Consumer medicine information

Tepmetko

Tepotinib

BRAND INFORMATION

Brand name

Tepmetko

Active ingredient

Tepotinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tepmetko.

SUMMARY CMI

TEPMETKO®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using TEPMETKO?

TEPMETKO contains the active ingredient tepotinib (as hydrochloride monohydrate). TEPMETKO is used to treat adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body or is advanced, and whose tumours have mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

For more information, see Section 1. Why am I using TEPMETKO? in the full CMI.

2. What should I know before I use TEPMETKO?

Do not use if you have ever had an allergic reaction to TEPMETKO or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to have a baby or are breastfeeding.

For more information, see Section 2. What should I know before I use TEPMETKO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TEPMETKO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TEPMETKO?

  • Recommended dose: 450 mg (two tablets) orally once daily with food.
  • Swallow the tablet(s) whole. Do not break, crush or chew the tablet(s).

More instructions can be found in Section 4. How do I use TEPMETKO? in the full CMI.

5. What should I know while using TEPMETKO?

Things you should do
  • Tell your doctor or pharmacist if you are about to start on taking any new medicines while using TEPMETKO
  • Tell your doctor if you become pregnant while using TEPMETKO
Things you should not do
  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not change the dose unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Driving or using machines
  • You should take special care when driving and using machines as you may feel unusually tired while taking TEPMETKO.
Looking after your medicine
  • Store TEPMETKO tablets below 30°C in the original package to protect from moisture.
  • Keep this medicine where children cannot reach it.
  • Do not use the medicine after the expiry date on the label

For more information, see Section 5. What should I know while using TEPMETKO? in the full CMI.

6. Are there any side effects?

Most common adverse reactions were swelling in your face or other parts of the body, nausea, vomiting, diarrhoea, stomach pain, constipation, tiredness. Serious side effects may include sudden difficulty in breathing with cough or fever, dark-coloured urine, yellow skin and eyes, loss of appetite. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

TEPMETKO®

Active ingredient: tepotinib (as hydrochloride monohydrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using TEPMETKO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TEPMETKO.

Where to find information in this leaflet:

1. Why am I using TEPMETKO?
2. What should I know before I use TEPMETKO?
3. What if I am taking other medicines?
4. How do I use TEPMETKO?
5. What should I know while using TEPMETKO?
6. Are there any side effects?
7. Product details

1. Why am I using TEPMETKO?

TEPMETKO contains the active ingredient tepotinib (as hydrochloride monohydrate). TEPMETKO belongs to anti-cancer medicines called mesenchymal epithelial transition (MET) tyrosine kinase inhibitors.

TEPMETKO is used to treat adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body or is advanced, and whose tumours have mesenchymal epithelial transition (MET) exon 14 skipping alterations.

The alterations in the MET gene can lead to a dysfunctional protein which can lead to uncontrolled cell growth and cancer. By blocking this dysfunctional protein, TEPMETKO may slow or stop the cancer from growing. It may also help to shrink the cancer.

2. What should I know before I use TEPMETKO?

Warnings

Do not use TEPMETKO if:

  • you are allergic to tepotinib, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have or have had any new or worsening symptoms indicative of inflammation of the lungs, e.g. sudden breathing difficulties, cough or fever
  • have or have had liver problems
  • take any medicines for any other conditions (see Section 3. What if I am taking other medicines?).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you:

  • are pregnant or if you (male or female) are planning to have a baby. TEPMETKO can harm your unborn baby.
    - Females who are able to become pregnant:
    -- Your doctor may do a pregnancy test before you start treatment with TEPMETKO.
    -- You should use effective birth control (contraception) during treatment and for at least one week after the final dose of TEPMETKO. Talk to your doctor about birth control methods that may be right for you.
    - Males with female partners who are able to become pregnant should use effective birth control during treatment with TEPMETKO and for at least one week after your final dose.
  • are breastfeeding or intend to breastfeed. It is not known if TEPMETKO passes into your breast milk. You should not breastfeed during treatment and for at least one week after your final dose.

Use in children and adolescents

The effectiveness of TEPMETKO in children and adolescents under the age of 18 years has not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may not work properly if you are taking TEPMETKO.

These include:

  • digoxin to treat heart conditions
  • metformin to treat high blood glucose levels

You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor may need to supervise their effects more closely.

Your doctor will have more information on medicines to be careful with or to avoid whilst using TEPMETKO.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TEPMETKO.

4. How do I use TEPMETKO?

How much to use/take TEPMETKO

Your doctor will tell you how many tablets you need to take each day.

The usual dose of TEPMETKO is 450 mg (two tablets) taken orally once per day at the same time.

Your doctor may change your dose during treatment. Follow the instructions provided by your doctor.

Do not change the dose or stop using TEPMETKO unless your doctor tells you to.

When to use/take TEPMETKO

TEPMETKO should be taken once per day at about the same time each day.

How to take TEPMETKO

Follow all directions given to you by your doctor or pharmacist carefully.

You should take TEPMETKO tablet(s) with food. Do not chew, crush or split the tablet(s).

If you forget to use TEPMETKO

TEPMETKO should be used regularly at the same time each day. If you miss your dose at the usual time, take your recommended dose as soon you remember.

If it is almost time for your next dose (e.g. within 8 hours), skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

If you use too much TEPMETKO

If you think that you have used too much TEPMETKO, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using TEPMETKO?

Things you should do

Call your doctor straight away if you:

  • are about to start on taking any new medicines.
  • become pregnant during treatment with TEPMETKO.
  • experience allergic reactions, including shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.
  • experience any side effects as listed in Section 6. Your doctor may keep or change your dose during treatment. If your condition worsens, your doctor may stop your treatment temporarily or permanently depending on your condition.

Remind any doctor, dentist or pharmacist you visit that you are using TEPMETKO.

TEPMETKO may interfere with the result of some laboratory tests.

Things you should not do

  • Do not stop using this medicine suddenly unless your doctor tells you to.
  • Do not give TEPMETKO to anyone else, even if their conditions seem similar to yours.
  • Do not change the dose without checking with your doctor.

Driving or using machines

You should take special care when driving and using machines as you may feel unusually tired while taking TEPMETKO.

Looking after your medicine

Keep your tablets in the pack in a dry cool place where the temperature stays below 30°C. Do not remove the tablets from the carton pack.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effectsWhat to do
  • Swelling in your face or other parts of your body
  • Diarrhoea
  • Nausea
  • Vomiting
  • Abdominal pain
  • Constipation
  • Fatigue or tiredness
  • Abnormal kidney or liver blood test results
  • Abnormal blood test results for digestive enzymes (amylase, lipase)
  • Reduced protein levels in the blood
Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Sudden difficulty in breathing with a cough or fever. This may be a sign of inflamed lungs called interstitial lung disease.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
  • Signs of liver problems, including dark-coloured urine, yellow skin and eyes, light-coloured stools, confusion, tiredness, loss of appetite, aching or tenderness on the right side of your stomach area, weakness and swelling in your stomach area.
Call your doctor straight away. Your doctor will do blood tests to check your liver function.

Depending on the severity of your condition, your doctor may reduce your dose or ask you to stop the treatment temporarily or permanently.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TEPMETKO contains

Active ingredient
(main ingredient)		Tepotinib (as hydrochloride monohydrate)
Other ingredients
(inactive ingredients)		Mannitol, colloidal anhydrous silica, crospovidone, magnesium stearate, microcrystalline cellulose
Film coating: Hypromellose, lactose monohydrate, macrogol 3350, triacetin, red iron oxide, titanium dioxide
Potential allergensNot applicable

Do not take this medicine if you are allergic to any of these ingredients.

What TEPMETKO looks like

TEPMETKO is white-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side (Aust R 370977). Each pack contains 60 tablets.

Who distributes TEPMETKO

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road, Macquarie Park
NSW 2113
Australia

This leaflet was prepared in July 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Tepmetko

Active ingredient

Tepotinib

Schedule

S4

 

1 Name of Medicine

Tepotinib (as hydrochloride monohydrate).

2 Qualitative and Quantitative Composition

Tepmetko is supplied as film coated tablets containing 225 mg tepotinib (equivalent to 250 mg tepotinib hydrochloride monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tepmetko is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

4.2 Dose and Method of Administration

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.

METex14 skipping alterations testing.

When considering the use of Tepmetko as a treatment for advanced NSCLC harbouring METex14 skipping alterations, the METex14 skipping status should be established prior to initiation of Tepmetko therapy. METex14 skipping status in tumour or plasma specimens should be determined using a validated or approved test. Only robust, reliable and sensitive tests for the determination of METex4 skipping status should be used.

Dosage and method of administration.

Recommended dose. The recommended dose of Tepmetko is 450 mg (two 225 mg tablets) orally once daily with food. Treatment should continue as long as clinical benefit is observed.
Missed dose. 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 adjustment. Dose adjustment may be required based on individual safety and tolerability. If dose adjustment is necessary, then the recommended dose reduction of Tepmetko is 225 mg (one tablet) orally once daily with food.
Treatment modification guidelines for the management of adverse reactions are provided hereafter (see Table 1):

Renal impairment.

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 Tepmetko in patients with severe renal impairment (creatinine clearance below 30 mL/min) have not been studied (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment is recommended in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. The pharmacokinetics and safety of Tepmetko in patients with severe hepatic impairment (Child Pugh C) have not been studied (see Section 5.2 Pharmacokinetic Properties).

Elderly (> 65 years of age).

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

Administration.

Tepmetko is for oral use. The tablet(s) should be taken with food and should be swallowed whole. Do not break, crush or chew the tablets.

4.3 Contraindications

Tepmetko is contraindicated in patients with known hypersensitivity to tepotinib or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Assessment of METex14 skipping alterations status.

Patients treated with Tepmetko must have a confirmed METex14 skipping status based on a validated or approved test.

Interstitial lung disease.

Interstitial lung disease (ILD) or ILD-like adverse reactions have been reported in 8 patients (2.6%) with advanced NSCLC with METex14 skipping alterations who received Tepmetko at the recommended dosage regimen (n=313), including 1 case of Grade 3 or higher; serious cases occurred in 4 patients (1.3%), 1 case was fatal.
Patients should be monitored for pulmonary symptoms indicative of 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 accordingly.

Monitoring of liver function.

Increases in ALT and/or AST have been reported in the VISION study in patients with advanced NSCLC harbouring METex14 skipping alterations (see Section 4.8 Adverse Effects (Undesirable Effects)), which were mostly non-serious and of low grade. ALT and/or AST increase did not lead to permanent drug discontinuation and infrequently led to temporary discontinuation or dose reduction.
Based on laboratories values, a worsening from baseline to grade 1 or higher was observed for 49.5% of patients for ALT and 39.9% for AST. A worsening to grade 3 or higher occurred in 4.9% of patients for ALT and 3.6% of patients for AST.
Monitor liver function tests (including ALT, AST and total bilirubin) prior to the start of Tepmetko, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. If grade 3 or higher increases occur, dose adjustment is recommended (see Section 4.2 Dose and Method of Administration, Dose adjustment).

Embryo-fetal toxicity.

Tepmetko can cause fetal harm when administered to pregnant women. There are no available data on the use of Tepmetko in pregnant women. However, studies in animals showed malformations (teratogenicity) (see Section 4.6 Fertility, Pregnancy and Lactation).
Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a fetus.
Women of childbearing potential must use effective contraception during Tepmetko treatment and for at least 1 week after the last dose. Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with Tepmetko.
Male patients with female partners of childbearing potential must use barrier contraception during Tepmetko treatment and for at least 1 week after the last dose.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mg Tepmetko once daily, 21.4%, 37.4%, 33.5% and 7.7% were < 65 years, 65 to < 75 years, 75 to < 85 years and 85 years or older, respectively. No clinically important differences in safety or efficacy were observed between patients aged 65 or older and younger patients in VISION study.

Paediatric use.

The safety and efficacy of Tepmetko in paediatric patients below the age of 18 years have not been studied.

Effects on laboratory tests.

Nonclinical studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins organic cation transporter (OCT) 2, multidrug and toxin extrusion transporters (MATE) 2K (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Creatinine is a substrate of these transporters, and the observed increases in creatinine (see Section 4.8 Adverse Effects (Undesirable Effects)) 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on tepotinib.

Strong CYP3A and/or P-gp inducers.

Tepotinib is a substrate for P-glycoprotein (P-gp). In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong inducer carbamazepine (300 mg twice daily for 14 days) decreased tepotinib AUCinf by 35% and Cmax by 11% compared to administration of tepotinib alone. The decreased exposure is not clinically relevant.

Dual strong CYP3A inhibitors and P-gp inhibitors.

In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inhibitor and P-gp inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUCinf by 22% with no change in tepotinib Cmax compared to administration of tepotinib alone. This is classified as a weak interaction, and the observed changes in systemic exposure to tepotinib are not considered clinically relevant. Therefore, CYP3A and P-gp inhibitors are not expected to influence tepotinib exposure.

Acid-reducing agents.

Co-administration of omeprazole had no marked effect on the pharmacokinetic profile of tepotinib and its metabolites when administered under fed conditions.

Effects of tepotinib on other medicines.

P-gp substrates.

Tepotinib is an inhibitor of P-gp in vitro. Tepotinib can inhibit the transport of sensitive substrates of P-gp. Multiple administrations of Tepmetko 450 mg orally once daily had a mild effect on the pharmacokinetics of the sensitive P-gp substrate dabigatran etexilate, increasing its AUCt by approximately 50% and Cmax by approximately 40%. 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 is an inhibitor of BCRP in vitro. Tepotinib can inhibit the transport of sensitive substrates of the breast cancer resistance protein (BCRP). Monitoring of the clinical effects of sensitive BCRP substrates is recommended during co-administration with Tepmetko.

Other transporters.

Tepotinib or its major circulating metabolite inhibited OCT2 and MATE2K in vitro at clinically relevant concentrations.
Based on in vitro data, tepotinib or its metabolite may have the potential to increase the AUC of co-administered metformin in humans through inhibition of metformin's renal excretion mediated via OCT2 and MATE2K. Monitoring of the clinical effects of metformin is recommended during co-administration with Tepmetko.

CYP 450 substrates.

Multiple administrations of Tepmetko 450 mg orally once daily had no clinically relevant effect on the PK of the sensitive CYP3A substrate midazolam. Based on in vitro data, neither tepotinib nor its major circulating metabolite present a perpetrator for other cytochrome P450 enzymes.

UGT substrates.

In vitro data do not predict clinically relevant effects on UGT substrates.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of Tepmetko on fertility are available. No specific studies with tepotinib have been conducted in animals to evaluate the effect on fertility. 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 in a 4-week repeat dose toxicity study at 450 mg/kg/day (comparable to human clinical exposure based on AUC).
(Category D)
There are no clinical data on the use of Tepmetko in pregnant women. Studies in animals have shown teratogenicity (including malformations). Based on the mechanism of action and findings in animals Tepmetko can cause fetal harm when administered to pregnant women. Tepmetko must not be used during pregnancy. Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a fetus (see Section 4.4 Special Warnings and Precautions for Use).
A dose-dependent increase in malformed fetuses (hyperextension of limbs and malrotation of limbs along with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus) was observed after oral administration of tepotinib to pregnant rabbits at ≥ 5 mg/kg/day (approximately 0.003 times the human exposure based on AUC).
 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

The safety profile of Tepmetko reflects exposure to tepotinib in 506 patients with various solid tumours enrolled in five open-label, single-arm studies, in which patients received tepotinib as a single agent at a dose of 450 mg once daily. This includes 313 patients with advanced NSCLC harbouring METex14 skipping alterations included in the main clinical study (VISION). The median duration of exposure in this study was 7.5 months (range 0 to 72 months).
Serious treatment emergent adverse events (TEAEs) occurred in 50.8% of patients who received Tepmetko. Serious TEAEs in ≥ 2% of patients included pleural effusion (6.1%), pneumonia (5.4%), general health deterioration (3.8%), dyspnoea (3.5%), peripheral oedema (3.2%), and pulmonary embolism (2.2%).
Permanent discontinuation due to TEAEs occurred in 24.9% of patients who received Tepmetko. Common TEAEs (> 1.0%) leading to permanent discontinuation of Tepmetko were peripheral oedema (5.4%), pleural effusion (1.6%), general health deterioration (1.6%), and oedema (1.3%).
Dosage interruptions due to TEAEs occurred in 52.7% of patients who received Tepmetko. TEAEs which required dosage interruption in > 2% of patients who received Tepmetko included peripheral oedema (19.8%), increased blood creatinine (5.8%), generalised oedema (4.8%), oedema (3.8%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.6%), localised oedema (2.2%), decreased appetite (2.2%) and dyspnoea (2.2%).
TEAEs leading to treatment dose reduction occurred in 36.1% of patients who received Tepmetko. The most frequent TEAEs (> 2.0%) leading to treatment dose reduction included peripheral oedema (15.7%), generalised oedema (3.2%), increased blood creatinine (2.9%), oedema (2.6%), pleural effusion (2.2%).
Table 2 summarises the incidence of adverse reactions that occurred in patients with NSCLC harbouring METex14 skipping alterations in VISION study.
The adverse drug reactions are listed by System Organ Class (SOC) and frequency categories, defined using the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tepotinib is a Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET. Tepotinib inhibits HGF-dependent and independent MET phosphorylation and MET-dependent downstream signalling including the phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular-signal regulated kinase pathways in a dose-dependent manner.

Clinical trials.

The efficacy of Tepmetko was evaluated in a single-arm, open-label, multicenter study (VISION) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations (MS200095-0022).
The study included patients with measurable disease according to response evaluation criteria in solid tumours (RECIST 1.1) and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Patients were to have histologically or cytologically confirmed advanced NSCLC (all types including squamous and sarcomatoid) and were either treatment-naïve or had progressed on up to 2 lines prior systemic therapies. Neurologically stable patients with central nervous system metastases were permitted. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) activating alterations were excluded. Before entering the study, eligible patients were required to have confirmed METex14 skipping alterations status by next-generation sequencing assay using tissue and/or liquid biopsy samples.
A total of 313 patients in VISION Cohorts A and C had received treatment with tepotinib. Patients had a median age of 72 years (range 41 to 94), 49% were female and 51% male. The majority of patients were Caucasians (62%), followed by Asian patients (34%) and were never (49%) or former smokers (45%). Most patients were ≥ 65 years of age (79%) and 41% of patients were ≥ 75 years of age. The majority of patients had stage IV disease (94%) and 81% had adenocarcinoma histology. Thirteen percent of the patients had stable brain metastases. Patients received Tepmetko as first-line (52%) or second- or later line (48%) therapy.
Patients received 450 mg Tepmetko once daily until disease progression or unacceptable toxicity.
The primary efficacy outcome measure was confirmed objective response (complete response or partial response) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included duration of response, objective disease control, progression-free survival, overall survival as well as patient-reported outcomes of quality of life.
The Kaplan-Meier curves for Progression-free Survival (PFS) and Overall Survival (OS) are shown in Figures 1 and 2, respectively.
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.

5.2 Pharmacokinetic Properties

Absorption.

A mean absolute bioavailability of 71.6% was observed for a single 450 mg dose of tepotinib administered 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 by about 1.6-fold and Cmax 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%).

Metabolism.

Metabolism is not the major route of elimination. No metabolic pathway accounted for more than 25% of tepotinib elimination in humans. Only one major circulating plasma metabolite (MSC2571109A) has been identified. There is only a minor contribution of the major circulating metabolite to the overall efficacy of tepotinib in humans.

Excretion.

After intravenous administration of single doses, a total systemic clearance (geometric mean and geoCV%) of 12.8 L/h was observed.
Tepotinib is mainly excreted via the faeces (approximately 85% total recovery of radioactivity), with urinary excretion being a minor excretion pathway. After a single oral administration of a radiolabelled dose of 450 mg tepotinib, the unchanged tepotinib represented 45% and 7% of the total radioactivity in faeces and urine, respectively. The major circulating metabolite accounted for only about 3% of the total radioactivity in the faeces.
The effective half-life for tepotinib is approximately 32 hours. After multiple daily administrations of 450 mg tepotinib, median accumulation was 2.5 fold for Cmax and 3.3 fold for AUC0-24h.

Special populations and conditions.

A population kinetic analysis did not show any effect of age (range 18 to 89 years), race, sex, body weight, or mild to moderate renal impairment (CLcr 30 to 89 mL/min) on the pharmacokinetics of tepotinib.

Patients with hepatic impairment.

Following a single oral dose of 450 mg Tepmetko, the exposure was similar in healthy subjects and patients with mild hepatic impairment (Child-Pugh Class A) and was slightly lower (-13% AUC and -29% Cmax) 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 Tepmetko have not been studied in patients with severe (Child Pugh Class C) hepatic impairment.

Patients with 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.

Dose and time dependence.

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

Cardiac electrophysiology.

In the VISION study (patients with METex14 skipping alterations; n = 181), 4 patients (2.2%) experienced a QTcF prolonged to > 500 ms and 10 patients (5.5%) had a QTcF prolonged by at least 60 ms from baseline.
In an exposure-QTc analysis, the QTcF interval prolongation potential of Tepmetko was assessed in 392 patients with various solid tumours following single or multiple daily doses of Tepmetko 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.

5.3 Preclinical Safety Data

Genotoxicity.

No mutagenic or genotoxic effects of tepotinib were observed in the bacterial reverse mutation assay and mouse lymphoma assay in vitro and a rat micronucleus test in vivo.
The major circulating metabolite was also shown to be non-mutagenic in the bacterial reverse mutation assay and mouse lymphoma assay in vitro.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Mannitol, colloidal anhydrous silica, crospovidone, magnesium stearate, microcrystalline cellulose.

Film coating.

Hypromellose, lactose monohydrate, macrogol 3350, triacetin, iron oxide red, titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C in the original package in order to protect from moisture.

6.5 Nature and Contents of Container

Blister foil.

Multilayer composite, consisting of polyvinylchloride-polyethylene-polyvinylidenechloride-polyethylene-polyvinylchloride.

Lidding foil (child-resistant).

Aluminum-polyethylene terephthalate.
Each pack contains 6 blister foils, each containing 10 Tepmetko tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 3-(1-(3-(5-(1-Methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl-benzyl)-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride hydrate.

CAS number.

1100598-30-8.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes