Augtyro · 4.4 Special warnings and precautions for use · 1

HOS-288914 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions in adults were dizziness (65%), dysgeusia (57%), constipation (39%), paraesthesia (39%), anaemia (38%), and dyspnoea (31%). The most common serious adverse reactions were pneumonia (6.2%), dyspnoea (3.5%), pleural effusion (3.0%), pyrexia (1.2%), muscular weakness (1.1%), anaemia (1.1%), and pneumonitis (1.1%). Grade ≥ 3 adverse reactions occurred in 43% of patients and anaemia (8.8%), dyspnoea (6.7%), pneumonia (5.7%), blood creatine phosphokinase increased (3.4%), weight increased (3.2%), aspartate aminotransferase increased (2.7%), pleural effusion (2.3%), and neutrophil count decreased (2.1%) were the most frequently reported. Permanent discontinuation due to an adverse reaction occurred in 6.2% patients. Tabulated list of adverse reactions Tables 3 and 4 summarise the adverse reactions reported in patients treated with AUGTYRO in the TRIDENT-1 study in adults (n = 565) and in the CARE study (n = 38) including paediatric patients respectively. These reactions are presented by system organ class and by frequency. Frequencies 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in patients exposed to AUGTYRO with a median duration of 7.6 months in clinical study. See section 5.1 for information on the main clinical study. Table 3: Adverse reactions occurring in adult patients treated with AUGTYRO % All Grades % ≥ 3 Grades Infections and infestations Very common pneumonia 10.3 5.7 Blood and lymphatic system disorders Very common anaemia 38.1 8.8 8  % All Grades % ≥ 3 Grades Metabolism and nutrition disorders Common hyperuricaemiaa 5.0 0.7 Nervous system disorders Very common dizzinessb 65.5 3.2 ataxiac 29.0 0.5 cognitive disordersd 22.3 1.2

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HOS-288910 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4

HOS-288909 · has-indication-information · PDF-Seite 2

AUGTYRO as monotherapy is indicated for the treatment of adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC). AUGTYRO as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age and older with advanced solid tumours expressing a NTRK gene fusion, and  who have received a prior NTRK inhibitor, or  have not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit, or have been exhausted (see sections 4.4 and 5.1)

HOS-288912 · has-interaction-information · PDF-Seite 6

Based on in vitro data repotrectinib is a substrate for CYP3A4 and P-gp. Effects of other agents on repotrectinib Effect of CYP3A4 inhibitors and P-gp inhibitors on repotrectinib Co-administration of multiple oral doses of itraconazole (a strong CYP3A4 and P-gp inhibitor) with a single 80 mg dose of repotrectinib increased repotrectinib AUC0-inf by 5.9-fold and Cmax by 1.7-fold. Co-administration of AUGTYRO with strong or moderate CYP3A4 or P-gp inhibitors (including but not limited to ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, verapamil, nifedipine, felodipine, fluvoxamine, grapefruit, or Seville oranges) increases repotrectinib plasma concentrations and should thus be avoided (see section 4.4). Effect of CYP3A4 and P-gp inducers on repotrectinib Co-administration of multiple oral doses of rifampicin (a strong CYP3A4 and P-gp inducer) with a single 160 mg repotrectinib dose reduced repotrectinib AUC0-inf by 92% and Cmax by 79%. Co- administration of AUGTYRO with strong or moderate CYP3A4 or P-gp inducers (including but not limited to carbamazepine, phenytoin, rifampicin, St. John’s Wort- Hypericum perforatum, apalutamide, ritonavir) decreases repotrectinib plasma concentrations and should thus be avoided (see section 4.4). Effects of repotrectinib on other agents Effect of repotrectinib on CYP3A4 substrates Repotrectinib is a moderate CYP3A4 inducer. Co-administration of 160 mg repotrectinib once daily for 14 days followed by twice daily dosing for 7 days reduced AUC0-inf by 69% and Cmax by 48% of a single oral dose of midazolam (a CYP3A4 substrate). Caution is advised when CYP3A4 substrates (including but not limited to cisapride, cyclosporin, fentanyl, tacrolimus, alfentanil, sirolimus, 6 everolimus, lovastatin, and simvastatin) are co-administered with repotrectinib, due to risk of therapeutic failure. Effect of repotrectinib on CYP2B6 substrates In vitro studies indicate that repotrectinib is a CYP2B6 inducer. Co-administration of AUGTYRO with sensitive substrates of CYP2B6 substrates (including but not limited to bupropion, efavirenz) may decrease their exposure. Effect of repotrectinib on substrates of PXR regulated enzymes In vitro studies indicate that repotrectinib may induce pregnane X receptor (PXR) regulated enzymes that include CYP2C8, CYP2C9, CYP2C19 and UGT. In vitro data also indicate that repotrectinib inhibits CYP2C8, CYP2C9 and UGT1A1. The i

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HOS-288913 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/ Contraception in males and females Female patients of childbearing potential should have medically supervised pregnancy testing prior to initiating AUGTYRO therapy. Female patients of childbearing potential must use highly effective contraception during treatment with AUGTYRO and for at least 2 months following the final dose. AUGTYRO may reduce the effectiveness of systemically acting hormonal contraceptives including oral contraceptives. If hormonal contraception is used, females of childbearing potential should be advised to use an additional barrier method of contraception (see section 4.5). Male patients with female partners of childbearing potential must use condoms during treatment and for 4 months following the final dose of AUGTYRO. Pregnancy There are no available data on AUGTYRO use in pregnant women. Based on animal studies and its mechanism of action, repotrectinib may cause foetal harm when administered to pregnant women. AUGTYRO should not be used unless clinical condition of the woman requires treatment with 7 AUGTYRO. Women of childbearing potential have to use highly effective contraception (see sections 4.4 and 5.3). Breast-feeding It is unknown whether repotrectinib or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with AUGTYRO and for 10 days after the final dose. Fertility No fertility studies have been conducted with repotrectinib (see section 5.3). The effect of repotrectinib on male and female fertility is unknown.

HOS-288911 · has-warning-information · PDF-Seite 5

Efficacy across tumour types The benefit of AUGTYRO has been established in single-arm studies encompassing adult patients (N = 88) whose tumours exhibit NTRK gene fusions. Favourable effects of AUGTYRO have been shown based on overall response rate and response duration in a limited number of tumour types. The effect may be quantitatively different depending on tumour type, as well as on concomitant genomic alterations (see section 5.1). Central nervous system (CNS) A broad spectrum of CNS adverse reactions has been reported in patients receiving AUGTYRO including dizziness, ataxia, and cognitive disorders (see section 4.8). Patients should be advised of these risks with AUGTYRO as they may influence the ability to drive and use machines. Patients should be advised not to drive or use machines if they are experiencing CNS adverse reactions (see section 4.7). AUGTYRO should be withheld and then resumed at the same or reduced dose upon improvement, or permanently discontinued based on severity (see section 4.2). Interstitial lung disease (ILD)/Pneumonitis Patients should be advised to report symptoms of ILD/pneumonitis, which may include shortness of breath, cough, wheezing, chest pain or tightness, and haemoptysis. Patients should be monitored for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. AUGTYRO should be withheld in patients with suspected ILD/pneumonitis and permanently discontinued if ILD/pneumonitis is confirmed (see section 4.2). Skeletal fractures Skeletal fractures have been reported in adults and paediatric patients treated with AUGTYRO across clinical studies. In adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area. Radiologic abnormalities possibly indicative of tumour involvement were reported in some patients. In both adult and paediatric patients, most fractures were lower extremity fractures (e.g., fibula, tibia, or foot). Patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures should be promptly evaluated. Hepatotoxicity Drug-induced hepatotoxicity has been reported in patients treated with AUGTYRO (see section 4.8). Liver function tests including ALT, AST and bilirubin should be monitored as clinically indicated. Hepatic impairment AUGTYRO has not been studied in patients with moderate or severe hepatic impairment. AUGTYRO should not be used in patients with moderate or severe hepatic impairment due to pote

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