TEPMETKO 225mg tablets medication leaflet

TEPMETKO 225 mg film-coated tablets

Each film-coated tablet contains 225 mg tepotinib (as hydrochloride hydrate).

Each film-coated tablet contains 4.4 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

White-pink, oval, biconvex film-coated tablet of approximately 18 x 9 mm in size, embossed with ‘M’on one side and plain on the other side.

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

Treatment must be initiated and supervised by a physician experienced in the use of anticancertherapies.

Prior to initiation of treatment with TEPMETKO the presence of METex14 skipping alterations shouldbe confirmed by a validated test method (see sections 4.4 and 5.1).

The recommended dose is 450 mg tepotinib (2 tablets) taken once daily. Treatment should continue aslong as clinical benefit is observed.

If a daily dose is missed, it can be taken as soon as remembered on the same day, unless the next doseis due within 8 hours.

The recommended dose reduction level for the management of adverse reactions is 225 mg (1 tablet)daily. Detailed recommendations for dose modification are provided in the table hereafter.

Table 1: Recommended dose modifications for TEPMETKO

Adverse reaction Severity Dose modification

Interstitial lung disease Any grade Withhold TEPMETKO if ILD is(ILD) (see section 4.4) suspected.

Permanently discontinue TEPMETKO if

ILD is confirmed.

Increased ALT and/or AST ALT and/or AST greater Withhold TEPMETKO until recovery towithout increased total than 5 times up to baseline ALT/AST.bilirubin (see section 4.4) 20 times ULN If recovered to baseline within 7 days,then resume TEPMETKO at the samedose; otherwise resume TEPMETKO at areduced dose.

ALT and/or AST greater Permanently discontinue TEPMETKO.than 20 times ULN

Increased ALT and/or AST ALT and/or AST greater Permanently discontinue TEPMETKO.with increased total than 3 times ULN withbilirubin in the absence of total bilirubin greatercholestasis or haemolysis than 2 times ULN(see section 4.4)

Other adverse reactions Grade 3 or higher Reduce TEPMETKO to 225 mg until the(see section 4.8) adverse reaction recovers to ≤ grade 2.

A temporary interruption of TEPMETKOtreatment for no more than 21 days canalso be considered.

ULN = upper limit of normal

No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinineclearance 30 to 89 mL/min) (see section 5.2). The pharmacokinetics and safety of tepotinib in patientswith severe renal impairment (creatinine clearance below 30 mL/min) have not been studied. The useof TEPMETKO in patients with severe renal impairment is therefore not recommended.

Renal function estimates that rely on serum creatinine (creatinine clearance or estimated glomerularfiltration rate) should be interpreted with caution (see section 4.4).

No dose adjustment is recommended in patients with mild (Child Pugh Class A) or moderate (Child

Pugh Class B) hepatic impairment (see section 5.2). The pharmacokinetics and safety of tepotinib inpatients with severe hepatic impairment (Child Pugh Class C) have not been studied. The use of

TEPMETKO in patients with severe hepatic impairment is therefore not recommended.

No dose adjustment is necessary in patients aged 65 years and above (see section 5.2).

Safety and efficacy of tepotinib in paediatric patients below 18 years of age have not been established.

No data are available.

TEPMETKO is for oral use. The tablet(s) should be taken with food and should be swallowed wholeto ensure that the full dose is administered.

If the patient is unable to swallow, the tablets can be dispersed in 30 mL of non-carbonated water. Noother liquids should be used or added. The tablets should be dropped in a glass with water withoutcrushing, stir until the tablets dispersed into small pieces which may take a few minutes (the tablet willnot completely dissolve). The dispersion should be swallowed within 1 hour. Rinse the glass withadditional 30 mL to ensure that no residues remain in the glass and drink immediately.

If an administration via a naso-gastric tube (with at least 8 French gauge) is required, the tabletsshould be dispersed in 30 mL of non-carbonated water as described above. The 30 mL of liquid shouldbe administered within 1 hour as per naso-gastric tube manufacturer’s instructions. Immediately rinsetwice with 30 mL each to ensure that no residues remain in the glass or syringe and the full dose isadministered.

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

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 negativeor 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 reportedin 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. TEPMETKOshould be withheld and patients should be promptly investigated for alternative diagnosis or specificaetiology of interstitial lung disease. TEPMETKO must be permanently discontinued if interstitiallung 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 therecommended dose regimen (see section 4.8).

Liver enzymes (ALT and AST) and bilirubin should be monitored prior to the start of TEPMETKOtreatment and thereafter as clinically indicated. If grade 3 or higher increases (ALT and/or AST greaterthan 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 ofdeveloping QTc prolongation, including patients with known electrolyte disturbances or takingconcomitant medicinal products known to have QTc prolongation effects, monitoring is recommendedas clinically indicated (e.g. ECG, electrolytes).

Embryo-foetal toxicity

Tepotinib can cause foetal harm when administered to pregnant women. Pregnancy testing isrecommended in women of childbearing potential prior to initiating treatment with TEPMETKO.

Women of childbearing potential and males with female partners of childbearing potential should useeffective contraception during TEPMETKO treatment and for at least 1 week after the last dose (seesection 4.6).

Interpretation of laboratory tests

In vitro studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporterproteins organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporters (MATE) 1and 2 (see section 5.2). Creatinine is a substrate of these transporters, and the observed increases increatinine (see section 4.8) may be the result of inhibition of active tubular secretion rather than renalinjury. Renal function estimates that rely on serum creatinine (creatinine clearance or estimatedglomerular filtration rate) should be interpreted with caution considering this effect. In case of bloodcreatinine increase while on treatment, it is recommended that further assessment of the renal functionbe performed to exclude renal impairment.

TEPMETKO contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 single450 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 CYP3Ainhibitor and P-gp inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUCinfby 22% with no change in tepotinib Cmax compared to administration of tepotinib alone. This isclassified as a weak interaction, and the observed changes in systemic exposure to tepotinib are notconsidered clinically relevant. Therefore, CYP3A and P-gp inhibitors are not expected to influencetepotinib exposure.

Co-administration of omeprazole under fed conditions had no clinically relevant effect on thepharmacokinetic profile of a single dose of tepotinib 450 mg and its metabolites (geometric mean ratiofor tepotinib of 110% for AUCinf (90% CI: 102; 119) and of 104% for Cmax (90% CI: 93; 117); similareffect on metabolites observed).

Effects of tepotinib on other medicinal products

Tepotinib is an inhibitor of P-gp. Administration of tepotinib 450 mg orally once daily for 8 daysincreased the AUC of the sensitive P-gp substrate dabigatran etexilate by approximately 50% and Cmaxby approximately 40%. Dose adjustment of dabigatran etexilate may be needed in case of concomitantuse. Caution and monitoring for adverse reactions of other P-gp-dependent substances with a narrowtherapeutic index (e.g. digoxin, aliskiren, everolimus, sirolimus) is recommended during co-administration with TEPMETKO.

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 ofsubstrates of the transporters OCT1 and 2 and MATE1 and 2 (see section 5.2). The most clinicallyrelevant example of substrates of these transporters is metformin. Monitoring of the clinical effects ofmetformin is recommended during co-administration with TEPMETKO.

Multiple administrations of 450 mg tepotinib orally once daily had no clinically relevant effect on thepharmacokinetics of the sensitive CYP3A4 substrate midazolam.

It is currently unknown whether tepotinib may reduce the effectiveness of systemically actinghormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives shouldadd a barrier method during TEPMETKO treatment and for at least 1 week after the last dose (seesection 4.6).

Pregnancy testing is recommended in women of childbearing potential prior to initiating treatmentwith TEPMETKO.

Women of childbearing potential should use effective contraception during TEPMETKO treatmentand for at least 1 week after the last dose. Women using systemically acting hormonal contraceptivesshould 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.

There are no clinical data on the use of tepotinib in pregnant women. Studies in animals have shownteratogenicity (see section 5.3). Based on the mechanism of action and findings in animals tepotinibcan cause foetal harm when administered to pregnant women.

TEPMETKO should not be used during pregnancy, unless the clinical condition of the womanrequires treatment with tepotinib. Women of childbearing potential or male patients with femalepartners of childbearing potential should be advised of the potential risk to a foetus.

There are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects onthe 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.

No human data on the effect of tepotinib on fertility are available. No morphological changes in maleor female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs, except forreduced secretion in seminal vesicles of male rats at comparable human clinical exposure (seesection 5.3).

TEPMETKO has no influence on the ability to drive and use machines.

The most common adverse reactions in ≥ 20% of exposed to tepotinib at the recommended dose in thetarget indication (N = 313) are oedema (81.5% of patients), 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 events leading to permanent treatment discontinuation is24.9%. The most common adverse reactions leading to permanent discontinuation in ≥ 1% of patientsare peripheral oedema (5.4%), oedema (1.3%), genital oedema (1.0%) and ILD (1.0%).

The percentage of patients who had adverse events leading to temporary treatment discontinuation is52.7%. The most common adverse reactions leading to temporary discontinuation in ≥ 2% of patientsare peripheral oedema (19.8%), increase in creatinine (5.8%), generalised oedema (4.8%), oedema(3.8%), increase in ALT (2.9%), nausea (3.2%) and increase in amylase (1.6%).

The percentage of patients who had adverse events leading to dose reduction is 36.1%. The mostcommon 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%).

List of adverse reactions

Adverse reactions described in the list below reflect exposure to tepotinib in 506 patients with varioussolid tumours enrolled in five open-label studies, in which patients received tepotinib as a single agentat a dose of 450 mg once daily.

The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in313 patients exposed to tepotinib at the recommended dose in the target indication, whereasfrequencies for changes in laboratory parameters are based on worsening from baseline by at least1 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 contributionsfrom 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.

The following definitions apply to the frequency terminology used hereafter:

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)

Frequency not known (cannot be estimated from the available data)

Table 2: Adverse reactions in patients with NSCLC harbouring METex14 skipping alterations(VISION)

System organ class/Adverse reaction TEPMETKO

N = 313

Frequency category All grades Grade ≥ 3% %

Decrease in albumin*,a Very common 78.6 8.9

QT prolongation* Common 2.6 ---

ILD-like reactions*,b,c Common 2.6 0.3

Nausea Very common 31.0 1.3

Diarrhoea Very common 28.8 0.6

Increase in amylase*,a Very common 24.0 5.1

Increase in lipase*,a Very common 20.4 5.1

Vomiting Very common 14.4 1.0

Increase in alkaline phosphatase (ALP)* Very common 50.8 1.6

Increase in alanine aminotransferase (ALT)*,a Very common 48.9 4.8

Increase in aspartate aminotransferase (AST)*,a Very common 39.3 3.5

Increase in creatinine*,a Very common 58.8 1.0

Oedema*,d Very common 81.5 15.7

* Additional information on the respective adverse reaction is provided belowa Represents the incidence of laboratory findings, not of reported adverse eventsb ILD as per integrated assessmentc includes terms interstitial lung disease, pneumonitis, acute respiratory failured includes terms oedema peripheral, oedema, generalised oedema, oedema genital, face oedema, localised oedema, periorbitaloedema, peripheral swelling, scrotal oedema

Interstitial lung disease (ILD) or ILD-like reactions have been reported in 8 patients (2.6%), including1 case of grade 3 or higher; serious cases occurred in 4 patients (1.3%), 1 case was fatal. Treatmentwas permanently discontinued in 5 patients and temporarily in 3 patients. Median time to onset of ILDwas 9.4 weeks. For clinical recommendations, see sections 4.2 and 4.4.

Increase in liver enzymes

ALT and/or AST increase led to permanent treatment discontinuation in 1 patient and infrequently ledto temporary discontinuation (3.2%) or dose reduction (0.3%) of tepotinib. Median time to first onsetfor ALT and/or AST increase of any grade reported as an adverse event by investigators was9.1 weeks. The median time to resolution was 3.6 weeks, 86% of events resolved. For clinicalrecommendations, see sections 4.2 and 4.4.

ALP increase did not lead to any dose reductions, temporary treatment discontinuation or permanentdiscontinuation. The observed ALP increase was not associated with cholestasis. Median time to firstonset for ALP increase of any grade reported as an adverse event by investigators was 9.1 weeks. Themedian time to resolution was 9.1 weeks, 80% of events resolved.

Oedema

The most frequently reported event was peripheral oedema (72.5% of patients), followed by oedema(8.3%) and generalised oedema (6.7%). Median time to onset of any-grade oedema was 9.1 weeks.

The median time to resolution was 71 weeks, 39.2% of events resolved. 8% of patients had oedemaevents leading to permanent treatment discontinuation, of whom 5.4% had peripheral oedema. 28.4%of patients temporarily discontinued treatment and 21.7% of patients had dose reductions due tooedema. Most frequently peripheral oedema led to temporary treatment discontinuation and dosereductions (19.8% and 15.7%, respectively). Generalised oedema events led to a dose reduction in3.2% of patients, to temporary treatment discontinuation in 4.8% and to permanent discontinuation in0.6%.

Increase in creatinine

Increase in creatinine led to permanent treatment discontinuation in 2 patients (0.6%), temporarytreatment discontinuation in 5.8% of patients and dose reduction in 2.9% of patients. Median time toonset of increase in creatinine reported as an adverse event by investigators was 3.4 weeks. Themedian time to resolution was 9.1 weeks, 78% of events resolved. The observed increases in creatinineare thought to occur mainly due to inhibition of renal tubular secretion (see section 4.4).

Hypoalbuminaemia

Hypoalbuminaemia appeared to be long-lasting but did not lead to permanent treatmentdiscontinuation. Dose reduction (1.6%) and temporary discontinuation (1.9%) were infrequent.

Median time to onset of any-grade hypoalbuminaemia reported as an adverse event by investigatorswas 9.4 weeks. The median time to resolution was 28.9 weeks, 48% of events resolved.

Increase in amylase or lipase

Increases in amylase or lipase reported as an adverse event by investigators were asymptomatic andnot associated with pancreatitis. 3.2% of patients temporarily discontinued treatment and there wereno permanent treatment discontinuation or dose reduction. Median time to onset of any grade inlipase/amylase increase was 15 weeks. The median time to resolution was 6.1 weeks, 83% of eventsresolved.

QTc prolongation

QTcF prolongation to > 500 ms was observed in 8 patients (2.6%) and a QTcF prolongation by at least60 ms from baseline in 19 patients (6.1%) (see section 4.4). The findings were isolated andasymptomatic; the clinical significance is unknown.

Additional information on special populations

Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mgtepotinib once daily, 79% were 65 years or older, and 8% were 85 years or older. The occurrence ofgrade ≥ 3 events increased with age. Treatment-related serious events were more frequent in patientsaged ≥ 75 years and < 85 years (21%) or those aged ≥ 85 years (20.8%) when compared to thoseyounger than 65 years (10.4%), although this comparison is limited by the small sample size inpatients aged ≥ 85 years.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Tepotinib has been investigated at doses up to 1 261 mg, but experience with doses higher than therecommended therapeutic dose is limited.

The symptoms of overdose are expected to be in the range of known adverse reactions (seesection 4.8). There is no specific antidote for TEPMETKO. Treatment of overdose is directed tosymptoms.

Pharmacotherapeutic group: Antineoplastic agents, other protein kinase inhibitors, ATC code:

L01EX21

Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of

MET. Tepotinib blocked MET phosphorylation and MET-dependent downstream signalling such asthe phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated proteinkinase/extracellular-signal regulated kinase (MAPK/ERK) pathways in a dose-dependent manner.

Tepotinib demonstrated pronounced anti-tumour activity in tumours with oncogenic activation of

MET, such as METex14 skipping alterations.

A concentration-dependent increase in QTc interval was observed in the concentration-QTc analysis.

At the recommended dose, no large mean increases in QTc (i.e. > 20 ms) were detected in patientswith various solid tumours. The QTc effect of tepotinib at supratherapeutic exposures has not beenevaluated. See sections 4.4. and 4.8.

Detection of METex14 skipping status

In clinical studies, identification of METex14 skipping alterations relied on next generationsequencing using RNA or DNA (1 patient) extracted from formalin-fixed paraffin embedded (FFPE)tumour tissue or using circulating cell free DNA from plasma. Additionally, a RNA-based reversetranscriptase polymerase chain reaction-based method specific for detecting METex14 skippingalterations from fresh frozen tissue was available to patients in Japan.

The efficacy of tepotinib was evaluated in a single-arm, open-label, multicentre study (VISION) inadult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring

METex14 skipping alterations (n = 313). Patients had an Eastern Cooperative Oncology Group

Performance Status (ECOG PS) of 0 to 1 and were either treatment-naïve or had progressed on up to2 lines prior systemic therapies. Neurologically stable patients with central nervous system metastaseswere permitted. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphomakinase (ALK) activating alterations were excluded. Patients received tepotinib as first-line (52%),second-line (29%) or later line (18%) therapy.

Patients who received tepotinib for second- or later line therapy (n = 149) had a median age of71 years (range 41 to 89), 52% were female and 48% male. The majority of patients were white(56%), followed by Asian patients (38%) and were never (53%) or former smokers (40%). Mostpatients were ≥ 65 years of age (75%) and 35% of patients were ≥ 75 years of age. The majority ofpatients (95%) had stage IV disease, 81% had adenocarcinoma histology. Thirteen percent of thepatients had stable brain metastases. Eighty-four percent of patients had received prior platinum-basedcancer therapy and 54% of patients had received immune-based cancer therapy, including 40% ofpatients who had received immunotherapy as monotherapy. METex14 skipping was prospectivelydetected by testing from tumour tissue in 65% of patients and by testing from plasma in 56% ofpatients; 56% of patients tested positive with both methods.

Patients received 450 mg tepotinib once daily until disease progression or unacceptable toxicity.

Median treatment duration was 7.5 months (range 0 to 72). The follow-up time was at least 18 and upto 72 months at the time of the data cut-off (cut-off date 20 November 2022).

The primary efficacy outcome measure was confirmed objective response (complete response orpartial response) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) asevaluated by an Independent Review Committee (IRC). Additional efficacy outcome measuresincluded duration of response and progression-free survival assessed by IRC as well as overallsurvival.

Table 3: Clinical outcomes in the VISION study by IRC assessment

Efficacy parameter Overall Previously treatedpopulation patients

N = 313 N = 149

Objective response rate (ORR), %a 51.4 45.0[95% CI] [45.8, 57.1] [36.8, 53.3]

Median duration of response (mDoR), monthsb 18.0 12.6[95% CI] [12.4, 46.4] [9.5, 18.5]

IRC = Independent Review Committee, CI = confidence intervala Only includes partial responseb Product-limit (Kaplan-Meier) estimates, 95% CI for the median using the Brookmeyer and Crowley method

Efficacy outcome was independent of the testing modality (in plasma or tumour specimens) used toestablish the METex14 skipping status. Consistent efficacy results in subgroups by prior therapy,presence of brain metastasis or age were observed.

The European Medicines Agency has waived the obligation to submit the results of studies with

TEPMETKO in all subsets of the paediatric population in treatment of non-small cell lung cancer(NSCLC) (see section 4.2 for information on paediatric use).

A mean absolute bioavailability of 71.6% was observed for a single 450 mg dose of tepotinibadministered in the fed state; the median time to Cmax was 8 hours (range from 6 to 12 hours).

The presence of food (standard high-fat, high-calorie breakfast) increased the AUC of tepotinib byabout 1.6-fold and Cmax by 2-fold.

In human plasma, tepotinib is highly protein bound (98%). The mean volume of distribution (Vz) oftepotinib after an intravenous tracer dose (geometric mean and geoCV%) was 574 L (14.4%).

Overall, metabolism is a major route of elimination, but no single metabolic pathway accounted formore than 25% of tepotinib elimination. Only one major circulating plasma metabolite has beenidentified, MSC2571109A. There is only a minor contribution of the major circulating metabolite tothe overall efficacy of tepotinib in humans.

In-vitro pharmacokinetic interaction studies

Effects of tepotinib on other transporters: Tepotinib or its major circulating metabolite inhibit P-gp,

BCRP, OCT1 and 2 and MATE1 and 2 at clinically relevant concentrations. At clinically relevantconcentrations tepotinib presents no risk for organic-anion-transporting polypeptide (OATP) 1B1 and

OATP1B3 or organic anion transporter (OAT) 1 and 3.

Effects of tepotinib on UDP-glucuronosyltransferase (UGT): Tepotinib is an inhibitor of UGT1A9 atclinically relevant concentrations, but the clinical relevance is unknown. Tepotinib and its majorcirculating metabolite are not inhibitors of the other isoforms (UGT1A1/3/4/6 and 2B7/15/17) atclinically relevant concentrations.

Effect of tepotinib on CYP 450 enzymes: At clinically relevant concentrations neither tepotinib nor themajor circulating metabolite represent a risk of inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6 and CYP2E1. Tepotinib or its major circulating metabolite do not induce

CYP1A2 and 2B6.

After intravenous administration of single doses, a total systemic clearance (geometric mean andgeoCV%) of 12.8 L/h was observed.

After a single oral administration of a radiolabelled dose of 450 mg tepotinib, tepotinib was mainlyexcreted via the faeces (approximately 78% of the dose was recovered in faeces), with urinaryexcretion being a minor excretion pathway.

Biliary excretion of tepotinib is a major elimination pathway. The unchanged tepotinib represented45% and 7% of the total radioactive dose in faeces and urine, respectively. The major circulatingmetabolite accounted for only about 3% of the total radioactive dose in the faeces.

The effective half-life for tepotinib is approximately 32 h. After multiple daily administrations of450 mg tepotinib, median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h.

Dose and time dependence

Tepotinib exposure increases approximately dose-proportionally over the clinically relevant doserange up to 450 mg. The pharmacokinetics of tepotinib did not change with respect to time.

A population kinetic analysis did not show any clinically meaningful effect of age (range 18 to89 years), race, gender or body weight, on the pharmacokinetics of tepotinib. Data on ethnicities otherthan Caucasian or Asian are limited.

There was no clinically meaningful change in exposure in patients with mild and moderate renalimpairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) werenot included in clinical studies.

Following a single oral dose of 450 mg, tepotinib exposure was similar in healthy subjects and patientswith mild hepatic impairment (Child-Pugh Class A) and was slightly lower (13% lower AUC and 29%lower Cmax) in patients with moderate hepatic impairment (Child-Pugh Class B) compared to healthysubjects. Based on unbound tepotinib concentrations, AUC was about 13% and 24% higher in patientswith mild and moderate hepatic impairment, respectively, compared to healthy subjects. Thepharmacokinetics of tepotinib have not been studied in patients with severe (Child Pugh Class C)hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology or repeated dose toxicity.

No mutagenic or genotoxic effects of tepotinib were observed in in vitro and in vivo studies. However,the maximally feasible dose used in the in vivo micronucleus test in rats provided an estimatedsystemic exposure close to 3-fold lower than the clinical plasma exposure. The major circulatingmetabolite was shown to be non-mutagenic.

No studies have been performed to evaluate the carcinogenic potential of tepotinib.

Reproduction toxicity

In a first oral embryo-foetal development study, pregnant rabbits received doses of 50, 150, and450 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. The dose of 450 mg perkg (approximately 61% of the human exposure at the recommended dose of TEPMETKO 450 mgonce daily based on AUC) was discontinued due to severe maternal toxic effects. In the 150 mg per kggroup (approximately 40% of the human exposure at the 450 mg clinical dose), two animals abortedand one animal died prematurely. Mean foetal body weight was decreased at doses of ≥ 150 mg per kgper day. A dose-dependent increase of skeletal malformations, including malrotations of fore and/orhind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneousand/or talus, were observed at 50 mg per kg (approximately 14% of the human exposure at the 450 mgclinical dose) and 150 mg per kg per day.

In the second embryo-foetal development study, pregnant rabbits received oral doses of 0.5, 5, and25 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. Two malformed foetuseswith malrotated hind limbs were observed: one in the 5 mg per kg group (approximately 0.21% of thehuman exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC) and onein the 25 mg per kg group (approximately 1.3% of the human exposure at the 450 mg clinical dose),together with a generally increased incidence of foetuses with hind limb hyperextension.

Fertility studies of tepotinib to evaluate the possible impairment of fertility have not been performed.

No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicitystudies in rats and dogs, except for reduced secretion in seminal vesicles of male rats in a 4-weekrepeat-dose toxicity study at 450 mg per kg per day (comparable to human exposure at the 450 mgclinical dose).

Environmental risk assessment studies have shown that tepotinib has the potential to be very persistentand toxic to the environment.

Mannitol

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Microcrystalline cellulose

Hypromellose

Lactose monohydrate

Macrogol

Triacetin

Red iron oxide (E172)

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require special storage conditions.

Aluminium/Polyvinyl chloride-polyethylene-polyvinylidene chloride-polyethylene-polyvinyl chloride(Al/PVC-PE-PVDC-PE-PVC) blister. Pack of 60 film-coated tablets.

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements.

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/21/1596/001

Date of first authorisation: 16 February 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.