Tepmetko · 4.4 Special warnings and precautions for use · 1

HOS-288207 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most common adverse reactions in ≥ 20% of patients exposed to tepotinib at the recommended dose in the target indication (N = 313) are oedema (81.5%), mainly peripheral oedema (72.5%), hypoalbuminaemia (32.9%), nausea (31.0%), increase in creatinine (29.1%) and diarrhoea (28.8%). The most common serious adverse reactions in ≥ 1% of patients are peripheral oedema (3.2%), generalised oedema (1.9%), and ILD (1.0%). The percentage of patients who had adverse reactions leading to permanent treatment discontinuation is 14.7%. The most common adverse reactions leading to permanent discontinuation in ≥ 1% of patients are peripheral oedema (5.4%), oedema (1.3%), genital oedema (1.0%), pneumonitis (1.0%), and ILD (1.0%). The percentage of patients who had adverse reactions leading to temporary treatment discontinuation is 43.1%. The most common adverse reactions leading to temporary discontinuation in ≥ 2% of patients are peripheral oedema (19.8%), increase in creatinine (5.8%), generalised oedema (4.8%), oedema (3.8%), nausea (3.2%), increase in ALT (2.9%), and localised oedema (2.2%). The percentage of patients who had adverse reactions leading to dose reduction is 33.5%. The most common adverse reactions leading to dose reduction in ≥ 2% of patients are peripheral oedema (15.7%), increase in creatinine (2.9%), generalised oedema (3.2%) and oedema (2.6%). Tabulated list of adverse reactions Adverse reactions described in the list below reflect exposure to tepotinib in 506 patients with various solid tumours enrolled in five open-label studies, in which patients received tepotinib as a single agent at a dose of 450 mg once daily. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 313 patients exposed to tepotinib at the recommended dose in the target indication, whereas frequencies for changes in laboratory parameters are based on worsening from baseline by at least 1 grade and shifts to ≥ grade 3. Median duration of treatment was 7.5 months (range 0 to 72). Frequencies presented may not be fully attributable to tepotinib alone but may contain contributions from the underlying disease or from other medicinal products used concomitantly. The severity of adverse reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening and grade 5 = death.

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HOS-288203 · has-contraindication-information · PDF-Seite 4

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

HOS-288202 · has-indication-information · PDF-Seite 2

TEPMETKO 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-288205 · has-interaction-information · PDF-Seite 5

Effects of other medicinal products on tepotinib CYP and P-gp inducers Tepotinib is a substrate for P-glycoprotein (P-gp). In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong inducer carbamazepine (300 mg twice daily for 14 days) decreased tepotinib AUCinf by 35% and Cmax by 11% compared to administration of tepotinib alone. The decreased exposure is not clinically relevant. Dual strong CYP3A inhibitors and P-gp inhibitors In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inhibitor and P-gp inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUCinf by 22% with no change in tepotinib Cmax compared to administration of tepotinib alone. This is classified as a weak interaction, and the observed changes in systemic exposure to tepotinib are not considered clinically relevant. Therefore, CYP3A and P-gp inhibitors are not expected to influence tepotinib exposure. Acid-reducing agents Co-administration of omeprazole under fed conditions had no clinically relevant effect on the pharmacokinetic profile of a single dose of tepotinib 450 mg and its metabolites (geometric mean ratio for tepotinib of 110% for AUCinf (90% CI: 102; 119) and of 104% for Cmax (90% CI: 93; 117); similar effect on metabolites observed). Effects of tepotinib on other medicinal products P-gp substrates Tepotinib is an inhibitor of P-gp. Administration of tepotinib 450 mg orally once daily for 8 days increased the AUC of the sensitive P-gp substrate dabigatran etexilate by approximately 50% and Cmax by approximately 40%. Dose adjustment of dabigatran etexilate may be needed in case of concomitant use. Caution and monitoring for adverse reactions of other P-gp-dependent substances with a narrow therapeutic index (e.g. digoxin, aliskiren, everolimus, sirolimus) is recommended during co-administration with TEPMETKO. 5 BCRP substrates Tepotinib can inhibit the transport of substrates of the breast cancer resistance protein (BCRP) in vitro (see section 5.2). Monitoring for adverse reactions of sensitive BCRP substrates (e.g. rosuvastatin, methotrexate, topotecan) is recommended during co-administration with TEPMETKO. Substrates of OCT and MATE Based on in vitro data, tepotinib or its metabolite may have the potential to alter the exposure of substrates of the transporters OCT1 and 2 and MATE1 and 2 (see section 5.2). The m

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HOS-288206 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential/Contraception in males and females Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with TEPMETKO. Women of childbearing potential should use effective contraception during TEPMETKO treatment and for at least 1 week after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method during TEPMETKO treatment and for at least 1 week after the last dose (see section 4.5). Male patients with female partners of childbearing potential should use barrier contraception during TEPMETKO treatment and for at least 1 week after the last dose. Pregnancy There are no clinical data on the use of tepotinib in pregnant women. Studies in animals have shown teratogenicity (see section 5.3). Based on the mechanism of action and findings in animals tepotinib can cause foetal harm when administered to pregnant women. TEPMETKO should not be used during pregnancy, unless the clinical condition of the woman requires treatment with tepotinib. Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a foetus. Breast-feeding There are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breast-fed child or milk production. Breast-feeding should be discontinued during treatment with TEPMETKO and for at least 1 week after the last dose. 6 Fertility No human data on the effect of tepotinib on fertility are available. No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs, except for reduced secretion in seminal vesicles of male rats at comparable human clinical exposure (see section 5.3).

HOS-288204 · has-warning-information · PDF-Seite 4

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 and pneumonitis Interstitial lung disease (ILD) or ILD-like adverse reactions including pneumonitis have been reported in patients who received tepotinib monotherapy at the recommended dose regimen and may be fatal (see section 4.8). Patients should be monitored for pulmonary symptoms indicative for ILD-like reactions. TEPMETKO should be withheld and patients should be promptly investigated for alternative diagnosis or specific aetiology of interstitial lung disease. TEPMETKO must be permanently discontinued if interstitial lung disease is confirmed and the patient be treated appropriately. Monitoring of liver enzymes Increase in ALT and/or AST have been reported in patients who received tepotinib monotherapy at the recommended dose regimen (see section 4.8). Liver enzymes (ALT and AST) and bilirubin should be monitored prior to the start of TEPMETKO treatment and thereafter as clinically indicated. If grade 3 or higher increases (ALT and/or AST greater than 5 times ULN) occur, dose adjustment or discontinuation is recommended (see section 4.2). QTc prolongation QTc prolongation was reported in a limited number of patients (see section 4.8). In patients at risk of developing QTc prolongation, including patients with known electrolyte disturbances or taking concomitant medicinal products known to have QTc prolongation effects, monitoring is recommended as clinically indicated (e.g. ECG, electrolytes). 4 Embryo-foetal toxicity Tepotinib can cause foetal harm when administered to pregnant women. Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with TEPMETKO. Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during TEPMETKO treatment and for at least 1 week after the last dose (see section 4.6). Interpretation of laboratory tests In vitro studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins organic cation transporter (OCT) 2 and multidrug and toxin

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