Apo-Gefitinib Drug Interactions

Overview: Gefitinib showed no enzyme induction effects in animal studies. Human liver microsome studies demonstrated that in vitro gefitinib was not a potent inhibitor of any human CYP enzyme activities. At the highest concentration studied, it produced approximately 50% inhibition of CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a small (35%) increase in exposure to metoprolol, which is not considered to be clinically relevant. However, such an increase has potential clinical relevance for CYP2D6 substrates with a narrow therapeutic index and caution is advised when co-administered with gefitinib.
In vitro studies have shown that the metabolism of gefitinib is predominantly via CYP3A4. Co-administration with rifampicin (a known potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% of that without rifampicin. Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort) may potentially reduce efficacy.
Co-administration with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. Substances that are inhibitors of CYP3A4 activity (e.g., azole antifungals such as ketoconazole and itraconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors, grapefruit juice etc.) may decrease metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure. Therefore, caution should be used when administering CYP3A4 inhibitors with gefitinib.
Co-administration of ranitidine (gastric pH above 5) reduced by 47% the mean gefitinib AUC in healthy volunteers. Drugs that cause significant sustained elevation in gastric pH (histamine H₂-receptor antagonists such as ranitidine or cimetidine; proton-pump inhibitors) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy (see Pharmacology: Pharmacokinetics: Metabolism under Actions).
International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.
Drug-Drug Interactions: See Table 8.

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Drug-Food Interactions: Grapefruit juice and other inhibitors of CYP3A4 may decrease metabolism and increase gefitinib plasma concentrations.
Drug-Herb Interactions: St. John's Wort and other inducers of CYP3A4 may potentially reduce the efficacy of gefitinib.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.