Tabrecta

HOS-287439 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions are peripheral oedema (68.1%), nausea (45.0%), fatigue (35.6%), blood creatinine increased (35.0%), vomiting (25.6%), dyspnoea (23.8%), decreased appetite (21.9%) and back pain (21.3%). The most common grade 3 or 4 adverse reactions are peripheral oedema (17.5%), lipase increased (9.4%), fatigue (8.8%), ALT increased (8.1%), dyspnoea (6.9%) and amylase increased (5.6%). Serious adverse reactions were reported in 38 of 160 patients (23.8%) who received Tabrecta. Serious adverse reactions in >2% of patients included dyspnoea (6.3%), ILD/pneumonitis (5.0%), cellulitis (3.1%) and peripheral oedema (3.1%). 8 Dose interruptions were reported in 84 of 160 patients (52.5%). Adverse reactions requiring dose interruption included peripheral oedema (16.9%), blood creatinine increased (13.1%), lipase increased (8.1%), nausea (8.1%), ALT increased (6.3%), amylase increased (5.6%), fatigue (5.6%), vomiting (5.6%), dyspnoea (4.4%), blood bilirubin increased (3.1%) and AST increased (3.1%). Dose reductions were reported in 53 of 160 patients (33.1%). Adverse reactions requiring dose reductions included peripheral oedema (18.8%), ALT increased (5.0%), blood creatinine increased (3.8%), fatigue (3.1%) and nausea (2.5%). Permanent discontinuation was reported in 22 of 160 patients (13.8%). The most frequent adverse reactions leading to permanent discontinuation of Tabrecta were ILD/pneumonitis (3.8%), peripheral oedema (2.5%), AST increased (1.9%), fatigue (1.9%), ALT increased (1.3%), blood bilirubin increased (1.3%), dyspnoea (1.3%), lipase increased (1.3%), amylase increased (0.6%), blood creatinine increased (0.6%) and urticaria (0.6%). Tabulated list of adverse reactions The safety of Tabrecta was evaluated in patients with locally-advanced or metastatic NSCLC in a pivotal, global, prospective, multi-cohort, non-randomised, open-label Phase II study (GEOMETRY mono-1) across all cohorts (N=373), regardless of prior treatment or MET dysregulation (mutation and/or amplification) status. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 160 patients with METex14 skipping mutations exposed to capmatinib at the recommended dose, whereas frequencies for changes in laboratory parameters are based on worsening from baseline shifts by at least 1 grade (grading according to CTCAE version 4.03). The safety profi

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HOS-287435 · has-contraindication-information · PDF-Seite 5

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

HOS-287434 · has-indication-information · PDF-Seite 2

Tabrecta as monotherapy is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harbouring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.

HOS-287437 · has-interaction-information · PDF-Seite 6

Capmatinib undergoes metabolism through CYP3A4 enzyme and aldehyde oxidase. The risk of a drug-drug interaction via aldehyde oxidase has not been evaluated as there are no confirmed clinically relevant inhibitors. 6 Effect of other medicinal products on Tabrecta Strong CYP3A inhibitors In healthy subjects, co-administration of a single 200 mg capmatinib dose with the strong CYP3A inhibitor itraconazole (200 mg once daily for 10 days) increased capmatinib AUCinf by 42% with no change in capmatinib Cmax compared to administration of capmatinib alone. Patients should be closely monitored for adverse reactions during co-administration of Tabrecta with strong CYP3A inhibitors, including but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole. Strong CYP3A inducers In healthy subjects, co-administration of a single 400 mg capmatinib dose with the strong CYP3A inducer rifampicin (600 mg once daily for 9 days) decreased capmatinib AUCinf by 67% and decreased Cmax by 56% compared to administration of capmatinib alone. Decreases in capmatinib exposure may decrease Tabrecta anti-tumour activity. Co-administration of Tabrecta with strong CYP3A inducers, including but not limited to, carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort (Hypericum perforatum), should be avoided. An alternative medicinal product with no or minimal potential to induce CYP3A should be considered. Moderate CYP3A inducers Simulations using physiologically-based pharmacokinetic (PBPK) models predicted that co- administration of a 400 mg capmatinib dose with the moderate CYP3A inducer efavirenz (600 mg daily for 20 days) would result in a 44% decrease in capmatinib AUC0-12h and 34% decrease in Cmax at steady-state compared to administration of capmatinib alone. Decreases in capmatinib exposure may decrease Tabrecta anti-tumour activity. Caution should be exercised during co-administration of Tabrecta with moderate CYP3A inducers. Agents that raise gastric pH Capmatinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. In healthy subjects, co-administration of a single 600 mg capmatinib dose with the proton pump inhibitor rabeprazole (20 mg once daily for 4 days) decreased capmatinib AUCinf by 25% and decreased Cmax by 38% c

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HOS-287438 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in males and females Sexually-active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Tabrecta and for at least 7 days after the last dose. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose. Pregnancy There are no data from the use of capmatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on findings from animal studies and its mechanism of action, capmatinib is suspected to cause congenital malformations when administered during pregnancy. Tabrecta should not be used during pregnancy unless the clinical condition of the woman requires treatment with capmatinib. The pregnancy status of women of childbearing potential should be verified prior to starting treatment with Tabrecta. Breast-feeding It is unknown whether capmatinib or its metabolites are excreted in human milk after administration of Tabrecta. There is insufficient information on the excretion of capmatinib or its metabolites in animal milk. A risk to the breast-fed infant cannot be excluded. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with Tabrecta and for at least 7 days after the last dose. Fertility No human fertility data on capmatinib are available. Fertility studies with capmatinib were not conducted in animals.

HOS-287436 · has-warning-information · PDF-Seite 5

Assessment of METex14 skipping alterations status When detecting the presence of alterations leading to METex14 skipping using tissue-based or plasma-based specimens, it is important that a well-validated and robust test is chosen to avoid false negative or false positive results. For the characteristics of tests used in clinical studies see section 5.1. Interstitial lung disease (ILD)/pneumonitis ILD/pneumonitis, which can be fatal, has occurred in patients treated with Tabrecta (see section 4.8). Prompt investigation should be performed in any patient with new or worsening of pulmonary 5 symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Tabrecta should be immediately withheld in patients with suspected ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis are identified (see section 4.2). Hepatic effects Transaminase elevations have occurred in patients treated with Tabrecta (see section 4.8). Liver function tests (including ALT, AST and total bilirubin) should be performed prior to the start of treatment, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase or bilirubin elevations. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue Tabrecta (see section 4.2). Elevations of pancreatic enzymes Elevations in amylase and lipase levels have occurred in patients treated with Tabrecta (see section 4.8). Amylase and lipase should be monitored at baseline and regularly during treatment with Tabrecta. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue Tabrecta (see section 4.2). Embryo-foetal toxicity Based on findings from animal studies and its mechanism of action, Tabrecta can cause foetal harm when administered to a pregnant woman due to its foetotoxicity and teratogenicity (see section 4.6). Pregnant women and women of childbearing potential should be advised of the potential risk to a foetus if Tabrecta is used during pregnancy or if the patient becomes pregnant while taking Tabrecta. Sexually active women of childbearing potential should use effective contraception during treatment with Tabrecta and for at least 7 days after the last dose. The pregnancy status of women of childbearing potential should be verifi

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