TEPMETKO 225 mg film-coated tablets

TEPMETKO is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET) exon 14 (METex14) skipping alterations.

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

Assessment of METex14 skipping alterations status

Prior to initiation of treatment with TEPMETKO the presence of METex14 skipping alterations should be confirmed by a validated test method using nucleic acids isolated from either tumour or plasma specimens. Testing for the presence of METex14 skipping alterations in tissue specimens is recommended because of higher sensitivity. However, plasma specimens may be used in patients for whom a tumour biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, the feasibility of biopsy for tumour tissue testing should be evaluated.

Posology

The recommended dose is 450 mg tepotinib (2 tablets) taken once daily. Treatment should continue until disease progression or unacceptable toxicity.

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.

Dose modification for adverse reactions

Dose interruption, dose reduction or discontinuation of treatment with TEPMETKO may be required based on adverse reactions. The recommended dose reduction level for the management of adverse reactions is 225 mg (1 tablet) daily. TEPMETKO should be permanently discontinued if patients are unable to tolerate 225 mg (1 tablet) daily. Detailed recommendations for dose modification are provided in the table below.

Renal impairment

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

Hepatic impairment

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 in patients with severe hepatic impairment (Child Pugh Class C) have not been studied.

Elderly

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

Paediatric population

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

Method of administration

TEPMETKO is for oral use. The tablet(s) should be taken with food and should be swallowed whole (patients should not crush or chew the tablet before swallowing).

If the patient is unable to swallow, the tablets can be dispersed in 30 mL of non-carbonated water. No other liquids should be used or added. The tablets should be dropped in a glass with water without crushing and stirred until the tablets are dispersed into small pieces (the tablet will not completely dissolve). The dispersion should be thoroughly stirred and should be swallowed immediately or within 1 hour. The pieces of the tablet should not be chewed. If the dispersion is taken within 1 hour, it should be thoroughly stirred again to ensure the whole dose is administered. In both cases, the glass should be rinsed with an additional 30 mL to ensure that no residue remains and should be swallowed immediately.

If an administration via a naso-gastric tube (with at least 8 French gauge) is required, the tablets should be dispersed in 30 mL of non-carbonated water as described above. The 30 mL of liquid should be thoroughly stirred, then drawn up by syringe and administered immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. If the drawn-up suspension in the syringe is administered within 1 hour, it should first be shaken thoroughly to disperse the contents again. In both cases, immediately rinse twice with 30 mL each to ensure that no residue remains in the syringe.

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

Interstitial lung disease/Pneumonitis

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) have been reported, including a fatal case (see section 4.8).

Patients should be monitored for new or worsening pulmonary symptoms indicative for ILD-like reactions (e.g. dyspnoea, cough, fever). TEPMETKO should be withheld immediately 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 according to local clinical practice.

Hepatotoxicity

Increases in ALT and/or AST have been reported (see section 4.8).

Liver enzymes (ALT and AST) and bilirubin should be monitored prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month. If grade 3 or higher increases occur, dose adjustment is recommended (see section 4.2).

Embryo-foetal toxicity

TEPMETKO can cause foetal harm when administered to pregnant women (see section 4.6).

Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a foetus.

Women of childbearing potential should use effective contraception during TEPMETKO treatment and for at least 1 week after the last dose.

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.

Interpretation of laboratory tests

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) 1 and 2 (see section 5.2). Creatinine is a substrate of these transporters, and the observed increases in creatinine (see section 4.8) may be the result of inhibition of active tubular secretion rather than 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. In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.

Lactose content

TEPMETKO contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacokinetic interactions

P-gp substrates

Tepotinib can inhibit the transport of sensitive substrates of P‑gp (see section 5.2). Monitoring of the clinical effects of P‑gp-dependent substances with a narrow therapeutic index (e.g. digoxin) is recommended during co-administration with TEPMETKO.

BCRP substrates

Tepotinib can inhibit the transport of sensitive substrates of the Breast Cancer Resistance Protein (BCRP) (see section 5.2). Monitoring of the clinical effects of sensitive BCRP substrates is recommended during co-administration with TEPMETKO.

Metformin

Based on in vitro data, tepotinib or its metabolite may have the potential to alter the exposure to co-administered metformin in humans through inhibition of metformin's renal excretion or hepatic uptake mediated via OCT1 and 2 and MATE1 and 2 (see section 5.2). Monitoring of the clinical effects of metformin is recommended during co-administration with TEPMETKO.

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.

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 TEPMETKO in pregnant women. Studies in animals have shown teratogenicity (see section 5.3). Based on the mechanism of action and findings in animals TEPMETKO 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 infant or milk production. Breast-feeding should be discontinued during treatment with TEPMETKO and for at least 1 week after the last dose.

Fertility

No human data on the effect of TEPMETKO 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 (see section 5.3).

TEPMETKO may have minor influence on the ability to drive and use machines. During treatment with tepotinib, fatigue and asthenia have been reported.

Summary of the safety profile

The safety data described reflect exposure to tepotinib 450 mg once daily in 313 patients with advanced NSCLC harbouring METex14 skipping alterations included in the main clinical study (VISION). Median duration of treatment was 32.4 weeks (range: 0 to 312 weeks).

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%), fatigue/asthenia (29.7%), 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%), asthenia (1.0%) and ILD (1.0%).

The percentage of patients who had adverse events leading to permanent treatment discontinuation is 24.9%. 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 events leading to temporary treatment discontinuation is 52.7%. 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 events leading to dose reduction is 36.1%. 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%).

List of adverse reactions

An asterisk (*) indicates that additional information on the respective adverse reaction is provided below the table.

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)

Description of selected adverse reactions

Interstitial lung disease

8 out of 313 patients (2.6%) in the VISION study developed interstitial lung disease (ILD) or ILD-like reactions, including 1 case (0.3%) of Grade 3 or higher; serious cases occurred in 4 patients (1.3%). The median time to onset was 9.43 weeks (range: 3.0 to 42.1 weeks). Treatment was permanently discontinued in 5 patients (1.6%) and temporarily discontinued in 3 patients (1.0%). One fatal case (0.3%) of acute respiratory failure secondary to ILD was reported. For clinical recommendations, see sections 4.2 and 4.4.

Hepatotoxicity

In the VISION study, based on laboratory assessment, ALT and AST a worsening from baseline to Grade 1 or higher was reported in 153 (49.5%) and 123 (39.9%) patients, respectively. A worsening to Grade 3 or higher ALT and AST were reported in 15 (4.9%) and 11 (3.6%) of patients, respectively. The median time to first onset was 9.07 weeks (range: 0.1 to 151.1 weeks) for any grade of ALT and/or AST increase. 10 patients (3.2%) temporarily discontinued treatment, and 2 patients (0.6%) required a dose reduction of tepotinib. The median time to resolution was 3.57 weeks (range: 0.1+ to 77.9 weeks). For clinical recommendations, see sections 4.2 and 4.4.

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher ALP increase was reported in 159 patients (51.6%). A worsening to Grade 3 or 4 occurred in 5 patients (1.6%). The median time to first onset for ALP increase of any grade was 9.14 weeks (range: 0.7 to 54.0 weeks) and the median time to resolution was 9.14 weeks (range: 0.9+* to 81.1 weeks). The observed ALP increase was not associated with cholestasis and did not lead to dose modification.

*'+' indicates censored observation

Oedema

Oedema was observed in 255 patients (81.5%). It includes peripheral oedema, which was the most frequent in 227 patients (72.5%), generalised oedema and localised oedema (e.g. oedema of the face, periorbital oedema, genital oedema). The median time to onset of any-grade oedema was 9.14 weeks (range: 0.1 to 96.6 weeks) and the median time to resolution was approximately 71.43 weeks (range: 0.1 to 286.6+ weeks). 25 patients (8.0%) had oedema events leading to permanent treatment discontinuation, of whom 17 (5.4%) had peripheral oedema. 89 patients (28.4%) temporarily discontinued treatment and 68 patients (21.7%) had dose reduction due to oedema. Most frequently peripheral oedema led to temporary treatment discontinuation and dose reductions (62 patients (19.8%) and 49 patients (15.7%), respectively). Generalised oedema events led to a dose reduction in 10 patients (3.2%) and to temporary treatment discontinuation in 15 patients (4.8%), and permanent discontinuation in 2 patients (0.6%).

Increase in creatinine

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher creatinine increase was reported in 184 patients (59.9%). A worsening to Grade 3 or 4 occurred in 3 patients (1.0%). The observed increases in creatinine are thought to occur due to competition of renal tubular secretion (see section 4.4). The median time to onset of increased creatinine was 3.43 weeks (range: 0.1 to 78.4 weeks) and the median time to resolution was 9.14 weeks (range: 0.3 to 223.9+ weeks). Two patients (0.6%) permanently discontinued treatment due to increase in creatinine, 18 patients (5.8%) temporarily discontinued treatment and 9 patients (2.9%) required a dose reduction.

Hypoalbuminaemia

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher decrease in albumin was reported in 246 patients (80.9%). A worsening to Grade 3 or 4 occurred in 28 patients (9.2%) . The median time to onset of any-grade hypoalbuminaemia was 9.43 weeks (range: 0.1 to 154.6 weeks) and the median time to resolution was 28.9 weeks (range 0.6 - 249.4+ weeks). Hypoalbuminaemia appeared to be long-lasting but did not lead to permanent treatment discontinuation. Dose reduction (5 patients (1.6%)) and temporary discontinuation (6 patients (1.9%)) were infrequent.

Increase in amylase or lipase

Based on laboratory assessment, increases in amylase and lipase from baseline were reported in 75 patients (24.9%) and 64 patients (21.2%), respectively. Grade 3 or 4 worsening in amylase and lipase were reported in 16 patients (5.3%) and 16 patients (5.3%), respectively. No pancreatitis was observed in the VISION study. The median time to onset of any grade in lipase/amylase increase was 15.0 weeks (range: 0.9 to 198 weeks). Median time to resolution was 6.14 weeks (range: 0.4 to 311.0+ weeks). 10 patients (3.2%) temporarily discontinued treatment. No patient required dose reduction or permanent treatment discontinuation.

Additional information on special populations

Elderly

Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mg tepotinib once daily, 79% were 65 years or older, and 8% were 85 years or older. No clinically important differences in safety were observed between patients aged 65 years or older and younger patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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, TEPMETKO should be withheld and symptomatic treatment initiated.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, cellular-mesenchymal-epithelial transition factor (c-MET) kinase inhibitors, ATC code: L01EP02

Mechanism of action

Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signalling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.

In vitro, tepotinib inhibited tumour cell proliferation, anchorage-independent growth, and migration of MET-dependent tumour cells. In mice implanted with tumour cell lines with oncogenic activation of MET, including METex14 skipping alterations, tepotinib inhibited tumour growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.

Pharmacodynamic effects

Cardiac electrophysiology

In an exposure-QTc analysis, the QTcF interval prolongation potential of tepotinib was assessed in 392 patients with various solid tumours following single or multiple daily doses of tepotinib ranging from 27 mg to 1,261 mg. At the recommended dose, no large mean increases in QTc (i.e. > 20 ms) were detected. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.

Clinical efficacy and safety

The efficacy of tepotinib was evaluated in a single-arm, open-label, multicentre study (VISION) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations (n = 313). The primary objective was to evaluate the activity of tepotinib by determining objective response rate (ORR).

Patients with measurable disease as determined by RECIST v1.1, with METex14 skipping alterations in plasma and/or tissue, as determined by the central laboratory or by an assay with appropriate regulatory status and with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 were enrolled. Neurologically stable patients with central nervous system metastases were permitted. Patients with symptomatic central nervous system metastases or leptomeningeal carcinomatosis were excluded, as were patients with clinically uncontrolled cardiac disease. Patients who had received treatment with any inhibitor of MET or HGF (hepatocyte growth factor), and those with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) activating alterations were also excluded.

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

METex14 skipping was prospectively tested by next-generation sequencing in tumour (RNA-based) and/or plasma (ctDNA-based).

The primary outcome measure was objective response (complete response or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Secondary outcome measures included duration of response, progression-free survival assessed by IRC and overall survival.

The population included 164 treatment-naïve (52%) and 149 previously-treated (48%) patients. The median age was 72 years (range: 41 to 94), 49% of patients were male. 62% of patients were white, 34% were Asians, 49% of patients were never-smokers and 45% were former smokers. Most patients were ≥ 65 years of age (79%) with 41% ≥ 75 years of age.

The majority of patients (94%) had stage IV disease, 81% had adenocarcinoma histology. Thirteen percent of the patients had stable brain metastases.

Median treatment duration was 7.5 months (range: 0.03 to 72).

The efficacy results summarised in the table below reflect patients with at least 18 months of follow-up from the start of treatment (n = 313).

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

Paediatric population

The licensing authority 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).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The MHRA will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Absorption

A mean absolute bioavailability of 71.6% was observed for a single 450 mg dose of tepotinib administered in the fed state in healthy subjects; the median time to C_max was 8 hours (range: 6 to 12 hours).

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

Distribution

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

In vitro studies indicate that tepotinib is a substrate for P-glycoprotein (P-gp) (see section 4.5).

Biotransformation

Metabolism is not the major route of elimination. No metabolic pathway accounted for more than 25% of tepotinib elimination. Only one major circulating plasma metabolite has been identified. There is only a minor contribution of the major circulating metabolite to the overall efficacy of tepotinib in humans.

Elimination

After a single oral administration of a radiolabelled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in faeces (45% unchanged) and 13.6% in urine (7% unchanged). The major circulating metabolite, M506, accounted for about 40.4% of the total radioactivity in plasma.

The elimination half-life for tepotinib is approximately 32 h following oral administration.

Dose and time dependence

Tepotinib exposure increases dose-proportionally over the clinically relevant dose range up to 450 mg. The oral clearance of tepotinib did not change with respect to time. After multiple daily administrations of 450 mg tepotinib, median accumulation was 2.5‑fold for C_max and 3.3‑fold forAUC_0-24h.

Special populations

A population kinetic analysis did not show any effect of age (range 18 to 89 years), race, gender or body weight, on the pharmacokinetics of tepotinib.

Renal impairment

There was no clinically meaningful change in exposure in patients with mild and moderate renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) were not included in clinical trials.

Hepatic impairment

Following a single oral dose of 450 mg, tepotinib exposure was similar in healthy subjects and patients with mild hepatic impairment (Child-Pugh Class A), and was slightly lower (-13% AUC and -29% C_max) in patients with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. However, the free plasma concentrations of tepotinib were in a similar range in the healthy subjects, patients with mild hepatic impairment and in patients with moderate hepatic impairment. The pharmacokinetics of tepotinib have not been studied in patients with severe (Child Pugh Class C) hepatic impairment.

Pharmacokinetic interaction studies

Clinical studies

Effect of CYP3A/P‑gp inducers on tepotinib: In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inducer carbamazepine (300 mg twice daily for 14 days) decreased tepotinib AUC_inf by 35% and C_max by 11% compared to administration of tepotinib alone.

Effect of CYP3A/P‑gp inhibitors on tepotinib: In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUC_inf by 22% with no change in tepotinib C_max compared to administration of tepotinib alone.

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

Effect of tepotinib on P-gp substrates: Tepotinib is an inhibitor of P-gp. Multiple administrations of tepotinib 450 mg orally once daily had a mild effect on the pharmacokinetics of the sensitive P‑gp substrate dabigatran etexilate, increasing its AUC_t by approximately 50% and C_max by approximately 40%.

Effect of acid-reducing agents on tepotinib: Co-administration of omeprazole under fed conditions had no marked effect on the pharmacokinetic profile of tepotinib and its metabolites.

In-vitro studies

Effects of tepotinib on other transporters: Tepotinib or its major circulating metabolite inhibit BCRP, OCT1 and 2, organic-anion-transporting polypeptide (OATP) 1B1 and MATE1 and 2 at clinically relevant concentrations. At clinically relevant concentrations tepotinib represents a remote risk for bile salt export pump (BSEP) whilst it presents no risk for OATP1B3, organic anion transporter (OAT) 1 and 3.

Effects of tepotinib on UDP-glucuronosyltransferase (UGT): Tepotinib or its major circulating metabolite, M506, do not inhibit UGT1A1, 1A9, 2B17 1A3/4/6 and 2B7/15 at clinically relevant concentrations.

Effect of tepotinib on CYP 450 enzymes: Tepotinib is a substrate of CYP3A4 and CYP2C8. Tepotinib and M506 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1.

Oral repeat-dose toxicity studies have been conducted in rats up to 26 weeks and dogs up to 39 weeks.

Increased hepato-biliary parameters concomitant with pronounced cholangitis and pericholangitis were seen in dogs starting at doses of 30 mg tepotinib hydrochloride hydrate per kg per day (approximately 18% the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC). Slightly increased liver enzymes were seen in rats starting at doses 15 mg tepotinib hydrochloride hydrate per kg per day (approximately 3% of the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC). In dogs vomiting and diarrhoea were seen starting at 2.5 mg tepotinib hydrochloride hydrate per kg per day and at exposures approximately 0.3% of the human exposure at the recommended dose of 450 mg TEPMETKO based on AUC. All changes proved to be reversible or showed indications of reversibility or improvements.

A no-observed-adverse-effect-level (NOAEL) was established at 45 mg tepotinib hydrochloride hydrate per kg per day in the 26‑week study in rats and at 10 mg tepotinib hydrochloride hydrate per kg per day in the 39‑week study in dogs (both equivalent to approximately 4% of the human exposure at the recommended dose of 450 mg TEPMETKO based on AUC).

Genotoxicity

No mutagenic or genotoxic effects of tepotinib were observed in in vitro and in vivo studies. The major circulating metabolite was also shown to be non-mutagenic.

Carcinogenicity

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, and 450 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. The dose of 450 mg per kg was discontinued due to severe maternal toxic effects. In the 150 mg per kg group, two animals aborted and one animal died prematurely. Mean foetal body weight was decreased at doses of ≥ 150 mg per kg per day. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, were observed at 50 and 150 mg per kg per day.

In the second embryo-foetal development study, pregnant rabbits received oral doses of 0.5, 5, and 25 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. Two malformed foetuses with malrotated hind limbs were observed (one in the 5 mg per kg group (approximately 0.21% of the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC) and one in the 25 mg per kg group), 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 toxicity studies in rats and dogs.

Tablet core

Mannitol

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Microcrystalline cellulose

Film-coating

Hypromellose

Lactose monohydrate

Macrogol

Triacetin

Red iron oxides (E172)

Titanium dioxide

Not applicable

3 years.

This medicinal product does not require special temperature storage conditions. Store in the original package in order to protect from moisture.

Aluminium/Polyvinyl chloride-polyethylene-polyvinylidene chloride-polyethylene-polyvinyl chloride blister. Pack of 60 film-coated tablets.

No special requirements.