Imachron Drug Interactions

Observed interactions resulting in a concomitant use not recommended: Drugs that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to imatinib mesylate (Imachron). Pretreatment of 14 healthy volunteers with multiple doses of rifampicin, 600 mg daily for 8 days, followed by a single 400 mg dose of imatinib mesylate (Imachron), increased imatinib mesylate (Imachron) 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 rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib mesylate (Imachron) while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib mesylate (Imachron) and a product containing St. John's wort led to a 30 to 32% reduction in the AUC of imatinib mesylate (Imachron). In patients where rifampicin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Other interactions that may affect exposure to imatinib mesylate (Imachron) or other drugs: Drugs that may increase imatinib mesylate plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib mesylate concentrations. There was a significant increase in exposure to imatinib mesylate (the mean C_max and AUC of imatinib mesylate 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 imatinib mesylate (Imachron) with inhibitors of the CYP3A4 family.
Drugs that may have their plasma concentration altered by imatinib mesylate (Imachron): Imatinib mesylate (Imachron) 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 mesylate (Imachron). Therefore, caution is recommended when administering imatinib mesylate (Imachron) with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide). Imatinib mesylate (Imachron) may increase plasma concentration of other CYP3A4 metabolized drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).
Imatinib mesylate (Imachron) also inhibits CYP2C9 and CYP2C19 activity in vitro. 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 Imatinib mesylate (Imachron) therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered.
In vitro, Imatinib mesylate (Imachron) inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib mesylate (Imachron) at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol C_max and AUC being increased by approximately 23%. Co-administration of imatinib mesylate (Imachron) with CYP2D6 substrates, such as metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary.
In vitro, imatinib mesylate (Imachron) inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 microM).
Co-administration of imatinib mesylate (Imachron) (400 mg/day for eight days) with acetaminophen/paracetamol (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen/paracetamol.
Imatinib mesylate (Imachron) pharmacokinetics was not altered in the presence of single-dose acetaminophen/paracetamol.
There is no PK or safety data on the concomitant use of imatinib mesylate (Imachron) at doses >400 mg/day or the chronic use of concomitant acetaminophen/paracetamol and imatinib mesylate (Imachron).