Tepmetko

/ Merck Serono LTD, Israel

Treatment must be initiated and supervised by a physician experienced in the use of anticancer therapies.
METex14 skipping alterations should be confirmed by a validated test method, using nucleic acids isolated from plasma or tumour specimens.
This medicinal product is for oral use.
The recommended dose is 450 mg tepotinib (2 film-coated tablets) taken once daily.
Duration of treatment: Treatment should continue as long as clinical benefit is observed.
Dose adjustment following undesirable effects: See prescribing information for recommended dose adjustments for undesirable effects.
Patients with impaired hepatic function: No dose adjustment is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied.
Patients with impaired renal function: No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min). The pharmacokinetics and safety of tepotinib in patients with severe renal impairment (creatinine clearance below 30 mL/min) have not been studied.
Elderly patients: No dose adjustment is necessary in patients aged 65 years and above. Of 255 patients with METex14 skipping alterations in the VISION study, 79% were 65 years or older, and 8% were 85 years or older.
Children and adolescents: Safety and effectiveness of tepotinib in paediatric patients below 18 years of age have not been established.
Delayed administration: If a daily dose is missed, it can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours.
See prescribing information for full details.

Treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harbouring a MET tyrosine kinase receptor exon 14 (METex14) skipping mutation.

Hypersensitivity to the active substance or to any of the excipients, See prescribing information for full details.

Interstitial lung disease: Interstitial lung disease (ILD) or ILD-like reactions that can be fatal were reported in the clinical study program in advanced NSCLC patients with METex14 skipping alterations who received tepotinib monotherapy at the recommended dosage regimen.
Patients should be monitored for pulmonary symptoms indicative for ILD-like reactions. Tepotinib should be withheld and patients should be promptly investigated for alternative diagnosis or specific aetiology of interstitial lung disease. Tepotinib must be permanently discontinued if interstitial lung disease is confirmed and the patient be treated appropriately. See prescribing information for full details.
Hepatotoxicity: Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. One fatal event of acute liver failure has occured. Liver enzymes (including ALT, AST and bilirubin) should be monitored prior to initiation of treatment with tepotinib, then every two weeks during the first three months of treatment and then once monthy or as clinically indicated. In patients found to have elevated transaminases or bilirubin levels, more frequently tests should be performed. Depending on severity of adverse drug reactions, tepotinib must be temporarily discontinued, the dose reduced or discontinued permanently. See prescribing information for full details.
Embryofoetal toxicity: Tepotinib can cause foetal harm when administered to pregnant women.
Women of childbearing potential or male patients with female partners of childbearing potential must be advised of the potential risk to a foetus.
Women of childbearing potential must use effective contraception during tepotinib treatment and for at least 1 week after the last dose.
Male patients with female partners of childbearing potential must use barrier contraception during tepotinib treatment and for at least 1 week after the last dose.
See prescribing information for full details.
QTc prolongation: In the nain clinical study, QTc prolongation was reported in a limited number of patients. In patients at risk for developing QTc prolongation, including patients with known long QT syndrome or clinically relevant bradyarrhythmia, ECG monitoring is recommended as clinically indicated. See prescribing information for full details.
Increase in creatinine: Nonclinical studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporters (MATE) 2. Creatinine is a substrate of these transporters, and the observed increases in creatinine may be the result of inhibition of active tubular secretion rather than actual renal injury. Renal function estimates that rely on serum creatinine (creatinine clearance or estimated glomerular filtration rate) should be interpreted with caution considering this effect. Alternative markers of renal function should be considered in line with local clinical practice if persistent elevations in serum creatinine are observed. See prescribing information for full details.
Oncogenic drivers: The efficacy and safety of tepotinib have not been studied in patients with EGFR or ALK tumour aberrations in line with the mutual exclusivity of oncogenic drivers in NSCLC. For recommended patient selection prior to tepotinib treatment, see prescribing information for full details.
Lactose: Patients suffering from galactose intolerance, complete lactase deficiency or glucose-galactose-malabsorption syndrome (rare hereditary diseases) should not use this drug.

The most common adverse reactions observed in the main clinical study (VISION) were oedema, mainly peripheral oedema, nausea, diarrhoea, increase in creatinine, hypoalbuminaemia and fatigue. See prescribing information for full details.

Effect of other medicinal products on the pharmacokinetics of tepotinib
Avoid concomitant adminisration
Dual strong CYP3A inhibitors and P-gp inhibitors: The effect of strong CYP3A inhibitors or P-gp inhibitors on tepotinib has not been studied clinically. However, metabolism and in vitro data suggest concomitant use of drugs that are strong CYP3A inhibitors and P-gp inhibitors may increase tepotinib exposure, which may increase the incidence and severity of adverse reactions of tepotinib. Concomitant use of tepotinib with dual strong CYP3A inhibitors and P-gp inhibitors (e.g. itraconazole, ketoconazole, ritonavir, saquinavir, nelfinavir) should be avoided.
Strong CYP3A and/or P-gp inducers: The effect of strong CYP3A and/or P-gp inducers on tepotinib has not been studied clinically. However, metabolism and in vitro data suggest concomitant use may decrease tepotinib exposure, which may reduce tepotinib efficacy. Concomitant use of tepotinib with strong CYP3A and/or P-gp inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s Wort) should be avoided.
Other interactions
Acid-reducing agents: Co-administration of omeprazole (40 mg daily for 5 days) had no marked effect on the pharmacokinetic profile of tepotinib when administered under fed conditions.
Effect of tepotinib on the pharmacokinetics of other medicinal products
Avoid concomitant administration
P-gp substrates: Tepotinib can inhibit the transport of sensitive substrates of P-gp, which can lead to more frequent or severe adverse reactions of these substrates. Multiple administrations of tepotinib 450 mg orally once daily together with the sensitive P-gp substrate dabigatran etexilate, increased its AUC_t 1.5-fold and its Cmax 1.4 fold. Concomitant administration of tepotinib with substrates of P-gp with a narrow therapeutic index (e.g. digoxin, dabigatran) should be avoided. If co-administration cannot be avoided, the product information of the respective medicinal product should be consulted with regard to possible measures (such as dose adjustments or monitoring of undesirable effects).
Caution when concomitant administration
BCRP substrates: Based on in vitro studies, tepotinib can inhibit the transport of sensitive substrates of the breast cancer resistance protein (BCRP). Monitoring of the clinical effects of sensitive BCRP substrates (e.g. rosuvastatin) is recommended during co-administration with tepotinib.
OCT2- and MATE2-substrates: Based on in vitro data, tepotinib or its metabolite have the potential to increase the AUC of co-administered OCT2- and MATE2 substrates, e.g. metformin in humans, by inhibiting the renal excretion of these agents
mediated via organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporter (MATE) 2. No clinically relevant differences in glucose levels were observed when metformin (an OCT2 and MATE2 substrate) was coadministered with tepotinib. Monitoring of the clinical effects of metforminis recommended during co-administration with tepotinib.
The inhibition of OCT2 and MATE2 by tepotinib or its metabolite can also contribute to an increase in creatinine.
OATP1B1 substrates: Based on in vitro data, Tepotinib or its active metabolite can inhibit the transport of sensitive substrates of the organic anion transporter polypeptide (OATP) 1B1. Monitoring of the clinical effects of sensitive OATP1B1 substrates (e.g. rosuvastatin) is recommended during co-administration with tepotinib.
Other interactions
OATP1B3 and organic anion transporter (OAT) 1 and 3 substrates: Based on in vitro data, tepotinib, at clinically relevant concentrations,poses a remote risk of bile salt export pump (BSEP) inhibirion butnot OATP1B3 or OAT1 and 3 inhibition.
UDP-glucuronosyltransferase (UGT): Based on in vitro data, tepotinib or its major circulating metabolite at clinically relevant concentrations is not expected to inhibit UGT1A1, 1A9, 2B17 UGT1A3/4/6, and 2B7/15.
CYP 450 enzymes: Based on in vitro data, tepotinib or its major circulating metabolite at clinically relevant concentration is not expected to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 or induce CYP1A2, and 2B6. Multiple administrations of 450 mg tepotinib orally once daily had no clinically relevant effect on the PK of the sensitive CYP3A4 substrate midazolam.

Contraception in males and females:
Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with tepotinib. Women of childbearing potential must use effective contraception during tepotinib treatment and for at least 1 week after the last dose.
Male patients with female partners of childbearing potential must use barrier contraception during tepotinib 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. Based on the mechanism of action and findings in animals tepotinib can cause foetal harm when administered to pregnant women.
Tepotinib must not be used during pregnancy, unless the clinical condition of the woman requires treatment. Women of childbearing potential or male patients with female partners of childbearing potential must be advised of the potential risk to a foetus.
Lactation:
There are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breast-fed infant or milk production. A risk to the infant cannot be excluded. Breast-feeding must be discontinued during treatment with tepotinib and for at least 1 week after the last dose.
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.

Tepotinib has been investigated at doses up to 1,261 mg. Symptoms of overdose have not been identified. There is no specific treatment in the event of tepotinib overdose. In case of overdose, Tepotinib should be withheld and symptomatic treatment initiated.