These Highlights Do Not Include All The Information Needed To Use Tepmetko Safely And Effectively. See Full Prescribing Information For Tepmetko.

Increased Creatinine

A median increase in serum creatinine of 30% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

Store TEPMETKO at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP-NF Controlled Room Temperature]. Store in original package.

Tepotinib is a kinase inhibitor. TEPMETKO (tepotinib) tablets for oral use are formulated with tepotinib hydrochloride hydrate. The chemical name for tepotinib hydrochloride hydrate is 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride hydrate. The molecular formula is C₂₉H₂₈N₆O₂∙HCl∙H₂O and the molecular weight is 547.05 g/mol for tepotinib hydrochloride hydrate and 492.58 g/mol for tepotinib (free base). The chemical structure is shown below:

Tepotinib hydrochloride hydrate is a white to off-white powder with a pKa of 9.5.

TEPMETKO is supplied as film-coated tablets containing 225 mg of tepotinib (equivalent to 250 mg tepotinib hydrochloride hydrate). Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, and colloidal silicon dioxide. The tablet coating consists of hypromellose, titanium dioxide, lactose monohydrate, polyethylene glycol, triacetin, and red iron oxides.

The safety and efficacy of TEPMETKO in pediatric patients have not been established.

Of 313 patients with NSCLC positive for METex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 41% were 75 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Four patients (0.8%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262).

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. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].

The efficacy of TEPMETKO was evaluated in a single-arm, open-label, multicenter, non-randomized, multicohort study (VISION, NCT02864992). Eligible patients were required to have advanced or metastatic NSCLC harboring METex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study.

Identification of METex14 skipping alterations was prospectively determined using central laboratories employing either a PCR-based or next-generation sequencing-based clinical trial assay using tissue (66%) and/or plasma (57%) samples.

Patients received TEPMETKO 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC.

The efficacy population included 164 treatment naïve patients and 149 previously treated patients. The median age was 72 years (range 41 to 94 years); 51% female; 62% White, 34% Asian; 26% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 74% had ECOG PS 1; 49% never smoked; 81% had adenocarcinoma; 94% had metastatic disease; and 13% had CNS metastases. Amongst previously treated patients, 84% received prior platinum-based chemotherapy.

Efficacy results are presented in Table 4.

None.

The following adverse reactions are described in greater detail elsewhere in the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Pancreatic Toxicity [see Warnings and Precautions (5.3)]

• Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. (7.1)

No dosage modification is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC_0-12h and C_max) increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg. At the recommended dosage, the geometric mean (coefficient of variation [CV] %) steady state C_max was 1,291 ng/mL (48.1%) and the AUC_0-24h was 27,438 ng∙h/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for C_max and 3.3-fold for AUC_0-24h after multiple daily doses of tepotinib.

The recommended dosage of TEPMETKO is 450 mg orally once daily with food [see Clinical Pharmacology (12.3)] until disease progression or unacceptable toxicity.

Instruct patients to take their dose of TEPMETKO at approximately the same time every day and to swallow tablets whole. Do not chew, crush or split tablets. Patients who have difficulty swallowing solids can disperse tablets in water [see Dosage and Administration (2.3)].

Advise patients not to make up a missed dose within 8 hours of the next scheduled dose.

If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time.

No dosage modification is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied [see Clinical Pharmacology (12.3)].

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

Elevations in amylase and lipase levels occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased amylase and/or lipase occurred in 13% of patients treated with TEPMETKO. Grade 3 and 4 increased amylase and/or lipase occurred in 5% and 1.2% of patients, respectively. Monitor amylase and lipase at baseline and regularly during treatment with TEPMETKO. Based on the severity of the adverse drug reaction, temporarily withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].

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 signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.

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

Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to a pregnant woman. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the last dose. [See Use in Specific Populations (8.1, 8.3)]

• Interstitial Lung Disease (ILD)/Pneumonitis: Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis. Permanently discontinue TEPMETKO in patients diagnosed with ILD/pneumonitis of any severity. (2.4, 5.1)
• Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.2)
• Pancreatic Toxicity: Monitor amylase and lipase. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.3)
• Embryo-fetal toxicity: TEPMETKO can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3)

• Select patients for treatment with TEPMETKO on the presence of METex14 skipping. (2.1, 14)
• Recommended dosage: 450 mg orally once daily with food until disease progression or unacceptable toxicity. (2.2)

Tablets: 225 mg, white-pink, oval, biconvex film-coated tablets with embossment "M" on one side and plain on the other side.

Lactation: Advise not to breastfeed. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to TEPMETKO in 506 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at a dose of 450 mg once daily. This included 313 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 506 patients who received TEPMETKO, 44% were exposed for 6 months or longer, and 22% were exposed for more than one year.

The data described below reflect exposure to TEPMETKO 450 mg once daily in 313 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION [see Clinical Studies (14)].

Serious adverse reactions occurred in 51% of patients who received TEPMETKO. Serious adverse reactions in > 2% of patients included pleural effusion (6%), pneumonia (6%), edema (5%), general health deterioration (3.8%), dyspnea (3.5%), musculoskeletal pain (2.9%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 1.9% of patients who received TEPMETKO, including pneumonitis (0.3%), hepatic failure (0.3%), dyspnea from fluid overload (0.3%), pneumonia (0.3%), sepsis (0.3%), and death of unknown cause (0.3%).

Permanent discontinuation due to an adverse reaction occurred in 25% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (8%), pleural effusion (1.6%), and general health deterioration (1.6%).

Dosage interruptions due to an adverse reaction occurred in 53% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in > 2% of patients who received TEPMETKO included edema (28%), increased blood creatinine (6%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.6%), decreased appetite (2.2%), and dyspnea (2.2%).

Dose reductions due to an adverse reaction occurred in 36% of patients who received TEPMETKO. Adverse reactions which required dose reductions in > 2% of patients who received TEPMETKO included edema (22%), increased blood creatinine (2.9%), fatigue (2.2%), and pleural effusion (2.2%).

The most common adverse reactions (≥ 20%) in patients who received TEPMETKO were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, decreased appetite, and rash. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased lipase, increased ALT, increased AST, and decreased hemoglobin.

Table 2 summarizes the adverse reactions in VISION.

Clinically relevant adverse reactions in < 10% of patients who received TEPMETKO included ILD/pneumonitis, fever, dizziness, pruritus, and headache.

Table 3 summarizes the laboratory abnormalities observed in VISION.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

TEPMETKO (tepotinib) tablets: 225 mg tepotinib, white-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side.

The blister cards consist of a child-resistant blister foil.

The recommended dose reduction of TEPMETKO for the management of adverse reactions is 225 mg orally once daily.

Permanently discontinue TEPMETKO in patients who are unable to tolerate 225 mg orally once daily.

The recommended dosage modifications of TEPMETKO for adverse reactions are provided in Table 1.

ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 2% patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. Five patients (1%) discontinued TEPMETKO due to ILD/pneumonitis.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.4)].

Based on animal data, TEPMETKO can cause malformations at doses less than the human exposure based on AUC at the 450 mg clinical dose [see Use in Specific Populations (8.1)].

Select patients for treatment with TEPMETKO based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Testing for the presence of MET exon 14 skipping alterations in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. An FDA-approved test for detection of MET exon 14 skipping alterations in NSCLC for selecting patients for treatment with TEPMETKO is not available.

NDC 44087-5000-3

TEPMETKO^®

(tepotinib) tablets

225 mg per tablet

Rx Only

Each tablet contains 225 mg of tepotinib

(equivalent to 250 mg tepotinib hydrochloride hydrate)

Each carton contains 3 child resistant blister

cards of 10 tablets each

30 tablets

EMD

SERONO

NDC 44087-5000-6

TEPMETKO^®

(tepotinib) tablets

225 mg per tablet

Rx Only

Each tablet contains 225 mg of tepotinib

(equivalent to 250 mg tepotinib hydrochloride hydrate)

Each carton contains 6 child resistant blister

cards of 10 tablets each

60 tablets

EMD

SERONO

Carcinogenicity studies have not been performed with tepotinib. Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay^, or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic in a rat micronucleus test.

Fertility studies of tepotinib have not been performed. There were no morphological changes in male or female reproductive organs in repeat-dose toxicity studies in dogs.

Place TEPMETKO tablet(s) in a glass containing 30 mL (1 ounce) of non-carbonated water. No other liquids should be used or added. Stir, without crushing, until the tablet(s) is dispersed into small pieces (tablets will not completely dissolve) and drink immediately or within 1 hour. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose is administered.

If an administration via a naso-gastric tube (with at least 8 French gauge) is required, disperse the tablet(s) in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. Immediately rinse twice with 30 mL each time to ensure that no residue remains in the glass or syringe and the full dose is administered.

Increased Creatinine

A median increase in serum creatinine of 30% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

Store TEPMETKO at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP-NF Controlled Room Temperature]. Store in original package.

Tepotinib is a kinase inhibitor. TEPMETKO (tepotinib) tablets for oral use are formulated with tepotinib hydrochloride hydrate. The chemical name for tepotinib hydrochloride hydrate is 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride hydrate. The molecular formula is C₂₉H₂₈N₆O₂∙HCl∙H₂O and the molecular weight is 547.05 g/mol for tepotinib hydrochloride hydrate and 492.58 g/mol for tepotinib (free base). The chemical structure is shown below:

Tepotinib hydrochloride hydrate is a white to off-white powder with a pKa of 9.5.

TEPMETKO is supplied as film-coated tablets containing 225 mg of tepotinib (equivalent to 250 mg tepotinib hydrochloride hydrate). Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, and colloidal silicon dioxide. The tablet coating consists of hypromellose, titanium dioxide, lactose monohydrate, polyethylene glycol, triacetin, and red iron oxides.

The safety and efficacy of TEPMETKO in pediatric patients have not been established.

Of 313 patients with NSCLC positive for METex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 41% were 75 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Four patients (0.8%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262).

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. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].

The efficacy of TEPMETKO was evaluated in a single-arm, open-label, multicenter, non-randomized, multicohort study (VISION, NCT02864992). Eligible patients were required to have advanced or metastatic NSCLC harboring METex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study.

Identification of METex14 skipping alterations was prospectively determined using central laboratories employing either a PCR-based or next-generation sequencing-based clinical trial assay using tissue (66%) and/or plasma (57%) samples.

Patients received TEPMETKO 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC.

The efficacy population included 164 treatment naïve patients and 149 previously treated patients. The median age was 72 years (range 41 to 94 years); 51% female; 62% White, 34% Asian; 26% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 74% had ECOG PS 1; 49% never smoked; 81% had adenocarcinoma; 94% had metastatic disease; and 13% had CNS metastases. Amongst previously treated patients, 84% received prior platinum-based chemotherapy.

Efficacy results are presented in Table 4.

None.

The following adverse reactions are described in greater detail elsewhere in the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Pancreatic Toxicity [see Warnings and Precautions (5.3)]

• Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. (7.1)

No dosage modification is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC_0-12h and C_max) increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg. At the recommended dosage, the geometric mean (coefficient of variation [CV] %) steady state C_max was 1,291 ng/mL (48.1%) and the AUC_0-24h was 27,438 ng∙h/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for C_max and 3.3-fold for AUC_0-24h after multiple daily doses of tepotinib.

The recommended dosage of TEPMETKO is 450 mg orally once daily with food [see Clinical Pharmacology (12.3)] until disease progression or unacceptable toxicity.

Instruct patients to take their dose of TEPMETKO at approximately the same time every day and to swallow tablets whole. Do not chew, crush or split tablets. Patients who have difficulty swallowing solids can disperse tablets in water [see Dosage and Administration (2.3)].

Advise patients not to make up a missed dose within 8 hours of the next scheduled dose.

If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time.

No dosage modification is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied [see Clinical Pharmacology (12.3)].

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

Elevations in amylase and lipase levels occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased amylase and/or lipase occurred in 13% of patients treated with TEPMETKO. Grade 3 and 4 increased amylase and/or lipase occurred in 5% and 1.2% of patients, respectively. Monitor amylase and lipase at baseline and regularly during treatment with TEPMETKO. Based on the severity of the adverse drug reaction, temporarily withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].

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 signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.

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

Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to a pregnant woman. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the last dose. [See Use in Specific Populations (8.1, 8.3)]

• Interstitial Lung Disease (ILD)/Pneumonitis: Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis. Permanently discontinue TEPMETKO in patients diagnosed with ILD/pneumonitis of any severity. (2.4, 5.1)
• Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.2)
• Pancreatic Toxicity: Monitor amylase and lipase. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.3)
• Embryo-fetal toxicity: TEPMETKO can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3)

• Select patients for treatment with TEPMETKO on the presence of METex14 skipping. (2.1, 14)
• Recommended dosage: 450 mg orally once daily with food until disease progression or unacceptable toxicity. (2.2)

Tablets: 225 mg, white-pink, oval, biconvex film-coated tablets with embossment "M" on one side and plain on the other side.

Lactation: Advise not to breastfeed. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to TEPMETKO in 506 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at a dose of 450 mg once daily. This included 313 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 506 patients who received TEPMETKO, 44% were exposed for 6 months or longer, and 22% were exposed for more than one year.

The data described below reflect exposure to TEPMETKO 450 mg once daily in 313 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION [see Clinical Studies (14)].

Serious adverse reactions occurred in 51% of patients who received TEPMETKO. Serious adverse reactions in > 2% of patients included pleural effusion (6%), pneumonia (6%), edema (5%), general health deterioration (3.8%), dyspnea (3.5%), musculoskeletal pain (2.9%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 1.9% of patients who received TEPMETKO, including pneumonitis (0.3%), hepatic failure (0.3%), dyspnea from fluid overload (0.3%), pneumonia (0.3%), sepsis (0.3%), and death of unknown cause (0.3%).

Permanent discontinuation due to an adverse reaction occurred in 25% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (8%), pleural effusion (1.6%), and general health deterioration (1.6%).

Dosage interruptions due to an adverse reaction occurred in 53% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in > 2% of patients who received TEPMETKO included edema (28%), increased blood creatinine (6%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.6%), decreased appetite (2.2%), and dyspnea (2.2%).

Dose reductions due to an adverse reaction occurred in 36% of patients who received TEPMETKO. Adverse reactions which required dose reductions in > 2% of patients who received TEPMETKO included edema (22%), increased blood creatinine (2.9%), fatigue (2.2%), and pleural effusion (2.2%).

The most common adverse reactions (≥ 20%) in patients who received TEPMETKO were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, decreased appetite, and rash. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased lipase, increased ALT, increased AST, and decreased hemoglobin.

Table 2 summarizes the adverse reactions in VISION.

Clinically relevant adverse reactions in < 10% of patients who received TEPMETKO included ILD/pneumonitis, fever, dizziness, pruritus, and headache.

Table 3 summarizes the laboratory abnormalities observed in VISION.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

TEPMETKO (tepotinib) tablets: 225 mg tepotinib, white-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side.

The blister cards consist of a child-resistant blister foil.

The recommended dose reduction of TEPMETKO for the management of adverse reactions is 225 mg orally once daily.

Permanently discontinue TEPMETKO in patients who are unable to tolerate 225 mg orally once daily.

The recommended dosage modifications of TEPMETKO for adverse reactions are provided in Table 1.

ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 2% patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. Five patients (1%) discontinued TEPMETKO due to ILD/pneumonitis.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.4)].

Based on animal data, TEPMETKO can cause malformations at doses less than the human exposure based on AUC at the 450 mg clinical dose [see Use in Specific Populations (8.1)].

Select patients for treatment with TEPMETKO based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Testing for the presence of MET exon 14 skipping alterations in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. An FDA-approved test for detection of MET exon 14 skipping alterations in NSCLC for selecting patients for treatment with TEPMETKO is not available.

NDC 44087-5000-3

TEPMETKO^®

(tepotinib) tablets

225 mg per tablet

Rx Only

Each tablet contains 225 mg of tepotinib

(equivalent to 250 mg tepotinib hydrochloride hydrate)

Each carton contains 3 child resistant blister

cards of 10 tablets each

30 tablets

EMD

SERONO

NDC 44087-5000-6

TEPMETKO^®

(tepotinib) tablets

225 mg per tablet

Rx Only

Each tablet contains 225 mg of tepotinib

(equivalent to 250 mg tepotinib hydrochloride hydrate)

Each carton contains 6 child resistant blister

cards of 10 tablets each

60 tablets

EMD

SERONO

Carcinogenicity studies have not been performed with tepotinib. Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay^, or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic in a rat micronucleus test.

Fertility studies of tepotinib have not been performed. There were no morphological changes in male or female reproductive organs in repeat-dose toxicity studies in dogs.

Place TEPMETKO tablet(s) in a glass containing 30 mL (1 ounce) of non-carbonated water. No other liquids should be used or added. Stir, without crushing, until the tablet(s) is dispersed into small pieces (tablets will not completely dissolve) and drink immediately or within 1 hour. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose is administered.

If an administration via a naso-gastric tube (with at least 8 French gauge) is required, disperse the tablet(s) in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. Immediately rinse twice with 30 mL each time to ensure that no residue remains in the glass or syringe and the full dose is administered.