Glivec Drug Interactions

Drugs That May Increase Imatinib Plasma Concentrations: Substances that inhibit the cytochrome P-450 isoenzyme CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean C_max and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering Glivec with inhibitors of the CYP3A4 family.
Drugs That May Decrease Imatinib Plasma Concentrations: Substances that are inducers of CYP3A4 activity could increase metabolism and decrease imatinib plasma concentrations. Co-medications which induce CYP3A4 (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's wort) may significantly reduce exposure to Glivec. Pre-treatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 8 days, followed by a single dose of Glivec 400 mg, increased Glivec oral dose clearance by 3.8-fold (90% confidence interval = 3.5- to 4.3-fold), which represents mean decreases C_max, AUC_(0-24) and AUC_(0-∞) by 54%, 68% and 74%, of the respective values without rifampin treatment. Similar results were observed in patients with malignant gliomas treated with Glivec while taking enzyme-inducing antiepileptic drugs (EIAEDs) eg, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In 2 published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30-32% reduction in the AUC of Glivec. In patients where rifampin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Drugs That May Have Their Plasma Concentration Altered by Glivec: Imatinib increases the mean C_max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Glivec with CYP3A4 substrates with a narrow therapeutic window (eg, cyclosporin or pimozide). Glivec may increase plasma concentration of other CYP3A4-metabolised drugs (eg, triazolobenzodiazepines, dihydropyridine, calcium-channel blockers, certain HMG-CoA reductase inhibitors ie, statins, etc).
Imatinib also inhibits CYP2C9 and CYP2C19 activity in vitro. Prothrombin time (PT) prolongation was observed following co-administration with warfarin. When giving coumarins, short-term PT monitoring is therefore necessary at the start and end of Glivec therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered.
In vitro, Glivec inhibits the cytochrome P-450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metropolol metabolism, with metoprolol C_max and AUC being increased by approximately 23%. Co-administration of imatinib with CYP2D6 substrates eg, metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary. In vitro, Glivec inhibits paracetamol/acetaminophen O-glucuronidation (K_I value of 58.5 micromol/L at therapeutic levels) (see Precautions).
Incompatibilities: Not applicable.