TEPMETKO Film-coated tablet Ref.[49902] Active ingredients: Tepotinib

Assessment of METex14 skipping alterations status

When detecting the presence of alterations leading to METex14 skipping using tissue-based or plasmabased 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).

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).

Interaction with other medicinal products

Concomitant use of TEPMETKO with strong CYP and P-gp inducers or dual strong CYP3A and P-gp inhibitors should be avoided (see section 4.5).

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 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 medicinal product.

Effects of other medicinal products on tepotinib

CYP and P-gp inducers

Tepotinib is a substrate for P-glycoprotein (P-gp) (see section 5.2). Strong P-gp inducers may have the potential to decrease tepotinib exposure. Strong CYP inducers may also decrease tepotinib exposure. Concomitant use of strong CYP and P-gp inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s wort) should be avoided.

Dual strong CYP3A and P-gp inhibitors, and P-gp inhibitors

The effect of strong CYP3A inhibitors or P-gp inhibitors on TEPMETKO has not been studied clinically. However, metabolism and in vitro data suggest concomitant use of medicinal products that are strong CYP3A inhibitors and P-gp inhibitors may increase tepotinib exposure (see section 5.2), which may increase the incidence and severity of adverse reactions of tepotinib. Concomitant use of TEPMETKO with dual strong CYP3A and P-gp inhibitors (e.g. itraconazole, ketoconazole, ritonavir, saquinavir, nelfinavir) should be avoided. Also for P-gp inhibitors that are not strong inhibitors of CYP3A (e.g. quinidine, verapamil) an increase in exposure for tepotinib cannot be excluded. Therefore, caution and monitoring for adverse reactions is advised in case of concomitant use.

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 AUC_inf (90% CI: 102; 119) and of 104% for C_max (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 C_max 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 coadministration with TEPMETKO.

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 most clinically relevant example of substrates of these transporters is metformin. Monitoring of the clinical effects of metformin is recommended during co-administration with TEPMETKO.

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.

Hormonal contraceptives

It is currently unknown whether tepotinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, 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 4.6).

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.

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).

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

Summary of the safety profile

The most common adverse reactions in ≥20% of exposed to tepotinib at the recommended dose in the target indication are oedema (77.3% of patients), mainly peripheral oedema (65.6%), nausea (30.2%), hypoalbuminaemia (28.5%), diarrhoea (27.8%) and increase in creatinine (27.1%).

The most common serious adverse reactions in ≥1% of patients are peripheral oedema (3.1%), generalised oedema (2.1%) and ILD (1.4%).

The percentage of patients who had adverse events leading to permanent treatment discontinuation is 23.7%. The most common adverse reactions leading to permanent discontinuation in ≥1% of patients are peripheral oedema (4.5%), oedema (1.0%), genital oedema (1.0%) and ILD (1.0%).

The percentage of patients who had adverse events leading to temporary treatment discontinuation is 49.1%. The most common adverse reactions leading to temporary discontinuation in ≥2% of patients are peripheral oedema (18.6%), increase in creatinine (5.8%), generalised oedema (3.8%), oedema (3.8%), increase in ALT (2.7%), nausea (2.7%) and increase in amylase (2.1%).

The percentage of patients who had adverse events leading to dose reduction is 34.0%. The most common adverse reactions leading to dose reduction in ≥2% of patients are peripheral oedema (15.1%), increase in creatinine (3.1%), generalised oedema (2.7%) and oedema (2.4%).

List of adverse reactions

Adverse reactions described in the list below reflect exposure to tepotinib in 484 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 291 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 27.6 weeks (range 0 to 220).

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.

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).

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

^* Additional information on the respective adverse reaction is provided below.
^a includes terms interstitial lung disease, pneumonitis, acute respiratory failure
^b includes terms oedema peripheral, oedema, generalised oedema, oedema genital, face oedema, localised oedema, periorbital oedema, peripheral swelling, scrotal oedema

Description of selected adverse reactions

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like reactions have been reported in 8 patients (2.7%), including 1 case of grade 3 or higher; serious cases occurred in 4 patients (1.4%), 1 case was fatal. Treatment was permanently discontinued in 5 patients and temporarily in 3 patients. Median time to onset of ILD was 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 led to temporary discontinuation (3.1%) or dose reduction (0.7%) of tepotinib. Median time to first onset for ALT and/or AST increase of any grade reported as an adverse event by investigators was 6.1 weeks and the median time to resolution was 4.9 weeks. 82% of patients recovered from all events. For clinical recommendations, see sections 4.2 and 4.4.

ALP increase did not lead to any dose reductions, temporary treatment discontinuation or permanent discontinuation. The observed ALP increase was not associated with cholestasis. Median time to first onset for ALP increase of any grade reported as an adverse event by investigators was 4.4 weeks and the median time to resolution was 11 weeks. 60% of patients recovered from all events.

Oedema

The most frequently reported event was peripheral oedema (65.6% of patients), followed by oedema (9.3%) and generalised oedema (5.8%). Median time to onset of any-grade oedema was 9.0 weeks and the median time to resolution was 69 weeks. 17% of patients recovered from all events. 7.2% of patients had oedema events leading to permanent treatment discontinuation, of whom 4.5% had peripheral oedema. 26% of patients temporarily discontinued treatment and 21% of patients had dose reductions due to oedema. Most frequently peripheral oedema led to temporary treatment discontinuation and dose reductions (19% and 15%, respectively). Generalised oedema events led to a dose reduction in 2.7% of patients, to temporary treatment discontinuation in 3.8% and to permanent discontinuation in 0.7%.

Increase in creatinine

Increase in creatinine led to permanent treatment discontinuation in 2 patients (0.7%), temporary treatment discontinuation in 5.8% of patients and dose reduction in 3.1% of patients. Median time to onset of increase in creatinine reported as an adverse event by investigators was 3.1 weeks and the median time to resolution was 11 weeks. 61% of patients recovered from all events. The observed increases in creatinine are 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 treatment discontinuation. Dose reduction (1.0%) and temporary discontinuation (1.4%) were infrequent. Median time to onset of any-grade hypoalbuminaemia reported as an adverse event by investigators was 9.4 weeks; a median time to resolution could not be estimated. 27% of patients recovered from all events.

Increase in amylase or lipase

Increases in amylase or lipase reported as an adverse event by investigators were asymptomatic and not associated with pancreatitis. 3.1% of patients temporarily discontinued treatment and there were no permanent treatment discontinuation or dose reduction. Median time to onset of any grade in lipase/amylase increase was 12 weeks and median time to resolution was 5.9 weeks. 65% of patients recovered from all events.

QTc prolongation

QTcF prolongation to >500 ms was observed in 6 patients (2.1%) and a QTcF prolongation by at least 60 ms from baseline in 15 patients (5.2%) (see section 4.4). The findings were isolated and asymptomatic; the clinical significance is unknown.

Additional information on special populations

Elderly

Of 291 patients with METex14 skipping alterations in the VISION study who received 450 mg tepotinib once daily, 78% were 65 years or older, and 8% were 85 years or older. The occurrence of grade ≥3 events increased with age. Treatment-related serious events were more frequent in patients aged ≥75 years and <85 years(19.8%) or those aged ≥85 years (20.8%) when compared to those younger than 65 years (7.8%), although this comparison is limited by the small sample size in patients aged ≥85 years.

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 the national reporting system listed in Appendix V.

Not applicable.