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Gleevec

Brand Name:	Gleevec	Trade Name:	imatinib mesylate
FDA Approved For:	Gleevec (imatinib mesylate) is indicated for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. The effectiveness of Gleevec is based on overall hematologic and cytogenetic response rates (see CLINICAL PHARMACOLOGY: CLINICAL STUDIES). There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.	Pediatric Use:	The safety and effectiveness of Gleevec in pediatric patients have not been established.
Carcinogen:	Carcinogenicity studies have not been performed with imatinib mesylate.	Mutagen:	Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay.
Manufacturer and/or Distributor:	Novartis

Adverse Reactions:

Complications of advanced CML and co-administered medications make causality of adverse events difficult to assess in single arm studies. The majority of Gleevec-treated patients experienced adverse events at some time. Most events were of mild to moderate grade, but drug was discontinued for adverse events in 1% of patients in chronic phase, 2% in accelerated phase and 5% in blast crisis. The most frequently reported drug-related adverse events were nausea, vomiting, edema, and muscle cramps (Table 2). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec (imatinib mesylate). (See DOSAGE AND ADMINISTRATION.) The frequency of severe edema was 1%-5%. A variety of adverse events represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These events 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 events were usually managed by interrupting Gleevec treatment and with diuretics or other appropriate supportive care measures. However, a few of these events may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure. Adverse events, regardless of relationship to study drug, that were reported in at least 10% of the patients treated in the Gleevec studies are shown in Table 2. (See Table) Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses >750 mg (Phase I study). The occurrence of cytopenias was also dependent on the stage of the disease, with a frequency of grade 3 or 4 neutropenia and thrombocytopenia between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Table 3). The median duration of the neutropenic and thrombocytopenic episodes ranged usually from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment. Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in 1.1%-3.5% (see Table 3) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 0.5% of patients. However, one patient, who was taking acetaminophen regularly for fever, died of acute liver failure. Adverse Effects in Subpopulations With the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse events in older patients (³65 years old). With the exception of a slight increase in the frequency of grade 1/2 periorbital edema, headache and fatigue in women, there was no evidence of a difference in the incidence or severity of adverse events between the sexes. No differences were seen related to race but the subsets were too small for proper evaluation. (See Table) CTC grades: neutropenia (grade 3 ³0.5 - 1.0 x 109/L, grade 4 <0.5 x 109L), thrombocytopenia (grade 3 ³10 - 50 x 109/L, grade 4 <10 x 109/L), anemia (hemoglobin ³65 - 80 g/L, grade 4 <65 g/L), elevated creatinine (grade 3 >3-6 x ULN (upper limit normal range), 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) )

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