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Internationalised Normal Ratio(INR) elevations and/or bleeding events have been reported in some patients taking warfarin(see Pharmacokinetic Properties' section). patients taking warfarin should be monitored regularly for changes in proth... Internationalised Normal Ratio(INR) elevations and/or bleeding events have been reported in some patients taking warfarin(see Pharmacokinetic Properties' section). patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. patients shouldbe advised to seek medical advice promptly in the event of developing any eye symptoms or severe or persistent diarrhoea ， nausea vomiting or anorexia(see Pharmacokinetic Properties' section). These symptoms should be managed as clinically indicated. Randomised controlled trials have demonstrated that Iressa combined with doublet ， platinum-based cytotoxic chemotherapy in advanced NSCLC provides no added benefit over ther cytototxic in patientswho have previously received treatment with cytotoxic chemotherapy. In a phase I/II trial of IRESSA and radiation in paediatric patients， newly diagnosed with brain stem glioma or incompletely resected supratentorialmalignant glioma， 4 cases(1fatal) of CNS haemorrhages have been reported from trialwith IRESSA alone. There is no evidence to suggest any increased risk of cerebral haemorrhage in adult patients with NSCLC receiving IRESSA. Phase IIclinical trial data， where IRESSA and vinorelbine have been used concomitantly， indicate that Iressa may exacebate the neutropenic effctof vinorbine. Interaction with other medicinal products and other forms of interaction In vitro studies with human hepatic microsomes have shown that the metabolism of gefitinib is predomiantly via the CYP3A4 isoform of the hepatic cytochromeP-450 system. Gefitinib may be sxpected to interact with otehr drgs that induce， inhibit or are metabolised by this system. Gefitinib showed littl enzyme induction effect in animal studies and in vitro sutdies have shown that gefitinib has limited potentialto inhibit CYP2D6. The clinically or potentially significantclinical drug interactions between gefitinib and the following drugs/ durg classes are described below. Other Drugs that effect gefitinib Demonstrated interactions Drugs that inhaibit CYP3A4 co-administraion with itraconazole(a CYP3A4)resuulted in an 80% increase in the mean AUC of gefitinibin healthy volunteers. This increase may bbe clinically relevant since adverse experiences are related to dose and exposure. Although interaction studies with other CYP3A4 inhibitors have not been performed it is expected that drugs such as ketoconaxole， clotrimazole， ritonovir would also inhibit gefitinib metabolism. Drugs that Increase gastric pH In a trial in healthy volunteers co-adminstrationof drugs that cause significant sustined elevations in gastric pH>=5， resulted in a reduced mean gefitinib AUC by 47%. This may reduce efficacy Rifampicin Co-administration with rifa mpicin(a known potent CYP3A4 inducer) in healthy volunteers reduced meangefitinib AUC by 83% of that without rifampicin. Theoretical interactions