Xalkori · 4.1 Therapeutic indications · 1

HOS-096246 · has-adverse-reaction-information · PDF-Seite 17

Summary of the safety profile in adult patients with ALK-positive or ROS1-positive advanced NSCLC The data described below reflect exposure to XALKORI in 1669 patients with ALK-positive advanced NSCLC who participated in 2 randomised Phase 3 studies (Studies 1007 and 1014) and in 2 single-arm studies (Studies 1001 and 1005), and in 53 patients with ROS1-positive advanced NSCLC who participated in single-arm Study 1001, for a total of 1722 patients (see section 5.1). These patients received a starting oral dose of 250 mg taken twice daily continuously. In Study 1014, the median duration of study treatment was 47 weeks for patients in the crizotinib arm (N=171); the median duration of treatment was 23 weeks for patients who crossed over from the chemotherapy arm to receive crizotinib treatment (N=109). In Study 1007, the median duration of study treatment was 48 weeks for patients in the crizotinib arm (N=172). For ALK-positive NSCLC patients in Studies 1001 (N=154) and 1005 (N=1063), the median duration of treatment was 57 and 45 weeks, respectively. For ROS1-positive NSCLC patients in Study 1001 (N=53), the median duration of treatment was 101 weeks. The most serious adverse reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation (see section 4.4). The most common adverse reactions (≥25%) in patients with either ALK-positive or ROS1-positive NSCLC were vision disorder, nausea, diarrhoea, vomiting, oedema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness and neuropathy. The most frequent adverse reactions (≥3%, all-causality frequency) associated with dosing interruptions were neutropenia (11%), elevated transaminases (7%), vomiting (5%) and nausea (4%). The most frequent adverse reactions (≥3%, all-causality frequency) associated with dose reductions were elevated transaminases (4%) and neutropenia (3%). All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients of which the most frequent (≥1%) were ILD (1%) and elevated transaminases (1%). Tabulated list of adverse reactions Table 9 presents adverse reactions reported in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC who received crizotinib across 2 randomised Phase 3 studies (1007 and 1014) and 2 single-arm clinical studies (1001 and 1005) (see section 5.1).

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HOS-096242 · has-contraindication-information · PDF-Seite 11

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

HOS-096241 · has-indication-information · PDF-Seite 3

XALKORI as monotherapy is indicated for:  The first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)  The treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)  The treatment of adults with ROS1-positive advanced non-small cell lung cancer (NSCLC)  The treatment of paediatric patients (age ≥1 to <18 years) with relapsed or refractory systemic anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL)  The treatment of paediatric patients (age ≥1 to <18 years) with recurrent or refractory anaplastic lymphoma kinase (ALK)-positive unresectable inflammatory myofibroblastic tumour (IMT)

HOS-096244 · has-interaction-information · PDF-Seite 14

Interaction studies with other medicinal products have been performed in adults. Pharmacokinetic interactions Agents that may increase crizotinib plasma concentrations Coadministration of crizotinib with strong CYP3A inhibitors is expected to increase crizotinib plasma concentrations. Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib area-under-the-plasma-concentration versus time curve from time zero to infinity (AUCinf) and maximum observed plasma concentration (Cmax) values that were approximately 3.2-fold and 1.4-fold, respectively, those seen when crizotinib was administered alone. Coadministration of repeated doses of crizotinib (250 mg once daily) with repeated doses of itraconazole (200 mg once daily), a strong CYP3A inhibitor, resulted in increases in crizotinib steady-state AUCtau and Cmax, that were approximately 1.6-fold and 1.3-fold, respectively, those seen when crizotinib was administered alone. 14 Therefore, the concomitant use of strong CYP3A inhibitors (including but not limited to atazanavir, ritonavir, cobicistat, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin and erythromycin) should be avoided. Unless the potential benefit to the patient outweighs the risk, in which case patients should be closely monitored for crizotinib adverse events (see section 4.4). Physiologically-based pharmacokinetic (PBPK) simulations predicted a 17% increase in crizotinib steady-state AUC after treatment with the moderate CYP3A inhibitors, diltiazem or verapamil. Caution is therefore recommended in case of coadministration of crizotinib with moderate CYP3A inhibitors. Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided (see sections 4.2 and 4.4). Agents that may decrease crizotinib plasma concentrations Coadministration of repeated doses of crizotinib (250 mg twice daily) with repeated doses of rifampicin (600 mg once daily), a strong CYP3A4 inducer, resulted in 84% and 79% decreases in crizotinib steady-state AUCtau and Cmax, respectively, compared to when crizotinib was given alone. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort, should be avoided (

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HOS-096245 · has-pregnancy-information · PDF-Seite 16

Women of childbearing potential Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. Contraception in males and females Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy (see section 4.5). Pregnancy XALKORI may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3). There are no data in pregnant women using crizotinib. This medicinal product should not be used during pregnancy unless the clinical condition of the mother requires treatment. Pregnant women, or patients becoming pregnant while receiving crizotinib, or treated male patients as partners of pregnant women, should be apprised of the potential hazard to the foetus. 16 Breast-feeding It is not known whether crizotinib and its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should be advised to avoid breast-feeding while receiving XALKORI (see section 5.3). Fertility Based on non-clinical safety findings, male and female fertility may be compromised by treatment with XALKORI (see section 5.3). Both men and women should seek advice on fertility preservation before treatment.

HOS-096243 · has-warning-information · PDF-Seite 11

Assessment of ALK and ROS1 status When assessing either ALK or ROS1 status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. Hepatotoxicity Drug-induced hepatotoxicity (including cases with fatal outcome in adult patients) has been reported in patients treated with crizotinib across clinical studies (see section 4.8). Liver function tests including ALT, AST, and total bilirubin should be monitored once a week during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevations. For patients who develop transaminase elevations, see section 4.2. Interstitial lung disease/pneumonitis Severe, life-threatening or fatal ILD/pneumonitis can occur in patients treated with crizotinib. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Crizotinib treatment should be withheld if ILD/pneumonitis is suspected. Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions such as: pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, lung infiltration, pneumonia, pulmonary oedema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis and bronchiectasis. Other potential causes of ILD/pneumonitis should be excluded, and crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). QT interval prolongation QTc prolongation has been observed in clinical studies in patients treated with crizotinib (see sections 4.8 and 5.2) which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de Pointes) or sudden death. The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant pre-existing cardiac disease and/or electrolyte disturbances. Crizotinib should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function

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