(n=532)
600 mg n=223
400 mg n=37 600 mg n=158
400 mg n=77 400 mg
% % %
CTC Grades1 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters
− Neutropenia 16 48 23 36 27 9
− Thrombocytopenia 30 33 31 13 21 <1
− Anemia 42 11 34 7 6 1
Biochemistry Parameters
− Elevated Creatinine 1.5 0 1.3 0 0.2 0
− Elevated Bilirubin 3.8 0 2.1 0 0.6 0
− Elevated Alkaline Phosphatase 4.6 0 5.5 0.4 0.2 0
− Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0
− Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0
1CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (hemoglobin ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN)
6.3 Hepatotoxicity
Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.
6.4 Adverse Reactions in Pediatric Population
The overall safety profile of pediatric patients treated with Gleevec 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. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.
6.5 Adverse Reactions in Other Subpopulations
In older patients (≥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 eva luation.
6.6 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, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.
6.7 Myelodysplastic/Myelop
