ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Most common adverse reactions (>= 20%) were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 448 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at dose of 450 mg once daily. This included 255 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 448 patients who received TEPMETKO, 32% were exposed for months or longer, and 12% were exposed for greater than one year.The data described below reflect exposure to TEPMETKO 450 mg once daily in 255 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION [see Clinical Studies (14)]. Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in 2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload.Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (5%), pleural effusion (2%), dyspnea (1.6%), general health deterioration (1.6%), and pneumonitis (1.2%).Dosage interruptions due to an adverse reaction occurred in 44% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in 2% of patients who received TEPMETKO included edema (23%), increased blood creatinine (6%), pleural effusion (4.3%), increased ALT (3.1%), and pneumonia (2.4%).Dose reductions due to an adverse reaction occurred in 30% of patients who received TEPMETKO. Adverse reactions which required dose reductions in 2% of patients who received TEPMETKO included edema (19%), pleural effusion (2.7%), and increased blood creatinine (2.7%).The most common adverse reactions (>= 20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin.Table summarizes the adverse reactions in VISION.Table 2:Adverse Reactions in >= 10% of Patients with NSCLC with METex14 Skipping Alterations Who Received TEPMETKO in VISIONAdverse ReactionsTEPMETKO(N 255)All Grades(%)Grades to 4(%)General disorders and administration-site conditions Edema Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema. 709 Fatigue Fatigue includes asthenia and fatigue. 271.6Gastrointestinal disorders Nausea270.8 Diarrhea260.4 Abdominal Pain Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain. 160.8 Constipation160 Vomiting Vomiting includes retching and vomiting. 131.2Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, non-cardiac chest pain, pain in extremity, and spinal pain. 242.4Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional. 202 Cough Cough includes cough, and productive cough. 150.4 Pleural effusion135Metabolism and nutrition disorders Decreased appetite161.2Infections and Infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial. 113.9Clinically relevant adverse reactions in 10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.Table summarizes the laboratory abnormalities observed in VISION.Table 3:Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients Who Received TEPMETKO in VISIONLaboratory AbnormalitiesTEPMETKOThe denominator used to calculate the rate varied from 207 to 246 based on the number of patients with baseline value and at least one post-treatment value. Grades to 4(%)Grades to 4(%)Chemistry Decreased albumin769 Increased creatinine550.4 Increased alkaline phosphatase aminotransferase501.6 Increased alanine aminotransferase444.1 Increased aspartate aminotransferase352.5 Decreased sodium318 Increased potassium251.6 Increased gamma-glutamyltransferase245 Increased amylase234.6Hematology Decreased lymphocytes4811 Decreased hemoglobin272 Decreased leukocytes230.8A clinically relevant laboratory abnormality in 20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades to 4.. Increased CreatinineA median increase in serum creatinine of 31% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tepotinib is 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 and imidazoline 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.. 12.2 Pharmacodynamics. Exposure-ResponseTepotinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.. Cardiac ElectrophysiologyAt the recommended dosage, no large mean increases in QTc (i.e. 20 ms) were detected in patients with various solid tumors. concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.. 12.3 Pharmacokinetics. The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC0-12h and Cmax) 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 Cmax was 1,291 ng/mL (48.1%) and the AUC0-24h was 27,438 ngh/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h after multiple daily doses of tepotinib.. AbsorptionThe median Tmax of tepotinib is hours (range from to 12 hours). The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects.. Effect of FoodThe mean AUC0-INF of tepotinib increased by 1.6-fold and Cmax increased by 2-fold, following administration of high-fat, high-calorie meal (approximately 800 to 1,000 calories, 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). The median Tmax shifted from 12 hours to hours.. DistributionThe geometric mean (CV%) apparent volume of distribution (VZ/F) of tepotinib is 1,038 (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration at clinically relevant exposures.. EliminationThe apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours following oral administration of TEPMETKO in patients with cancer.. MetabolismTepotinib is primarily metabolized by CYP3A4 and CYP2C8. One major circulating plasma metabolite (M506) has been identified.. ExcretionFollowing single oral administration of radiolabeled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in feces (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.. Specific PopulationsNo clinically significant effects on tepotinib pharmacokinetics were observed based on age (18 to 89 years), race/ethnicity (White, Black, Asian, Japanese, and Hispanic), sex, body weight (35.5 to 136 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min), or mild to moderate hepatic impairment (Child-Pugh and B). The effect of severe renal impairment (CLcr 30 mL/min) and severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of tepotinib has not been studied.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. P-gp Substrates: Coadministration of TEPMETKO with dabigatran etexilate (P-gp substrate) increased dabigatran Cmax by 40% and AUC0-INF by 50%.. Acid-Reducing Agents: No clinically significant differences in tepotinib pharmacokinetics were observed when coadministered with multiple daily doses (40 mg daily for days) of omeprazole (proton pump inhibitor) under fed conditions.. CYP3A Substrates: Coadministration of TEPMETKO had no clinically significant effect on the pharmacokinetics of midazolam (sensitive CYP3A substrate).. MATE2 and OCT2 Substrates: No clinically relevant differences in glucose levels were observed when metformin (MATE2 and OCT2 substrate) was coadministered with tepotinib.. CYP2C9 Substrates: Physiologically based pharmacokinetic modeling suggested CYP2C9 inhibition is not clinically significant.. In Vitro Studies. Cytochrome P450 Enzymes: Tepotinib is substrate of CYP3A4 and CYP2C8. Tepotinib and M506 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 or CYP2E1, and do not induce CYP1A2 or 2B6 at clinically relevant concentrations.. UDP-Glucuronosyltransferase (UGT): Tepotinib and M506 do not inhibit UGT 1A1, 1A9, 2B17, 1A3/4/6 and 2B7/15 at clinically relevant concentrations.. Transporter Systems: Tepotinib is P-gp substrate. Tepotinib may inhibit intestinal BCRP at clinically relevant concentrations. Tepotinib does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, B3, or organic anion transporter (OAT)1 and 3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of TEPMETKO was evaluated in 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 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 PCR-based or next-generation sequencing-based clinical trial assay using tissue (58%) and/or plasma (65%) 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 Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC.The efficacy population included 69 treatment naive patients and 83 previously treated patients. The median age was 73 years (range 41 to 94 years); 48% female; 71% White, 25% Asian; 27% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) and 73% had ECOG PS 1; 43% never smoked; 86% had adenocarcinoma; 98% had metastatic disease; and 10% had CNS metastases. Amongst previously treated patients, 89% received prior platinum-based chemotherapy.Efficacy results are presented in Table 4.Table 4:Efficacy Results in the VISION studyEfficacy parameterTreatment-NaiveN 69 Previously TreatedN 83CI=confidence interval, NE=Not estimableOverall response rate, (95% CI) Blinded Independent Review Committee (BIRC) review Confirmed Responses 43 (32, 56)43 (33, 55)Median duration of response, months Product-limit (Kaplan-Meier) estimates, 95% CI for the median using the Brookmeyer and Crowley method. (95% CI)10.8 (6.9, NE)11.1 (9.5, 18.5) Patients with DOR >= months, %6775 Patients with DOR >= months, %3050.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 448 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at dose of 450 mg once daily. This included 255 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 448 patients who received TEPMETKO, 32% were exposed for months or longer, and 12% were exposed for greater than one year.The data described below reflect exposure to TEPMETKO 450 mg once daily in 255 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION [see Clinical Studies (14)]. Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in 2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload.Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (5%), pleural effusion (2%), dyspnea (1.6%), general health deterioration (1.6%), and pneumonitis (1.2%).Dosage interruptions due to an adverse reaction occurred in 44% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in 2% of patients who received TEPMETKO included edema (23%), increased blood creatinine (6%), pleural effusion (4.3%), increased ALT (3.1%), and pneumonia (2.4%).Dose reductions due to an adverse reaction occurred in 30% of patients who received TEPMETKO. Adverse reactions which required dose reductions in 2% of patients who received TEPMETKO included edema (19%), pleural effusion (2.7%), and increased blood creatinine (2.7%).The most common adverse reactions (>= 20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin.Table summarizes the adverse reactions in VISION.Table 2:Adverse Reactions in >= 10% of Patients with NSCLC with METex14 Skipping Alterations Who Received TEPMETKO in VISIONAdverse ReactionsTEPMETKO(N 255)All Grades(%)Grades to 4(%)General disorders and administration-site conditions Edema Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema. 709 Fatigue Fatigue includes asthenia and fatigue. 271.6Gastrointestinal disorders Nausea270.8 Diarrhea260.4 Abdominal Pain Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain. 160.8 Constipation160 Vomiting Vomiting includes retching and vomiting. 131.2Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, non-cardiac chest pain, pain in extremity, and spinal pain. 242.4Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional. 202 Cough Cough includes cough, and productive cough. 150.4 Pleural effusion135Metabolism and nutrition disorders Decreased appetite161.2Infections and Infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial. 113.9Clinically relevant adverse reactions in 10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.Table summarizes the laboratory abnormalities observed in VISION.Table 3:Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients Who Received TEPMETKO in VISIONLaboratory AbnormalitiesTEPMETKOThe denominator used to calculate the rate varied from 207 to 246 based on the number of patients with baseline value and at least one post-treatment value. Grades to 4(%)Grades to 4(%)Chemistry Decreased albumin769 Increased creatinine550.4 Increased alkaline phosphatase aminotransferase501.6 Increased alanine aminotransferase444.1 Increased aspartate aminotransferase352.5 Decreased sodium318 Increased potassium251.6 Increased gamma-glutamyltransferase245 Increased amylase234.6Hematology Decreased lymphocytes4811 Decreased hemoglobin272 Decreased leukocytes230.8A clinically relevant laboratory abnormality in 20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades to 4.. Increased CreatinineA median increase in serum creatinine of 31% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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). 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). 2.1Patient Selection for METex14 Skipping Alterations. 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 tumor biopsy cannot be obtained. If an alteration is not detected in 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.. 2.2Recommended Dosage. 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.Advise patients not to make up missed dose within hours of the next scheduled dose.If vomiting occurs after taking dose of TEPMETKO, advise patients to take the next dose at the scheduled time.. 2.3Dose Modifications for Adverse Reactions. 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.Table 1:Recommended TEPMETKO Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityDose ModificationInterstitial Lung Disease (ILD) /Pneumonitis [see Warnings and Precautions (5.1)] Any gradeWithhold TEPMETKO if ILD is suspected.Permanently discontinue TEPMETKO if ILD is confirmed.Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2)] Grade 3Withhold TEPMETKO until recovery to baseline ALT/AST.If recovered to baseline within days, then resume TEPMETKO at the same dose; otherwise resume TEPMETKO at reduced dose.Grade 4Permanently discontinue TEPMETKO.Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis [see Warnings and Precautions (5.2)] ALT and/or AST greater than times ULN with total bilirubin greater than times ULNPermanently discontinue TEPMETKO.Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2)] Grade 3Withhold TEPMETKO until recovery to baseline bilirubin.If recovered to baseline within days, then resume TEPMETKO at reduced dose; otherwise permanently discontinue.Grade 4Permanently discontinue TEPMETKO.Other adverse reactions [see Adverse Reactions (6.1)] Grade 2Maintain dose level. If intolerable, consider withholding TEPMETKO until resolved, then resume TEPMETKO at reduced dose.Grade 3Withhold TEPMETKO until resolved, then resume TEPMETKO at reduced dose.Grade 4Permanently discontinue TEPMETKO.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Dual strong CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use. (7.1)Strong CYP3A inducers: Avoid concomitant use. (7.1)Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. (7.2). Dual strong CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use. (7.1). Strong CYP3A inducers: Avoid concomitant use. (7.1). Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. (7.2). 7.1Effects of Other Drugs on TEPMETKO. Dual Strong CYP3A Inhibitors and P-gp InhibitorsThe 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 drugs that are strong CYP3A inhibitors and P-gp inhibitors may increase tepotinib exposure [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of TEPMETKO. Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors.. Strong CYP3A InducersThe effect of strong CYP3A inducers on TEPMETKO has not been studied clinically. However, metabolism and in vitro data suggest concomitant use may decrease tepotinib exposure [see Clinical Pharmacology (12.3)], which may reduce TEPMETKO efficacy. Avoid concomitant use of TEPMETKO with strong CYP3A inducers.. 7.2Effects of TEPMETKO on Other Drugs. Certain P-gp SubstratesTepotinib is P-gp inhibitor. Concomitant use of TEPMETKO increases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of these substrates. Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Interstitial Lung Disease (ILD)/PneumonitisInform patients of the risk of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].. HepatotoxicityInform patients that they will need to undergo lab tests to monitor liver function. Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction [see Warnings and Precautions (5.2)].. Embryo-Fetal ToxicityAdvise males and females of reproductive potential that TEPMETKO can cause fetal harm.Advise females of reproductive potential to use effective contraception during and for one week after the final dose of TEPMETKO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose of TEPMETKO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3)]. LactationAdvise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose [see Use in Specific Populations (8.2)].. Drug InteractionsAdvise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs and herbal products [see Drug Interactions (7)]. Dosing and AdministrationInstruct patients to take 450 mg TEPMETKO once daily with food [see Dosage and Administration (2.2)].. Missed DoseAdvise patients that missed dose of TEPMETKO can be taken as soon as remembered on the same day, unless the next dose is due within hours. If vomiting occurs after taking dose of TEPMETKO, advise patients to take the next dose at the scheduled time [see Dosage and Administration (2.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC0-12h and Cmax) 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 Cmax was 1,291 ng/mL (48.1%) and the AUC0-24h was 27,438 ngh/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h after multiple daily doses of tepotinib.. AbsorptionThe median Tmax of tepotinib is hours (range from to 12 hours). The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects.. Effect of FoodThe mean AUC0-INF of tepotinib increased by 1.6-fold and Cmax increased by 2-fold, following administration of high-fat, high-calorie meal (approximately 800 to 1,000 calories, 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). The median Tmax shifted from 12 hours to hours.. DistributionThe geometric mean (CV%) apparent volume of distribution (VZ/F) of tepotinib is 1,038 (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration at clinically relevant exposures.. EliminationThe apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours following oral administration of TEPMETKO in patients with cancer.. MetabolismTepotinib is primarily metabolized by CYP3A4 and CYP2C8. One major circulating plasma metabolite (M506) has been identified.. ExcretionFollowing single oral administration of radiolabeled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in feces (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.. Specific PopulationsNo clinically significant effects on tepotinib pharmacokinetics were observed based on age (18 to 89 years), race/ethnicity (White, Black, Asian, Japanese, and Hispanic), sex, body weight (35.5 to 136 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min), or mild to moderate hepatic impairment (Child-Pugh and B). The effect of severe renal impairment (CLcr 30 mL/min) and severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of tepotinib has not been studied.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. P-gp Substrates: Coadministration of TEPMETKO with dabigatran etexilate (P-gp substrate) increased dabigatran Cmax by 40% and AUC0-INF by 50%.. Acid-Reducing Agents: No clinically significant differences in tepotinib pharmacokinetics were observed when coadministered with multiple daily doses (40 mg daily for days) of omeprazole (proton pump inhibitor) under fed conditions.. CYP3A Substrates: Coadministration of TEPMETKO had no clinically significant effect on the pharmacokinetics of midazolam (sensitive CYP3A substrate).. MATE2 and OCT2 Substrates: No clinically relevant differences in glucose levels were observed when metformin (MATE2 and OCT2 substrate) was coadministered with tepotinib.. CYP2C9 Substrates: Physiologically based pharmacokinetic modeling suggested CYP2C9 inhibition is not clinically significant.. In Vitro Studies. Cytochrome P450 Enzymes: Tepotinib is substrate of CYP3A4 and CYP2C8. Tepotinib and M506 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 or CYP2E1, and do not induce CYP1A2 or 2B6 at clinically relevant concentrations.. UDP-Glucuronosyltransferase (UGT): Tepotinib and M506 do not inhibit UGT 1A1, 1A9, 2B17, 1A3/4/6 and 2B7/15 at clinically relevant concentrations.. Transporter Systems: Tepotinib is P-gp substrate. Tepotinib may inhibit intestinal BCRP at clinically relevant concentrations. Tepotinib does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, B3, or organic anion transporter (OAT)1 and 3.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], TEPMETKO can cause fetal harm when administered to pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose (see Data). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. 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, occurred at doses >= mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the mg/kg dose level.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued:2/2021PATIENT INFORMATIONTEPMETKO(R) (tep-MET-co)(tepotinib)tablets, for oral useWhat is the most important information should know about TEPMETKOTEPMETKO may cause serious side effects, including:Lung problems. TEPMETKO may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Tell your healthcare provider right away if you develop any new or worsening symptoms of lung problems, including:trouble breathingshortness of breathcoughfever See What are possible side effects of TEPMETKO for more information about side effects.What is TEPMETKOTEPMETKO is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC) that:has spread to other parts of the body (metastatic), andwhose tumors have an abnormal mesenchymal epithelial transition (MET) gene. Your healthcare provider will perform test to make sure that TEPMETKO is right for you.It is not known if TEPMETKO is safe and effective in children.Before you receive TEPMETKO, tell your healthcare provider about all of your medical conditions, including if you:have or have had lung or breathing problems other than your lung cancerhave or have had liver problemsare pregnant or plan to become pregnant. TEPMETKO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider may do pregnancy test before you start treatment with TEPMETKO.You should use effective birth control (contraception) during treatment and for week after the final dose of TEPMETKO. Talk to your healthcare provider 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 week after the final dose of TEPMETKO.are breastfeeding or plan to breastfeed. It is not known if TEPMETKO passes into your breast milk. Do not breastfeed during treatment and for week after the final dose of TEPMETKO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take TEPMETKOTake TEPMETKO exactly as your healthcare provider tells you to.Take TEPMETKO time day with food.Swallow TEPMETKO tablets. Do not chew, crush or split tablets.Take your dose of TEPMETKO at about the same time each day.Do not change your dose or stop taking TEPMETKO unless your healthcare provider tells you to.If you miss dose of TEPMETKO, take it as soon as you remember. If your next dose is due within hours, skip the missed dose and take your next dose at your regular scheduled time.If you vomit after taking dose of TEPMETKO, take your next dose at your regular scheduled time.What are the possible side effects of TEPMETKOTEPMETKO may cause serious side effects, including:See What is the most important information should know about TEPMETKO Liver problems. TEPMETKO may cause abnormal liver blood test results. Your healthcare provider will do blood tests to check your liver function before you start treatment and during treatment with TEPMETKO. Tell your healthcare provider right away if you develop any signs and symptoms of liver problems, including:your skin or the white part of your eyes turns yellowdark or tea colored urinelight-colored stools (bowel movements)confusiontirednessloss of appetite for several days or longernausea and vomitingpain, aching, or tenderness on the right side of your stomach-area (abdomen)weaknessswelling in your stomach-areaThe most common side effects of TEPMETKO include:swelling in your face or other parts of your bodytirednessnauseadiarrheamuscle and joint painshortness of breathYour healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TEPMETKO if you develop serious side effects during treatment.These are not all of the possible side effects of TEPMETKO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TEPMETKOStore TEPMETKO at room temperature between 68F to 77F (20C to 25C).TEPMETKO tablets come in blister cards with child-resistant blister foil.Store TEPMETKO in original package.Keep TEPMETKO and all medicines out of the reach of children.General information about the safe and effective use of TEPMETKO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TEPMETKO for condition for which it was not prescribed. Do not give TEPMETKO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TEPMETKO that is written for health professionals.What are the ingredients in TEPMETKOActive ingredient: tepotinibInactive ingredients: mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, and colloidal silicon dioxide.Tablet coating: hypromellose, titanium dioxide, lactose monohydrate, polyethylene glycol, triacetin, and red iron oxides.Manufactured for: EMD Serono, Inc.,Rockland, MA 02370, U.S.A.TEPMETKO is trademark of Merck KGaA, Darmstadt, Germany.For more information, call toll-free 1-844-662-3631 or go to www.TEPMETKO.com.Product of Germany. Lung problems. TEPMETKO may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Tell your healthcare provider right away if you develop any new or worsening symptoms of lung problems, including:trouble breathingshortness of breathcoughfever trouble breathing. shortness of breath. cough. fever. has spread to other parts of the body (metastatic), and. whose tumors have an abnormal mesenchymal epithelial transition (MET) gene. Your healthcare provider will perform test to make sure that TEPMETKO is right for you.. have or have had lung or breathing problems other than your lung cancer. have or have had liver problems. are pregnant or plan to become pregnant. TEPMETKO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider may do pregnancy test before you start treatment with TEPMETKO.You should use effective birth control (contraception) during treatment and for week after the final dose of TEPMETKO. Talk to your healthcare provider 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 week after the final dose of TEPMETKO.. Your healthcare provider may do pregnancy test before you start treatment with TEPMETKO.. You should use effective birth control (contraception) during treatment and for week after the final dose of TEPMETKO. Talk to your healthcare provider about birth control methods that may be right for you.. are breastfeeding or plan to breastfeed. It is not known if TEPMETKO passes into your breast milk. Do not breastfeed during treatment and for week after the final dose of TEPMETKO.. Take TEPMETKO exactly as your healthcare provider tells you to.. Take TEPMETKO time day with food.. Swallow TEPMETKO tablets. Do not chew, crush or split tablets.. Take your dose of TEPMETKO at about the same time each day.. Do not change your dose or stop taking TEPMETKO unless your healthcare provider tells you to.. If you miss dose of TEPMETKO, take it as soon as you remember. If your next dose is due within hours, skip the missed dose and take your next dose at your regular scheduled time.. If you vomit after taking dose of TEPMETKO, take your next dose at your regular scheduled time.. See What is the most important information should know about TEPMETKO Liver problems. TEPMETKO may cause abnormal liver blood test results. Your healthcare provider will do blood tests to check your liver function before you start treatment and during treatment with TEPMETKO. Tell your healthcare provider right away if you develop any signs and symptoms of liver problems, including:. your skin or the white part of your eyes turns yellow. dark or tea colored urine. light-colored stools (bowel movements). confusion. tiredness. loss of appetite for several days or longer. nausea and vomiting. pain, aching, or tenderness on the right side of your stomach-area (abdomen). weakness. swelling in your stomach-area. swelling in your face or other parts of your body. tiredness. nausea. diarrhea. muscle and joint pain. shortness of breath. Store TEPMETKO at room temperature between 68F to 77F (20C to 25C).. TEPMETKO tablets come in blister cards with child-resistant blister foil.. Store TEPMETKO in original package.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], TEPMETKO can cause fetal harm when administered to pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose (see Data). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. 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, occurred at doses >= mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the mg/kg dose level.. 8.2 Lactation. Risk SummaryThere are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breastfed infant or milk production. Advise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose.. 8.3 Females and Males of Reproductive Potential. 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)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TEPMETKO [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose.. MalesAdvise male patients with female partners of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose.. 8.4 Pediatric Use. The safety and efficacy of TEPMETKO in pediatric patients have not been established.. 8.5 Geriatric Use. Of 255 patients with METex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 43% 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.. 8.6 Renal Impairment. 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)]. 8.7 Hepatic Impairment. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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. (2.3, 5.1)Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.2)Embryo-fetal toxicity: TEPMETKO can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. (5.3, 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. (2.3, 5.1). Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. (5.2). Embryo-fetal toxicity: TEPMETKO can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. (5.3, 8.1, 8.3). 5.1Interstitial Lung Disease (ILD)/Pneumonitis. ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 2.2% patients treated with TEPMETKO, with one patient experiencing Grade or higher event; this event resulted in death. Four patients (0.9%) 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 (2.3)]. 5.2Hepatotoxicity. Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with TEPMETKO. Grade or increased ALT/AST occurred in 4.2% of patients. fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Three patients (0.7%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade or higher increased ALT/AST was 30 days (range to 178).Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every weeks during the first months of treatment, then once 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 (2.3)].. 5.3Embryo-Fetal Toxicity. Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to 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 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 final dose. [See Use in Specific Populations (8.1, 8.3)].