tablets exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration. The safety of imatinib mesylate tablets 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 tablets.

    The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate tablets. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1,425 cycles of therapy, 778 with imatinib mesylate tablets, and 647 without imatinib mesylate tablets.

    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 tablets 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%) 9 Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia. *Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib mesylate tablets (includes patients with Ph+ ALL that received cycles with imatinib mesylate tablets). *Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib mesylate tablets (includes patients with Ph+ ALL that received cycles without imatinib mesylate tablets as well as all patients with Ph- ALL who did not receive imatinib mesylate tablets in any treatment cycle). 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 2 Abbreviation: MPD, myeloproliferative disease. Aggressive Systemic Mastocytosis All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time.

    The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued imatinib mesylate due to drug-related adverse reactions or abnormal laboratory values. Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib mesylate observed in other hematologic malignancy populations, such as Ph+ CML.

    All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia. Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are shown in Table 10.

    Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study Greater Than or Equal to 2 Abbreviation: DFSP, dermatofibrosarcoma protuberans. 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. Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials, the majority of imatinib mesylate-treated patients experienced adverse reactions at some time.

    The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate.

    Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 12: Number (%) of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors.

    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. Adjuvant Treatment of GIST In Study 1, the majority of both imatinib mesylate and placebo-treated patients experienced at least one adverse reaction at some time.

    The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST-treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.

    As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. There were no deaths attributable to imatinib mesylate treatment in either trial. Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 Greater Than or Equal to 5% of 0 0 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). *NCI Common Terminology Criteria for Adverse Events, version 3.0.

    A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombotic microangiopathy Cardiac Disorders: pericarditis, cardiac tamponade 1 Eye Disorders: vitreous hemorrhage Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation 1, diverticulitis, gastric antral vascular ectasia Infections: hepatitis B virus reactivation 1 Musculoskeletal and Connective Tissue Disorders: osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain), bone marrow edema.

    Nervous System Disorders: cerebral edema 1 Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure 1, interstitial lung disease Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus Vascular Disorders: thrombosis/embolism, anaphylactic shock 1 Including some fatalities.

    All GradesCTC* Grades 3/4
    Imatinib mesylateIFN+Ara−CImatinib mesylateIFN+Ara−C
    Preferred termN = 551 (%)N = 533 (%)N = 551 (%)N = 533 (%)
    Fluid retention61.711.12.50.9
    − Superficial edema59.99.61.50.4
    − Other fluid retention reactions 26.91.91.30.6
    Nausea49.561.51.35.1
    Muscle cramps49.211.82.20.2
    Musculoskeletal pain4744.85.48.6
    Diarrhea45.443.33.33.2
    Rash and related terms40.126.12.92.4
    Fatigue38.8671.825.1
    Headache3743.30.53.8
    Joint pain31.438.12.57.7
    Abdominal pain36.525.94.23.9
    Nasopharyngitis30.58.800.4
    Hemorrhage28.921.21.81.7
    - GI hemorrhage1.61.10.50.2
    - CNS hemorrhage0.20.400.4
    Myalgia24.138.81.58.3
    Vomiting22.527.823.4
    Dyspepsia18.98.300.8
    Cough2023.10.20.6
    Pharyngolaryngeal pain18.111.40.20
    Upper respiratory tract infection21.28.40.20.4
    Dizziness19.424.40.93.8
    Pyrexia17.842.60.93
    Weight increased15.62.620.4
    Insomnia14.718.602.3
    Depression14.935.80.513.1
    Influenza13.86.20.20.2
    Bone pain11.315.61.63.4
    Constipation11.414.40.70.2
    Sinusitis11.460.20.2
    Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. *NCI Common Terminology Criteria for Adverse Events, version 3.0. (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.
    Patients With Newly Diagnosed Ph+ CML-CP
    Imatinib mesylate 400 mg once-daily N = 280Nilotinib 300 mg twice-daily N = 279Imatinib mesylate 400 mg once-daily N = 280Nilotinib 300 mg twice-daily N = 279
    Body system and preferred termAll Grades (%)CTC Grades b 3/4 (%)
    Skin and subcutaneous tissue disordersRash19382<1
    Pruritus7210<1
    Alopecia71300
    Dry skin61200
    Gastrointestinal disordersNausea412222
    Constipation8200<1
    Diarrhea461941
    Vomiting2715<1<1
    Abdominal pain upper1418<11
    Abdominal pain121502
    Dyspepsia121000
    Nervous system disordersHeadache2332<13
    Dizziness1112<1<1
    General disorders and administration-site conditionsFatigue202311
    Pyrexia13140<1
    Asthenia12140<1
    Peripheral edema2090<1
    Face edema14<1<10
    Musculoskeletal and connective tissue disordersMyalgia1919<1<1
    Arthralgia1722<1<1
    Muscle spasms341210
    Pain in extremity1615<1<1
    Back pain171911
    Respiratory, thoracic and mediastinal disordersCough131700
    Oropharyngeal pain61200
    Dyspnea611<12
    Infections and infestationsNasopharyngitis212700
    Upper respiratory tract infection14170<1
    Influenza91300
    Gastroenteritis107<10
    Eye disordersEyelid edema191<10
    Periorbital edema15<100
    Psychiatric disordersInsomnia91100
    Vascular disorderHypertension410<11
    Myeloid blast CrisisAccelerated phaseChronic phase, IFN
    (n = 260)(n = 235)failure
    (n = 532)
    %%%
    Preferred termAll GradesGrade 3/4All GradesGrade 3/4All GradesGrade 3/4
    Fluid retention7211766694
    -Superficial edema666743672
    -Other fluid retention reactions (2)22615472
    Nausea715735633
    Muscle cramps281470.4622
    Vomiting544583362
    Diarrhea434575483
    Hemorrhage53194911302
    - CNS hemorrhage973321
    - GI hemorrhage846520.4
    Musculoskeletal pain429499382
    Fatigue304464481
    Skin rash365475473
    Pyrexia417418212
    Arthralgia255346401
    Headache275322360.6
    Abdominal pain306334321
    Weight increased51175327
    Cough140.8270.9200
    Dyspepsia120220270
    Myalgia90242270.2
    Nasopharyngitis100170220.2
    Asthenia185215150.2
    Dyspnea154217120.9
    Upper respiratory tract infection30120.4190
    Anorexia14217270
    Night sweats130.8171140.2
    Constipation162160.990.4
    Dizziness120.4130160.2
    Pharyngitis100120150
    Insomnia100140140.2
    Pruritus81140.9140.8
    Hypokalemia1349260.8
    Pneumonia13710741
    Anxiety80.812080.4
    Liver toxicity10512663
    Rigors100120.4100
    Chest pain72100.4110.8
    Influenza0.80.460110.2
    Sinusitis40.4110.490.4
    Imatinib Mesylate N = 551 %IFN+Ara−C N = 533 %
    CTC GradesGrade 3Grade 4Grade 3Grade 4
    Hematology parameters*
    − Neutropenia*13.13.620.84.5
    − Thrombocytopenia*8.50.415.90.6
    − Anemia3.31.14.10.2
    Biochemistry parameters
    − Elevated creatinine000.40
    − Elevated bilirubin0.90.20.20
    − Elevated alkaline phosphatase0.200.80
    − Elevated SGOT (AST)/SGPT (ALT)4.70.57.10.4
    Myeloid blast crisisAccelerated phaseChronic phase, IFN failure
    (n = 260) 600 mg n = 223 400 mg n = 37 %(n = 235) 600 mg n = 158 400 mg n = 77 %(n = 532) 400 mg %
    CTC Grades 1Grade 3Grade 4Grade 3Grade 4Grade 3Grade 4
    Hematology parameters
    − Neutropenia16482336279
    − Thrombocytopenia3033311321<1
    − Anemia421134761
    Biochemistry parameters
    − Elevated creatinine1.501.300.20
    − Elevated bilirubin3.802.100.60
    − Elevated alkaline phosphatase4.605.50.40.20
    − Elevated SGOT (AST)1.903.002.30
    − Elevated SGPT (ALT)2.30.44.302.10
    Adverse event Grade 3 and 4 adverse eventsPer patient incidence Ph+ ALL with Imatinib Mesylate Tablets N = 92 n (%)Per patient incidence Ph- ALL no Imatinib Mesylate Tablets N = 65 n (%)Per patient per cycle incidence with Imatinib Mesylate Tablets* N = 778 n (%)Per patient per cycle incidence no Imatinib Mesylate Tablets* N = 647 n (%)
    Nausea and/or vomiting15 (16)6 (9)28 (4)8 (1)
    Hypokalemia31 (34)16 (25)72 (9)32 (5)
    Pneumonitis7 (8)1 (1)7 (1)1 (< 1)
    Pleural effusion6 (7)06 (1)0
    Abdominal pain8 (9)2 (3)9 (1)3 (< 1)
    Anorexia10 (11)3 (5)19 (2)4 (1)
    Hemorrhage11 (12)4 (6)17 (2)8 (1)
    Hypoxia8 (9)2 (3)12 (2)2 (< 1)
    Myalgia5 (5)04 (1)1 (< 1)
    Stomatitis15 (16)8 (12)22 (3)14 (2)
    Diarrhea8 (9)3 (5)12 (2)3 (< 1)
    Rash/Skin disorder4 (4)05 (1)0
    Infection49 (53)32 (49)131 (17)92 (14)
    Hepatic (transaminase and/or bilirubin)52 (57)38 (58)172 (22)113 (17)
    Hypotension10 (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)
    Preferred TermN = 7 n (%)
    Nausea4 (57.1)
    Diarrhea3 (42.9)
    Anemia2 (28.6)
    Fatigue2 (28.6)
    Muscle cramp3 (42.9)
    Arthralgia2 (28.6)
    Periorbital edema2 (28.6)
    Preferred termN = 12 n (%)
    Nausea5 (41.7)
    Diarrhea3 (25)
    Vomiting3 (25)
    Periorbital edema4 (33.3)
    Face edema2 (16.7)
    Rash3 (25)
    Fatigue5 (41.7)
    Edema peripheral4 (33.3)
    Pyrexia2 (16.7)
    Eye edema4 (33.3)
    Lacrimation increased3 (25)
    Dyspnea exertional2 (16.7)
    Anemia3 (25)
    Rhinitis2 (16.7)
    Anorexia2 (16.7)
    Imatinib 400 mg N= 818Imatinib 800 mg N=822
    All GradesGrades 3/4/5All GradesGrades 3/4/5
    Reported or specified term%%%%
    Edema76.7986.113.1
    Fatigue/lethargy, malaise, asthenia69.311.774.912.2
    Nausea58.1964.57.8
    Abdominal pain/cramping57.213.855.211.8
    Diarrhea56.28.158.28.6
    Rash/desquamation38.17.649.88.9
    Vomiting37.49.240.67.5
    Myalgia32.25.630.23.8
    Anemia324.934.86.4
    Anorexia31.16.635.84.7
    Other GI toxicity25.28.128.16.6
    Headache225.719.73.6
    Other pain (excluding tumor related pain)20.45.920.85
    Other dermatology/skin toxicity17.65.920.15.7
    Leukopenia170.719.61.6
    Other constitutional symptoms16.76.415.24.4
    Cough16.14.514.53.2
    Infection (without neutropenia)15.56.616.55.6
    Pruritus15.45.418.94.3
    Other neurological toxicity156.415.24.9
    Constipation14.85.114.44.1
    Other renal/genitourinary toxicity14.26.513.65.2
    Arthralgia (joint pain)13.64.812.33
    Dyspnea (shortness of breath)13.66.814.25.6
    Fever in absence of neutropenia (ANC < 1.0 x 10 9 /L)13.24.912.93.4
    Sweating12.74.68.52.8
    Other hemorrhage12.36.713.36.1
    Weight gain12110.60.6
    Alopecia11.94.314.83.2
    Dyspepsia/heartburn11.50.610.90.5
    Neutropenia/granulocytopenia11.53.116.14.1
    Rigors/chills114.610.23
    Dizziness/lightheadedness114.8102.8
    Creatinine increase10.80.410.10.6
    Flatulence100.210.10.1
    Stomatitis/pharyngitis (oral/pharyngeal mucositis)9.25.4104.3
    Lymphopenia60.710.11.9
    400 mg (n = 73) %600 mg (n = 74) %
    CTC Grades 1Grade 3Grade 4Grade 3Grade 4
    Hematology parameters
    -Anemia3081
    -Thrombocytopenia0010
    -Neutropenia7383
    Biochemistry parameters
    -Elevated creatinine0030
    -Reduced albumin3040
    -Elevated bilirubin1013
    -Elevated alkaline phosphatase0030
    -Elevated SGOT (AST)4033
    -Elevated SGPT (ALT)6071
    All CTC GradesCTC Grade 3* and Above
    Imatinib MesylatePlaceboImatinib MesylatePlacebo
    (n=337)(n=345)(n=337)(n=345)
    Preferred term%%%%
    Diarrhea59.329.331.4
    Fatigue5740.92.11.2
    Nausea53.127.82.41.2
    Periorbital edema47.214.51.20
    Hemoglobin decreased46.9270.60
    Peripheral edema26.714.80.30
    Rash (Exfoliative)26.112.82.70
    Vomiting25.513.92.40.6
    Abdominal pain21.122.331.4
    Headache19.320.30.60
    Dyspepsia17.2130.90
    Anorexia16.98.70.30
    Weight increased16.911.60.30
    Liver enzymes (ALT) increased16.6132.70
    Muscle spasms16.33.300
    Neutrophil count decreased166.13.30.9
    Arthralgia15.114.500.3
    White blood cell count decreased14.54.30.60.3
    Constipation12.817.700.3
    Dizziness12.510.700.3
    Liver enzymes (AST) increased12.27.52.10
    Myalgia12.211.600.3
    Blood creatinine increased11.65.800.3
    Cough1111.300
    Pruritus117.80.90
    Weight decreased10.15.200
    Hyperglycemia9.811.30.61.7
    Insomnia9.87.20.90
    Lacrimation increased9.83.800
    Alopecia9.56.700
    Flatulence8.99.600
    Rash8.95.20.90
    Abdominal distension7.46.40.30.3
    Back pain7.48.10.60
    Pain in extremity7.47.20.30
    Hypokalemia7.120.90.6
    Depression6.86.40.90.6
    Facial edema6.81.20.30
    Blood alkaline phosphatase increased6.57.500
    Dry skin6.55.200
    Dysgeusia6.52.900
    Abdominal pain upper6.26.40.30
    Neuropathy peripheral5.96.400
    Hypocalcemia5.61.70.30
    Leukopenia52.60.30
    Platelet count decreased53.500
    Stomatitis51.70.60
    Upper respiratory tract infection53.500
    Vision blurred52.300
    Preferred termAll CTC GradesCTC Grades 3 and Above
    Imatinib MesylateImatinib MesylateImatinib MesylateImatinib Mesylate
    12 Months36 Months12 Months36 Months
    (N = 194)(N = 198)(N = 194)(N = 198)
    %%%%
    Patients with at least one AE9910020.132.8
    Hemoglobin decreased72.280.30.50.5
    Periorbital edema59.374.20.51
    Blood lactate dehydrogenase increased43.360.100
    Diarrhea43.8540.52
    Nausea44.8511.50.5
    Muscle spasms30.9490.51
    Fatigue48.548.510.5
    White blood cell count decreased34.5472.13
    Pain25.845.513
    Blood creatinine increased30.444.400
    Peripheral edema3340.90.51
    Dermatitis29.438.92.11.5
    Aspartate aminotransferase increased30.937.91.53
    Alanine aminotransferase increased28.934.32.13
    Neutrophil count decreased24.233.34.65.1
    Hypoproteinemia23.731.800
    Infection13.927.81.52.5
    Weight increased13.426.800.5
    Pruritus12.925.800
    Flatulence19.124.710.5
    Vomiting10.822.20.51
    Dyspepsia17.521.70.51
    Hypoalbuminemia11.921.200
    Edema10.819.700.5
    Abdominal distension11.919.20.50
    Headache8.218.200
    Lacrimation increased1817.700
    Arthralgia8.817.201
    Blood alkaline phosphatase increased10.816.700.5
    Dyspnea6.216.20.51.5
    Myalgia9.315.201
    Platelet count decreased11.314.100
    Blood bilirubin increased11.313.100
    Dysgeusia9.312.600
    Paresthesia5.212.100.5
    Vision blurred10.811.11.00.5
    Alopecia11.310.600
    Decreased appetite9.810.100
    Constipation8.89.600
    Pyrexia6.29.600
    Depression3.18.100
    Abdominal pain2.67.600
    Conjunctivitis5.27.600
    Photosensitivity reaction3.67.100
    Dizziness4.66.60.50
    Hemorrhage3.16.600
    Dry skin6.76.10.50
    Nasopharyngitis16.100.5
    Palpitations5.25.100

    Warnings & Cautions for Imatinib

    Fluid Retention and Edema

    Imatinib mesylate is often associated with edema and occasionally serious fluid retention. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment.

    The probability of edema was increased with higher imatinib mesylate dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate.

    Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate for GIST. In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg twice daily. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months).

    In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy.

    Congestive Heart Failure and Left Ventricular Dysfunction

    Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib mesylate. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib mesylate compared to 0.9% of patients taking IFN + Ara-C.

    In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib mesylate arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

    Hepatotoxicity

    Hepatotoxicity, occasionally severe, may occur with imatinib mesylate. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib mesylate. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated.

    Manage laboratory abnormalities with imatinib mesylate interruption and/or dose reduction. When imatinib mesylate is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure.

    Monitoring of hepatic function is recommended.

    Hemorrhage In a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm.

    In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

    Gastrointestinal Disorders

    Imatinib mesylate is sometimes associated with GI irritation. Imatinib mesylate tablets should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.

    Hypereosinophilic Cardiac Toxicity

    In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels.

    Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate at the initiation of therapy.

    Dermatologic Toxicities

    Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib mesylate. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate therapy after resolution or improvement of the bullous reaction.

    In these instances, imatinib mesylate was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

    Hypothyroidism

    Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate tablets. Monitor TSH levels in such patients.

    Embryo-Fetal Toxicity

    Imatinib mesylate can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA.

    Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate tablets and for 14 days after stopping imatinib mesylate tablets. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

    Growth Retardation in Children and Adolescents

    Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate tablets. The long-term effects of prolonged treatment with imatinib mesylate on growth in children are unknown. Therefore, monitor growth in children under imatinib mesylate treatment.

    Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome

    (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib mesylate tablets. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions.

    Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate.

    Impairments Related to Driving and Using Machinery

    Motor vehicle accidents have been reported in patients receiving imatinib mesylate tablets. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate. Recommend caution when driving a car or operating machinery.

    Renal Toxicity

    A decline in renal function may occur in patients receiving imatinib mesylate tablets. Evaluate renal function prior to initiating imatinib mesylate tablets and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

    Drug Interactions with Imatinib

    Agents Inducing CYP3A Metabolism

    Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

    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.

    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.

    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.

    Pregnancy Safety for Imatinib

    Pregnancy Risk Summary Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy.

    Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

    The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones.

    Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.

    In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4.

    In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F 1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses.

    The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

    Pediatric Use of Imatinib

    Pediatric Use The safety and effectiveness of imatinib mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL. There are no data in children under 1 year of age.

    Overdosage Information for Imatinib

    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): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate (imatinib as free base) 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 (imatinib as free base) without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate (imatinib as free base) daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed.

    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.

    Clinical Studies of Imatinib

    Chronic Myeloid Leukemia 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. Baseline characteristics were well balanced between the two arms.

    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. 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% in the imatinib mesylate arm compared to the 85.1%, (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 0.001).

    Figure 1: Progression Free Survival (ITT Principle) Figure 2: Time to Progression to AP or BC (ITT Principle) A total of patients died in the imatinib mesylate and IFN+Ara-C group, respectively. The hazard ratio is This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to imatinib mesylate. Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints.

    Response data are shown in Table 18. Complete hematologic response, major cytogenetic response and CCyR were also statistically significantly higher in the imatinib mesylate arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses). Table 18: Response in Newly Diagnosed CML Study (84-Month Data) Molecular response was defined as follows: in the peripheral blood, after 12 months of therapy, reduction of greater than or equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline.

    Molecular response was only evaluated in a subset of patients who had a CCyR by 12 months or later (N = 333). 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 six 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.

    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 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. Table 19: Efficacy (MMR and CCyR) of Imatinib Mesylate Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP, complete cytogenetic response; MMR, major molecular response; Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. a CMH test stratified by Sokal risk group. b CCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample.

    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: Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of imatinib mesylate in patients with Ph+ CML: 1 in the chronic phase after failure of IFN therapy, 2 in accelerated phase disease, or 3 in myeloid blast crisis. About 45% of patients were women and 6% were black. Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed.

    The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or CCyR (0% Ph+ metaphases). Efficacy results are reported in Table 20.

    Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients. Accelerated Phase: 235 patients with accelerated phase disease were enrolled.

    Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., 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. Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled.

    These patients had greater than or equal to 30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). 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.

    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 20: Response in Chronic Myeloid Leukemia Studies Abbreviations: BM, bone marrow; PB, peripheral blood. 1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): CHR: Chronic phase study and in the accelerated and blast crisis studies. A major response (0% to 35%) combines both complete and partial responses. 3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation. 4 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study.

    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 90.8%.

    An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% of hematologic responders maintained their response 2 years after achieving their initial response.

    Median survival was 6.9 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.

    Pediatric CML

    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 /day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy.

    The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between Months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months.

    Patients were allowed to be removed from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation. Thirty-one children received stem cell transplantation. Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range, 4 to 24).

    One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. In addition 2 patients with relapsed/refractory Ph+ ALL received imatinib mesylate 600 mg/day in a Phase 1 study. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.

    Table 21: Effect of Imatinib Mesylate on Relapsed/Refractory Ph+ ALL, partial cytogenic response; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; PHR, partial hematologic response; RTC, return to chronic phase.

    Pediatric ALL 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 tablets (340 mg/m 2 /day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor.

    There were 92 eligible patients with Ph+ ALL enrolled. Sixty-four percent were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black. In 5 successive cohorts of patients, imatinib mesylate tablets exposure was systematically increased by earlier introduction and prolonged duration.

    Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of imatinib mesylate tablets exposure. There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received imatinib mesylate tablets plus chemotherapy; 30 were treated exclusively with chemotherapy and imatinib mesylate tablets and 20 received chemotherapy plus imatinib mesylate tablets and then underwent hematopoietic stem cell transplant, followed by further imatinib mesylate tablets treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to imatinib mesylate tablets beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy.

    Patients who underwent hematopoietic stem cell transplant received 42 days of imatinib mesylate tablets prior to HSCT, and 28 weeks (196 days) of imatinib mesylate tablets after the immediate post-transplant period. The estimated 4-year EFS of patients in cohort The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.

    Myelodysplastic/Myeloproliferative Diseases

    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 (imatinib as free base).

    The ages of the enrolled patients ranged from 20 to 86 years. These patients also received imatinib mesylate at a dose of 400 mg (imatinib as free base) daily with the exception of three patients who received lower doses. 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. 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.6 Aggressive Systemic Mastocytosis 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 (imatinib as free base) daily. These 5 patients ranged from 49 to 74 years of age.

    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-PDGFRα 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. 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 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.

    Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

    This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1000 mg of imatinib mesylate daily. The ages of these patients ranged from 16 to 64 years.

    These patients received imatinib mesylate at doses of 75 mg to 800 mg (imatinib as free base) daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 107 23 Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor.

    Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease.

    Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 25. 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.

    Gastrointestinal Stromal Tumors

    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. 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. Median follow up for the combined studies was 37.5 months.

    There were no observed differences in overall survival between the treatment groups (p = 0.98). One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. 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. 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 (imatinib as free base) 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 p less than 0.0001. 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. The median follow-up for OS in patients still living was 61 months.

    There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range, 22 to 84 years). Thirty-six months of imatinib mesylate treatment significantly prolonged RFS compared to 12 months of imatinib mesylate treatment with a hazard ratio of p less than 0.0001 (Figure 4 ).

    Thirty-six months of imatinib mesylate treatment significantly prolonged OS compared to 12 months of imatinib mesylate treatment with a hazard ratio of p=0.0187 (Figure 5 ).

    Best response rateImatinib Mesylate n = 553I FN+Ara-C n = 553
    Hematologic response 1
    CHR Rate n (%)534 (96.6%)313 (56.6%)
    [95% CI][94.7%, 97.9%][52.4%, 60.8%]
    Cytogenetic response 2
    Major cytogenetic response n (%)472 (85.4%)93 (16.8%)
    [95% CI][82.1%, 88.2%][13.8%, 20.2%]
    Unconfirmed 388.6%23.3%
    Complete cytogenetic response n (%) (%)413 (74.7%)36 (6.5%)
    [95% CI][70.8, 78.3][4.6, 8.9]
    Unconfirmed 382.5%11.6%
    *p less than 0.001, Fischer's exact test. 1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocyte + metamyelocyte less than 5% in blood, no blasts and promyelocytes in blood, no extramedullary involvement. 2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1% to 35%). A major response (0% to 35%) combines both complete and partial responses. 3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.
    Imatinib Mesylate 400 mg once dailyNilotinib 300 mg twice daily
    N = 283N = 282
    MMR at 12 months (95% CI)22% (17.6, 27.6)44% (38.4, 50.3)
    P-Value a<0.0001
    CCyR b by 12 months (95% CI)65% (59.2, 70.6)80% (75.0, 84.6)
    MMR at 24 months (95% CI)38% (31.8, 43.4)62% (55.8, 67.4)
    CCyR b by 24 months (95% CI)77% (71.7, 81.8)87% (82.4, 90.6)
    Chronic phase IFN failure(n = 532)Accelerated phase(n = 235)Myeloid blast crisis(n = 260)
    400 mg600 mg n = 158400 mg n = 77600 mg n = 223400 mg n = 37
    % of patients [CI 95% ]
    Hematologic response 195% [92.3−96.3]71% [64.8-76.8]31% [25.2−36.8]
    Complete hematologic response (CHR)95%38%7%
    No evidence of leukemia (NEL)Not applicable13%5%
    Return to chronic phase (RTC)Not applicable20%18%
    Major cytogenetic response 260% [55.3−63.8]21% [16.2−27.1]7% [4.5−11.2]
    (Unconfirmed 3 )(65%)(27%)(15%)
    Complete 4 (Unconfirmed 3 )39% (47%)16% (20%)2% (7%)
    Phase 2 study (N = 43) n (%)Phase 1 study (N = 2) n (%)
    CHR8 (19)2 (100)
    NEL5 (12)
    RTC/PHR11 (26)
    MCyR15 (35)
    CCyR9 (21)
    PCyR6 (14)
    Number of patients NComplete hematologic response N (%)Major cytogenetic response N ( % )
    Overall population3114 (45)12 (39)
    Chromosome 5 translocation1411 (79)11 (79)
    Chromosome 4 translocation22 (100)1 (50)
    Others/no translocation141 (7)0
    Molecular relapse1NE 1NE 1
    Abbreviations: NE, not evaluable; MDS/MPD, myelodysplastic/myeloproliferative disease.
    Cytogenetic abnormalityNumber of patients NComplete hematologic response N (%)Partial hematologic response N (%)
    FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion)77 (100)0
    Juxtamembrane mutation202 (100)
    Unknown or no cytogenetic abnormality detected1507 (44)
    D816V mutation41* (25)0
    Total288 (29)9 (32)
    Abbreviations: ASM, aggressive systemic mastocytosis; PDGFR, platelet-derived growth factor receptor. *Patient had concomitant chronic myeloid leukemia CML and ASM.
    Cytogenetic abnormalityNumber o f patientsComplete hematological response N (%)Partial hematological response N (%)
    Positive FIP1L1-PDGFRα fusion kinase6161 (100)0
    Negative FIP1L1-PDGFRα fusion kinase5612 (21)9 (16)
    Unknown cytogenetic abnormality5934 (58)7 (12)
    Total176107 (61)23 (13)
    Number of patients ( n = 18)%
    Complete response739
    Partial response844
    Total responders1583
    5 patients made disease free by surgery.
    Imatinib Mesylate 400 mgImatinib Mesylate 800 mg
    N = 818N = 822
    Progression-free survival (months) Median18.923.2
    95% CI17.4–21.220.8–24.9
    Overall survival (months)4948.7
    95% CI45.3–6045.3–51.6
    Best overall tumor response Complete response43 (5.3%)41 (5%)
    Partial response377 (46.1%)402 (48.9%)

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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