Iressa

[gefitinib tablets]

Drug-Drug Interactions

In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 activities at concentrations ranging from 2- 5000 ng/ mL. At the highest concentration studied (5000 ng/ mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%. Exposure to metoprolol, a substrate of CYP2D6, was increased by 30% when it was given in combination with gefitinib (500 mg daily for 28 days) in patients with solid tumors. Rifampicin, an inducer of CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male volunteers (see PRECAUTIONS-Drug Interactions and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).

Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg single dose) to healthy male volunteers, increased mean gefitinib AUC by 88% (see PRECAUTIONS-Drug Interactions section). Co- administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) reduced mean gefitinib AUC by 44% (see PRECAU-TIONS- Drug Interactions section).

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International Normalized Ratio (INR) elevations and/ or bleeding events have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections).

Clinical Studies

Non- Small Cell Lung Cancer (NSCLC) Ð A multicenter clinical trial in the United States evaluated the tumor response rate of IRESSA 250 and 500 mg/ day in patients with advanced non- small cell lung cancer whose disease had progressed after at least two prior chemotherapy regimens including a platinum drug and docetaxel. IRESSA was taken once daily at approximately the same time each day. Two hundred and sixteen patients received IRESSA, 102 (47%) and 114 (53%) receiving 250 mg and 500 mg daily doses, respectively. Study patient demographics and disease characteristics are summarized in Table 1. Forty-one percent of the patients had received two prior treatment regimens, 33% three prior treatment regimens, and 25% four or more prior treatment regimens.

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