Iressa - Warnings & Precautions

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In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse events should be carefully monitored (see CLINICAL PHARMA-COLOGY- Pharmacokinetics-Drug-Drug Interactions and DOSAGE AND ADMIN-ISTRATION- Dosage Adjustment sections). 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 CLINICAL PHARMACOLOGY-Pharmacokinetics- Drug-Drug Interactions and ADVERSE REACTIONS sections). Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentra-tions.

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 IRESSA (see CLINICAL PHARMACOLOGY-Pharmacokinetics-Drug- Drug Interactions and ADVERSE REACTIONS sections). Drugs that cause significant sustained elevation in gastric pH (histamine H 2 -receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of IRESSA and therefore potentially may reduce efficacy (see CLINICAL PHARMA-COLOGY- Drug-Drug Interactions section).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage. Carcinogenicity studies have not been conducted with gefitinib.

Pregnancy

Pregnancy Category D (see WARNINGS and PRECAUTIONS-Information for Patients sections).

Nursing Mothers

It is not known whether IRESSA is excreted in human milk. Following oral adminis-tration of carbon-14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11- to- 19- fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/ kg. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast- feeding while receiving IRESSA therapy.