Iressa · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-095334 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients), the most frequently reported adverse drug reactions (ADRs), occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR. Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported. Tabulated list of adverse reactions The safety profile presented in Table 1 is based on the gefitinib clinical development programme and postmarketed experience. Adverse reactions have been assigned to the frequency categories in Table 1 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients). Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1 Adverse reactions Adverse reactions by system organ class and frequency Metabolism and nutrition Very common Anorexia mild or moderate disorders (CTC grade 1 or 2) Eye disorders Common Conjunctivitis, blepharitis, and dry eye*, mainly mild (CTC grade 1) Uncommon Corneal erosion, reversible and sometimes in association with aberrant eyelash growth Keratitis (0.12%) Vascular disorders Common Haemorrhage, such as epistaxis and haematuria Respiratory, thoracic and Common

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HOS-095330 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6).

HOS-095329 · has-indication-information · PDF-Seite 2

IRESSA is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (see section 4.4).

HOS-095332 · has-interaction-information · PDF-Seite 5

The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6. Active substances that may increase gefitinib plasma concentrations In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding. Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions. There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold (see section 5.2). If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions. Active substances that may reduce gefitinib plasma concentrations Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John’s wort/ Hypericum perforatum) should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% (see section 4.4). Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib. Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥ 5 resulted in a reduced mean gefitinib AUC by 47% in healthy volunteers (see section 4.4 and 5.2). Activ

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HOS-095333 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential Women of childbearing potential must be advised not to get pregnant during therapy. Pregnancy There are no data from the use of gefitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IRESSA should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether gefitinib is secreted in human milk. Gefitinib and metabolites of gefitinib accumulated in milk of lactating rats (see section 5.3). Gefitinib is contraindicated during breast-feeding and therefore breast-feeding must be discontinued while receiving gefitinib therapy (see section 4.3).

HOS-095331 · has-warning-information · PDF-Seite 3

When considering the use of IRESSA as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used. Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations (see section 5.1). Interstitial lung disease (ILD) Interstitial lung disease (ILD) which may be acute in onset, has been observed in 1.3% of patients receiving gefitinib, and some cases have been fatal (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and the patient should be promptly investigated. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately. In a Japanese pharmacoepidemiological case control study in 3,159 patients with NSCLC receiving gefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received IRESSA or chemotherapy) were identified: smoking, poor performance status (PS ≥ 2), CT scan evidence of reduced normal lung (≤ 50%), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, older age (≥ 55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on IRESSA or chemotherapy was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤ 50%), pre-existing ILD, older age (≥ 65 years old), and extensive areas adherent to pleura (≥ 50%). Hepatotoxicity and liver impairment Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis (see section 4.8). There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in

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