Alunbrig · 4.3 Contraindications · 1

HOS-217439 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most common adverse reactions (≥ 25%) reported in patients treated with Alunbrig at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, diarrhoea, increased ALT, increased amylase, anaemia, nausea, fatigue, hypophosphataemia, decreased lymphocyte count, cough, increased alkaline phosphatase, rash, increased APTT, myalgia, headache, hypertension, decreased white blood cell count, dyspnoea, and vomiting. The most common serious adverse reactions (≥ 2%) reported in patients treated with Alunbrig at the recommended dosing regimen other than events related to neoplasm progression were pneumonia, pneumonitis, dyspnoea and pyrexia. Tabulated list of adverse reactions The data described below reflect exposure to Alunbrig at the recommended dosing regimen in three clinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previously not treated with an ALK-inhibitor (N = 136), a Phase 2 trial (ALTA) in patients treated with Alunbrig with ALK-positive NSCLC who previously progressed on crizotinib (N = 110), and a phase 1/2 dose escalation/expansion trial in patients with advanced malignancies (N = 28). Across these studies, the median duration of exposure in patients receiving Alunbrig at the recommended dosing regimen was 21.8 months. Adverse reactions reported are presented in Table 3 and are listed by system organ class, preferred term and frequency. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1 000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of frequency. 12 Table 3: Adverse reactions reported in patients treated with Alunbrig (per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) at the 180 mg regimen (N = 274) System organ Frequency Adverse reactions† Adverse reactions class category all grades Grade 3-4 Infections and Very Pneumoniaa,b infestations common Upper respiratory tract infection Common Pneumoniaa Blood and Very Anaemia Lymphocyte count decreased lymphatic common Lymphocyte count decreased system APTT increased disorders

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HOS-217435 · has-contraindication-information · PDF-Seite 7

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

HOS-217434 · has-indication-information · PDF-Seite 2

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor. Alunbrig is indicated as monotherapy for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib. 2

HOS-217437 · has-interaction-information · PDF-Seite 9

Agents that may increase brigatinib plasma concentrations CYP3A inhibitors In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. In healthy subjects, coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, with a single 90 mg brigatinib dose increased brigatinib Cmax by 21%, AUC0-INF by 101% (2-fold), and AUC0-120 by 82% (< 2-fold), relative to a 90 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inhibitors with Alunbrig, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., ketoconazole, voriconazole), and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). After 9 discontinuation of a strong CYP3A inhibitor, Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor. Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No dose adjustment is required for Alunbrig in combination with moderate CYP3A inhibitors. Patients should be closely monitored when Alunbrig is coadministered with moderate CYP3A inhibitors. Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided (see section 4.2). CYP2C8 inhibitors In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. In healthy subjects, coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose reduced brigatinib Cmax by 41%, AUC0-INF by 12%, and AUC0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown. No dose adjustment is required during coadministration with strong CYP2C8 inhibitors. P-gp and BCRP inhibitors Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. Given that brigatinib exhibits high solubility and hi

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HOS-217438 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential/Contraception in males and females Women of childbearing age being treated with Alunbrig should be advised not to become pregnant and men being treated with Alunbrig should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with Alunbrig and for at least 4 months following the final dose. Men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of Alunbrig. Pregnancy Alunbrig may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3). There are no clinical data on the use of Alunbrig in pregnant women. Alunbrig should not be used during pregnancy unless the clinical condition of the mother requires treatment. If Alunbrig is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to a foetus. Breast-feeding It is unknown whether Alunbrig is excreted in human milk. Available data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with Alunbrig. Fertility No human data on the effect of Alunbrig on fertility are available. Based on repeat-dose toxicity studies in male animals, Alunbrig may cause reduced fertility in males (see section 5.3). The clinical relevance of these findings to human fertility is unknown.

HOS-217436 · has-warning-information · PDF-Seite 7

Pulmonary adverse reactions Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur in patients treated with Alunbrig (see section 4.8). Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of Alunbrig were independently associated with an increased rate of these pulmonary adverse reactions. These factors should be considered when initiating treatment with Alunbrig. Patients with a history of ILD or drug-induced pneumonitis were excluded from the pivotal trials. Some patients experienced pneumonitis later in treatment with Alunbrig. Patients should be monitored for new or worsening respiratory symptoms (e.g., dyspnoea, cough, etc.), particularly in the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be promptly investigated. If pneumonitis is suspected, the dose of Alunbrig should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonary embolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly (see section 4.2). Hypertension Hypertension has occurred in patients treated with Alunbrig (see section 4.8). Blood pressure should be monitored regularly during treatment with Alunbrig. Hypertension should be treated according to standard guidelines to control blood pressure. Heart rate should be monitored more frequently in patients if concomitant use of a medicinal product known to cause bradycardia 7 cannot be avoided. For severe hypertension (≥ Grade 3), Alunbrig should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly (see section 4.2). Bradycardia Bradycardia has occurred in patients treated with Alunbrig (see section 4.8). Caution should be exercised when administering Alunbrig in combination with other agents known to cause bradycardia. Heart rate and blood pressure should be monitored regularly. If symptomatic bradycardia occurs, treatment with Alunbrig should be withheld and concomitant medicinal products known to cause bradycardia should be evaluated. Upon recovery, the dose should be modif

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