DRUG INTERACTIONS Drug -Drug Interactions
CYP3A4 Inhibitors: There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). (See PRECAUTIONS.)
CYP3A4 Substrates: Gleevec increased the mean Cmax and AUC of simvastatin (CYP3A4 substrate) by 2- and 3.5-fold, respectively, indicating an inhibition of CYP3A4 by Gleevec. (See PRECAUTIONS.)
CYP3A4 Inducers: Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 8 days, followed by a single 400-mg dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold (90% confidence interval = 3.5- to 4.3-fold), which represents mean decreases in Cmax, AUC(0-24) and AUC(0-∞) by 54%, 68% and 74%, of the respective values without rifampin treatment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
In Vitro Studies of CYP Enzyme Inhibition: Human liver microsome studies demonstrated that Gleevec is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5 and 8 µM, respectively. Gleevec is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5. (See PRECAUTIONS.)
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OVERDOSAGE
Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec® (imatinib mesylate) overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given.
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 Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse events. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse events occurred and the patient resumed therapy.
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