Tarceva · 4.3 Contraindications · 1

HOS-094104 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile Safety evaluation of Tarceva is based on the data from more than 1500 patients treated with at least one 150 mg dose of Tarceva monotherapy and more than 300 patients who received Tarceva 100 or 150 mg in combination with gemcitabine. Non-small cell lung cancer (Tarceva administered as monotherapy) First-Line Treatment of Patients with EGFR Mutations In an open-label, randomised phase III study, ML20650 conducted in 154 patients, the safety of Tarceva for first-line treatment of NSCLC patients with EGFR activating mutations was assessed in 75 patients. The most frequent adverse drug reactions (ADRs) seen in patients treated with Tarceva in study ML20650 were rash and diarrhoea, most were Grade 1/2 in severity and manageable without intervention. Full grade and incidence information for rash and diarrhoea for all clinical studies is available in the ‘Description of selected adverse reactions’ section below. Maintenance treatment In two other double-blind, randomised, placebo-controlled Phase III studies BO18192 (SATURN) and BO25460 (IUNO); Tarceva was administered as maintenance after first-line chemotherapy. These studies were conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy. The most frequent ADRs seen in patients treated with Tarceva in studies BO18192 and BO25460 were rash and diarrhoea. Second and Further Line Treatment In a randomised double-blind study (BR.21; Tarceva administered as second line therapy), rash and diarrhoea were the most commonly reported adverse drug reactions (ADRs). Most were Grade 1/2 in severity and manageable without intervention. The median time to onset of rash was 8 days, and the median time to onset of diarrhoea was 12 days. Pancreatic cancer (Tarceva administered concurrently with gemcitabine) The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving Tarceva 100 mg plus gemcitabine were fatigue, rash and diarrhoea. The median time to onset of rash and diarrhoea was 10 days and 15 days, respectively. Tabulated summary of adverse reactions The incidence of ADRs from clinical trials and the post marketing setting reported with Tarceva alone or in combination with chemotherapy are summarised in Table 1. Adverse drug reactions are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following

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HOS-094100 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to erlotinib or to any of the excipients listed in section 6.1.

HOS-094099 · has-indication-information · PDF-Seite 2

Non-Small Cell Lung Cancer (NSCLC) Tarceva is indicated for the first-line treatment of patients with locally advanced or metastatic non- small cell lung cancer (NSCLC) with EGFR activating mutations. Tarceva is also indicated for switch maintenance treatment in patients with locally advanced or metastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy. 2 Tarceva is also indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. In patients with tumours without EGFR activating mutations, Tarceva is indicated when other treatment options are not considered suitable. When prescribing Tarceva, factors associated with prolonged survival should be taken into account. No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with Epidermal Growth Factor Receptor (EGFR)-IHC negative tumours (see section 5.1). Pancreatic cancer Tarceva in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer. When prescribing Tarceva, factors associated with prolonged survival should be taken into account (see sections 4.2 and 5.1). No survival advantage could be shown for patients with locally advanced disease.

HOS-094102 · has-interaction-information · PDF-Seite 6

Interaction studies have only been performed in adults. Erlotinib and other CYP substrates Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation by UGT1A1 in vitro. The physiological relevance of the strong inhibition of CYP1A1 is unknown due to the very limited expression of CYP1A1 in human tissues. When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced. Pre-treatment or co-administration of Tarceva did not alter the clearance of the prototypical CYP3A4 substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance of other CYP3A4 substrates are therefore unlikely. The inhibition of glucuronidation may cause interactions with medicinal products which are substrates of UGT1A1 and exclusively cleared by this pathway. Patients with low expression levels of UGT1A1 or genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution. Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes. Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase

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HOS-094103 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential Women of childbearing potential must be advised to avoid pregnancy while on Tarceva. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus. Breast-feeding It is not known whether erlotinib is excreted in human milk. No studies have been conducted to assess the impact of Tarceva on milk production or its presence in breast milk. As the potential for harm to the nursing infant is unknown, mothers should be advised against breast-feeding while receiving Tarceva and for at least 2 weeks after the final dose. Fertility Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters (see section 5.3). The potential risk for humans is unknown. 8

HOS-094101 · has-warning-information · PDF-Seite 4

Assessment of EGFR mutation status When considering the use of Tarceva as a first line or maintenance treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation status of a patient is determined. A validated, robust, reliable and sensitive test with a prespecified positivity threshold and demonstrated utility for the determination of EGFR mutation status, using either tumor DNA derived from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed according to local medical practice. If a plasma-based cfDNA test is used and the result is negative for activating mutations, perform a tissue test wherever possible due to the potential for false negative results from a plasma-based test. Smokers Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant (see sections 4.2, 4.5, 5.1 and 5.2). Interstitial Lung Disease Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving Tarceva for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the same in both the placebo and Tarceva groups. In a meta-analysis of NSCLC randomised controlled clinical trials (excluding phase I and single-arm phase II studies due to lack of control groups), the incidence of ILD-like events was 0.9% on Tarceva compared to 0.4% in patients in the control arms. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the Tarceva plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating Tarceva therapy. Confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. A higher incidence of ILD (

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