CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Capmatinib is kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in protein with missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by mutant MET variant lacking exon 14 at clinically achievable concentrations and demonstrated anti-tumor activity in murine tumor xenograft models derived from human lung tumors with either mutation leading to MET exon 14 skipping or MET amplification. Capmatinib inhibited the phosphorylation of MET triggered by binding of hepatocyte growth factor or by MET amplification, as well as MET-mediated phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells.. 12.2 Pharmacodynamics. Exposure-ResponseCapmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown.Cardiac ElectrophysiologyNo large mean increase in QTc (i.e. 20 ms) was detected following treatment with TABRECTA at the recommended dosage of 400 mg orally twice daily.. 12.3 Pharmacokinetics. Capmatinib exposure (AUC0-12h and Cmax) increased approximately proportionally over dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day following twice daily dosing, with mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).AbsorptionAfter administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (Cmax) were reached in approximately to hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%.Effect of FoodA high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC0-INF by 46% with no change in Cmax compared to under fasted conditions. low-fat meal (containing approximately 300 calories and 20% fat) in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg orally twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.DistributionCapmatinib plasma protein binding is 96%, independent of capmatinib concentration. The apparent mean volume of distribution at steady-state is 164 L.The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.EliminationThe effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).MetabolismCapmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.ExcretionFollowing single oral administration of radiolabeled-capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.Specific PopulationsNo clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification). The effect of severe renal impairment (baseline CLcr 15 to 29 mL/min) on capmatinib pharmacokinetics has not been studied.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesStrong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC0-INF by 42% with no change in capmatinib Cmax.Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%.Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC0-12h by 44% and decrease Cmax by 34%.Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC0-INF by 25% and decreased Cmax by 38%.Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC0-INF by 134% with no change in its Cmax. Coadministration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).P-gp Substrates: Coadministration of capmatinib increased digoxin (a P-gp substrate) AUC0-INF by 47% and increased Cmax by 74%.BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC0-INF by 108% and increased Cmax by 204%.In Vitro StudiesTransporter Systems: Capmatinib is substrate of P-gp, but not substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:ILD/Pneumonitis [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] ILD/Pneumonitis [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] The most common adverse reactions (>= 20%) are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. (6)To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical 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.Metastatic Non-Small Cell Lung CancerThe safety of TABRECTA was evaluated in GEOMETRY mono-1 [see Clinical Studies (14)]. Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N 334). Among patients who received TABRECTA, 31% were exposed for at least months and 16% were exposed for at least one year.Serious adverse reactions occurred in 51% of patients who received TABRECTA. Serious adverse reactions in >= 2% of patients included dyspnea (7%), pneumonia (4.8%), pleural effusion (3.6%), general physical health deterioration (3%), vomiting (2.4%), and nausea (2.1%). fatal adverse reaction occurred in one patient (0.3%) due to pneumonitis.Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 16% of patients. The most frequent adverse reactions (>= 1%) leading to permanent discontinuation of TABRECTA were peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%).Dose interruptions due to an adverse reaction occurred in 54% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in 2% of patients who received TABRECTA included peripheral edema, increased blood creatinine, nausea, vomiting, increased lipase, increased ALT, dyspnea, increased amylase, increased AST, increased blood bilirubin, fatigue, and pneumonia.Dose reductions due to an adverse reaction occurred in 23% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in 2% of patients who received TABRECTA included peripheral edema, increased ALT, increased blood creatinine, and nausea.The most common adverse reactions (>= 20%) in patients who received TABRECTA were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.Table summarizes the adverse reactions in GEOMETRY mono-1.Table 3: Adverse Reactions (>= 10%) in Patients Who Received TABRECTA in GEOMETRY mono-1aOnly includes Grade adverse reactions with exception of dyspnea. Grade dyspnea was reported in 0.6% of patients.bPeripheral edema includes peripheral swelling, peripheral edema, and fluid overload.cFatigue includes fatigue and asthenia.dNon-cardiac chest pain includes chest discomfort, musculoskeletal chest pain, non-cardiac chest pain, and chest pain.ePyrexia includes pyrexia and body temperature increased.Adverse ReactionsTABRECTA(N 334)Grades to 4(%)Grades to 4a (%)General disorders and administration-site conditions Peripheral edemab 529 Fatiguec 328 Non-cardiac chest paind 152.1 Back pain140.9 Pyrexiae 140.6 Weight decreased100.6Gastrointestinal disorders Nausea442.7 Vomiting282.4 Constipation180.9 Diarrhea180.3Respiratory, thoracic, and mediastinal disorders Dyspnea247a Cough160.6Metabolism and nutrition disorders Decreased appetite210.9Clinically relevant adverse reactions occurring in 10% of patients treated with TABRECTA included pruritus (allergic and generalized), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.Table summarizes the laboratory abnormalities in GEOMETRY mono-1.Table 4: Select Laboratory Abnormalities (>= 20%) Worsening from Baseline in Patients Who Received TABRECTA in GEOMETRY mono-1aThe denominator used to calculate the rate varied from 320 to 325 based on the number of patients with baseline value and at least one post-treatment value.Laboratory AbnormalitiesTABRECTAa Grades to 4(%)Grades to 4(%)Chemistry Decreased albumin681.8 Increased creatinine620.3 Increased alanine aminotransferase378 Increased alkaline phosphatase320.3 Increased amylase314.4 Increased gamma-glutamyltransferase297 Increased lipase267 Increased aspartate aminotransferase254.9 Decreased sodium236 Decreased phosphate234.6 Increased potassium233.1 Decreased glucose210.3Hematology Decreased lymphocytes4414 Decreased hemoglobin242.8 Decreased leukocytes230.9.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Metastatic NSCLC with Mutation that Leads to MET Exon 14 SkippingThe efficacy of TABRECTA was evaluated in GEOMETRY mono-1, multicenter, non-randomized, open-label, multi-cohort study (NCT02414139). Eligible patients were required to have NSCLC with mutation that leads to MET exon 14 skipping, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 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.Out of the 97 patients enrolled in GEOMETRY mono-1 following the central confirmation of MET exon 14 skipping by RNA-based clinical trial assay, 78 patient samples were retested with the FDA-approved FoundationOne(R) CDx (22 treatment-naive and 56 previously treated patients) to detect mutations that lead to MET exon 14 skipping. Out of 78 samples retested with FoundationOne(R) CDx, 73 samples were evaluable (20 treatment-naive and 53 previously treated patients), 72 (20 treatment-naive and 52 previously treated patients) of which were confirmed to have mutation that leads to MET exon 14 skipping, demonstrating an estimated positive percentage agreement of 99% (72/73) between the clinical trial assay and the FDA-approved assay.Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) as determined by Blinded Independent Review Committee (BIRC) according to RECIST 1.1. An additional efficacy outcome measure was duration of response (DOR) by BIRC.The efficacy population included 28 treatment-naive patients and 69 previously treated patients. The median age was 71 years (range: 49 to 90 years); 60% female; 75% White; 24% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) and 75% had ECOG PS 1; 60% never smoked; 80% had adenocarcinoma; and 12% had CNS metastases. Amongst previously treated patients, 88% received prior platinum-based chemotherapy.Efficacy results are presented in Table 5.Table 5: Efficacy Results in GEOMETRY mono-1Abbreviations: CI Confidence Interval aBlinded Independent Review Committee (BIRC) review. bConfirmed response. cClopper and Pearson exact binomial 95% CI. dBased on Kaplan-Meier estimate.Efficacy ParametersTreatment-NaiveN 28Previously TreatedN 69Overall Response Ratea,b (95% CI)c 68% (48, 84)41% (29, 53) Complete Response4%0 Partial Response64%41%Duration of Response (DOR)a Median (months) (95% CI)d 12.6 (5.5, 25.3)9.7 (5.5, 13.0) Patients with DOR >= 12 months47%32%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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.Metastatic Non-Small Cell Lung CancerThe safety of TABRECTA was evaluated in GEOMETRY mono-1 [see Clinical Studies (14)]. Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N 334). Among patients who received TABRECTA, 31% were exposed for at least months and 16% were exposed for at least one year.Serious adverse reactions occurred in 51% of patients who received TABRECTA. Serious adverse reactions in >= 2% of patients included dyspnea (7%), pneumonia (4.8%), pleural effusion (3.6%), general physical health deterioration (3%), vomiting (2.4%), and nausea (2.1%). fatal adverse reaction occurred in one patient (0.3%) due to pneumonitis.Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 16% of patients. The most frequent adverse reactions (>= 1%) leading to permanent discontinuation of TABRECTA were peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%).Dose interruptions due to an adverse reaction occurred in 54% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in 2% of patients who received TABRECTA included peripheral edema, increased blood creatinine, nausea, vomiting, increased lipase, increased ALT, dyspnea, increased amylase, increased AST, increased blood bilirubin, fatigue, and pneumonia.Dose reductions due to an adverse reaction occurred in 23% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in 2% of patients who received TABRECTA included peripheral edema, increased ALT, increased blood creatinine, and nausea.The most common adverse reactions (>= 20%) in patients who received TABRECTA were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.Table summarizes the adverse reactions in GEOMETRY mono-1.Table 3: Adverse Reactions (>= 10%) in Patients Who Received TABRECTA in GEOMETRY mono-1aOnly includes Grade adverse reactions with exception of dyspnea. Grade dyspnea was reported in 0.6% of patients.bPeripheral edema includes peripheral swelling, peripheral edema, and fluid overload.cFatigue includes fatigue and asthenia.dNon-cardiac chest pain includes chest discomfort, musculoskeletal chest pain, non-cardiac chest pain, and chest pain.ePyrexia includes pyrexia and body temperature increased.Adverse ReactionsTABRECTA(N 334)Grades to 4(%)Grades to 4a (%)General disorders and administration-site conditions Peripheral edemab 529 Fatiguec 328 Non-cardiac chest paind 152.1 Back pain140.9 Pyrexiae 140.6 Weight decreased100.6Gastrointestinal disorders Nausea442.7 Vomiting282.4 Constipation180.9 Diarrhea180.3Respiratory, thoracic, and mediastinal disorders Dyspnea247a Cough160.6Metabolism and nutrition disorders Decreased appetite210.9Clinically relevant adverse reactions occurring in 10% of patients treated with TABRECTA included pruritus (allergic and generalized), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.Table summarizes the laboratory abnormalities in GEOMETRY mono-1.Table 4: Select Laboratory Abnormalities (>= 20%) Worsening from Baseline in Patients Who Received TABRECTA in GEOMETRY mono-1aThe denominator used to calculate the rate varied from 320 to 325 based on the number of patients with baseline value and at least one post-treatment value.Laboratory AbnormalitiesTABRECTAa Grades to 4(%)Grades to 4(%)Chemistry Decreased albumin681.8 Increased creatinine620.3 Increased alanine aminotransferase378 Increased alkaline phosphatase320.3 Increased amylase314.4 Increased gamma-glutamyltransferase297 Increased lipase267 Increased aspartate aminotransferase254.9 Decreased sodium236 Decreased phosphate234.6 Increased potassium233.1 Decreased glucose210.3Hematology Decreased lymphocytes4414 Decreased hemoglobin242.8 Decreased leukocytes230.9.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Select patients for treatment with TABRECTA based on presence of mutation that leads to MET exon 14 skipping. (2.1)Recommended dosage: 400 mg orally twice daily with or without food. (2.2). Select patients for treatment with TABRECTA based on presence of mutation that leads to MET exon 14 skipping. (2.1). Recommended dosage: 400 mg orally twice daily with or without food. (2.2). 2.1 Patient Selection. Select patients for treatment with TABRECTA based on the presence of mutation that leads to MET exon 14 skipping in tumor or plasma specimens [see Clinical Studies (14)]. If mutation that leads to MET exon 14 skipping is not detected in plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage. The recommended dosage of TABRECTA is 400 mg orally twice daily with or without food.Swallow TABRECTA tablets whole. Do not break, crush or chew the tablets.If patient misses or vomits dose, instruct the patient not to make up the dose, but to take the next dose at its scheduled time.. 2.3 Dosage Modifications for Adverse Reactions. The recommended dose reductions for the management of adverse reactions are listed in Table 1.Table 1: Recommended TABRECTA Dose Reductions for Adverse ReactionsDose ReductionDose and ScheduleFirst300 mg orally twice dailySecond200 mg orally twice dailyPermanently discontinue TABRECTA in patients who are unable to tolerate 200 mg orally twice daily.The recommended dosage modifications of TABRECTA for adverse reactions are provided in Table 2.Table 2: Recommended TABRECTA Dosage Modifications for Adverse ReactionsAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal.Grading according to CTCAE Version 4.03 (CTCAE Common Terminology Criteria for Adverse Events).Adverse ReactionSeverityDosage ModificationInterstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)] Any gradePermanently discontinue TABRECTA.Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2)] Grade 3Withhold TABRECTA until recovery to baseline ALT/AST. If recovered to baseline within days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at reduced dose.Grade 4Permanently discontinue TABRECTA.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 TABRECTA.Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2)] Grade 2Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at reduced dose.Grade 3Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within days, then resume TABRECTA at reduced dose; otherwise permanently discontinue TABRECTA.Grade 4Permanently discontinue TABRECTA.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 2Maintain dose level. If intolerable, consider withholding TABRECTA until resolved, then resume TABRECTA at reduced dose.Grade 3Withhold TABRECTA until resolved, then resume TABRECTA at reduced dose.Grade 4Permanently discontinue TABRECTA.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong and Moderate CYP3A Inducers: Avoid concomitant use. (7.1). 7.1 Effect of Other Drugs on TABRECTA. Strong CYP3A InhibitorsCoadministration of TABRECTA with strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of TABRECTA [see Clinical Pharmacology (12.3)]. Closely monitor patients for adverse reactions during coadministration of TABRECTA with strong CYP3A inhibitors.Strong and Moderate CYP3A InducersCoadministration of TABRECTA with strong CYP3A inducer decreased capmatinib exposure. Coadministration of TABRECTA with moderate CYP3A inducer may also decrease capmatinib exposure. Decreases in capmatinib exposure may decrease TABRECTA anti-tumor activity [see Clinical Pharmacology (12.3)]. Avoid coadministration of TABRECTA with strong and moderate CYP3A inducers.. 7.2 Effect of TABRECTA on Other Drugs. CYP1A2 SubstratesCoadministration of TABRECTA increased the exposure of CYP1A2 substrate, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) SubstratesCoadministration of TABRECTA increased the exposure of P-gp substrate and BCRP substrate, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information.MATE1 and MATE2K SubstratesCoadministration of TABRECTA may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information.

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 risks of severe or fatal ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for 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)].Risk of PhotosensitivityInform patients that there is potential risk of photosensitivity reactions with TABRECTA. Advise patients to limit direct ultraviolet exposure by using sunscreen or protective clothing during treatment with TABRECTA [see Warnings and Precautions (5.3)].Embryo-Fetal ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose [see Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose [see Use in Specific Populations (8.3)].Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].LactationAdvise women not to breastfeed during treatment with TABRECTA and for week after the last dose [see Use in Specific Populations (8.2)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2022-04.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Capmatinib exposure (AUC0-12h and Cmax) increased approximately proportionally over dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day following twice daily dosing, with mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).AbsorptionAfter administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (Cmax) were reached in approximately to hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%.Effect of FoodA high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC0-INF by 46% with no change in Cmax compared to under fasted conditions. low-fat meal (containing approximately 300 calories and 20% fat) in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg orally twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.DistributionCapmatinib plasma protein binding is 96%, independent of capmatinib concentration. The apparent mean volume of distribution at steady-state is 164 L.The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.EliminationThe effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).MetabolismCapmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.ExcretionFollowing single oral administration of radiolabeled-capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.Specific PopulationsNo clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification). The effect of severe renal impairment (baseline CLcr 15 to 29 mL/min) on capmatinib pharmacokinetics has not been studied.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesStrong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC0-INF by 42% with no change in capmatinib Cmax.Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%.Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC0-12h by 44% and decrease Cmax by 34%.Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC0-INF by 25% and decreased Cmax by 38%.Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC0-INF by 134% with no change in its Cmax. Coadministration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).P-gp Substrates: Coadministration of capmatinib increased digoxin (a P-gp substrate) AUC0-INF by 47% and increased Cmax by 74%.BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC0-INF by 108% and increased Cmax by 204%.In Vitro StudiesTransporter Systems: Capmatinib is substrate of P-gp, but not substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TABRECTA can cause fetal harm when administered to pregnant woman. There are no available data on TABRECTA use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice 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.DataAnimal DataIn rats, maternal toxicity (reduced body weight gain and food consumption) occurred at 30 mg/kg/day (approximately 1.4 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of/reduced flexion at the humerus/ulna joints, and narrowed or small tongue) at doses of >= 10 mg/kg/day (approximately 0.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose).In rabbits, no maternal effects were detected at doses up to 60 mg/kg/day (approximately 1.5 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included small lung lobe at >= mg/kg/day (approximately 0.016 times the human exposure based on AUC at the 400 mg twice daily clinical dose), and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations (e.g., abnormal flexure/malrotation of hindpaws/forepaws, thinness of forelimbs/hindlimbs, lack of/reduced flexion at the humerus/ulna joints, small lung lobes, narrowed or small tongue) at the dose of 60 mg/kg/day.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 5/2020PATIENT INFORMATIONTABRECTA(TM) (ta brek tah)(capmatinib) tabletsWhat is TABRECTATABRECTA is prescription medicine used to treat adults with kind of lung cancer called non-small cell lung cancer (NSCLC) that:has spread to other parts of the body or cannot be removed by surgery (metastatic), andwhose tumors have an abnormal mesenchymal epithelial transition (MET) geneIt is not known if TABRECTA is safe and effective in children.Before taking TABRECTA, 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. TABRECTA can harm your unborn baby. Females who are able to become pregnant:Your healthcare provider should do pregnancy test before you start your treatment with TABRECTA.You should use effective birth control during treatment and for week after your last dose of TABRECTA. Talk to your healthcare provider about birth control choices that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TABRECTA. Males who have female partners who can become pregnant: You should use effective birth control during treatment and for week after your last dose of TABRECTA. are breastfeeding or plan to breastfeed. It is not known if TABRECTA passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of TABRECTA.Tell your healthcare provider about all the medicines you take or start taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take TABRECTATake TABRECTA exactly as your healthcare provider tells you.Take TABRECTA times day with or without food.Swallow TABRECTA tablets whole. Do not break, chew, or crush TABRECTA tablets.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TABRECTA if you have certain side effects.Do not change your dose or stop taking TABRECTA unless your healthcare provider tells you to.If you miss or vomit dose of TABRECTA, do not make up the dose. Take your next dose at your regular scheduled time.What should avoid while taking TABRECTAYour skin may be sensitive to the sun (photosensitivity) during treatment with TABRECTA. Use sunscreen or wear clothes that cover your skin during your treatment with TABRECTA to limit direct sunlight exposure.What are the possible side effects of TABRECTATABRECTA may cause serious side effects, including:lung or breathing problems. TABRECTA may cause inflammation of the lungs that can cause death. Tell your healthcare provider right away if you develop any new or worsening symptoms, including: cough fever trouble breathing or shortness of breath Your healthcare provider may temporarily stop or permanently stop treatment with TABRECTA if you develop lung or breathing problems during treatment. liver problems. TABRECTA 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 TABRECTA. 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 (jaundice) 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 Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TABRECTA if you develop liver problems during treatment. risk of sensitivity to sunlight (photosensitivity). See What should avoid while taking TABRECTA The most common side effects of TABRECTA include: oswelling of your hands or feet onausea otiredness and weakness vomiting oloss of appetite ochanges in certain blood testsThese are not all of the possible side effects of TABRECTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TABRECTAStore TABRECTA at room temperature between 68F to 77F (20C to 25C).Store TABRECTA in the original package with the drying agent (desiccant) cartridge.Protect TABRECTA from moisture.Throw away (discard) any unused TABRECTA you have left after weeks of first opening the bottle.Keep TABRECTA and all medicines out of the reach of children.General information about the safe and effective use of TABRECTA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TABRECTA for condition for which it was not prescribed. Do not give TABRECTA 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 TABRECTA that is written for health professionals.What are the ingredients in TABRECTAActive ingredient: capmatinibInactive ingredients: Tablet core: colloidal silicon dioxide; crospovidone; magnesium stearate; mannitol; microcrystalline cellulose; povidone; and sodium lauryl sulfate.Tablet coating (150 mg): ferric oxide, red; ferric oxide, yellow; ferrosoferric oxide; hypromellose; polyethylene glycol (PEG) 4000; talc; and titanium dioxide.Tablet coating (200 mg): ferric oxide, yellow; hypromellose; polyethylene glycol (PEG) 4000; talc; and titanium dioxide.Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936For more information, go to www.TABRECTA.com or call 1-844-638-5864.(C) NovartisT2020-48. has spread to other parts of the body or cannot be removed by surgery (metastatic), and. whose tumors have an abnormal mesenchymal epithelial transition (MET) gene. 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. TABRECTA can harm your unborn baby. Females who are able to become pregnant:Your healthcare provider should do pregnancy test before you start your treatment with TABRECTA.You should use effective birth control during treatment and for week after your last dose of TABRECTA. Talk to your healthcare provider about birth control choices that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TABRECTA. Males who have female partners who can become pregnant: You should use effective birth control during treatment and for week after your last dose of TABRECTA. Your healthcare provider should do pregnancy test before you start your treatment with TABRECTA.. You should use effective birth control during treatment and for week after your last dose of TABRECTA. Talk to your healthcare provider about birth control choices that might be right for you during this time.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TABRECTA.. You should use effective birth control during treatment and for week after your last dose of TABRECTA.. are breastfeeding or plan to breastfeed. It is not known if TABRECTA passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of TABRECTA.. Take TABRECTA exactly as your healthcare provider tells you.. Take TABRECTA times day with or without food.. Swallow TABRECTA tablets whole. Do not break, chew, or crush TABRECTA tablets.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TABRECTA if you have certain side effects.. Do not change your dose or stop taking TABRECTA unless your healthcare provider tells you to.. If you miss or vomit dose of TABRECTA, do not make up the dose. Take your next dose at your regular scheduled time.. Your skin may be sensitive to the sun (photosensitivity) during treatment with TABRECTA. Use sunscreen or wear clothes that cover your skin during your treatment with TABRECTA to limit direct sunlight exposure.. lung or breathing problems. TABRECTA may cause inflammation of the lungs that can cause death. Tell your healthcare provider right away if you develop any new or worsening symptoms, including:. liver problems. TABRECTA 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 TABRECTA. Tell your healthcare provider right away if you develop any signs and symptoms of liver problems, including:. risk of sensitivity to sunlight (photosensitivity). See What should avoid while taking TABRECTA Store TABRECTA at room temperature between 68F to 77F (20C to 25C).. Store TABRECTA in the original package with the drying agent (desiccant) cartridge.. Protect TABRECTA from moisture.. Throw away (discard) any unused TABRECTA you have left after weeks of first opening the bottle.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TABRECTA can cause fetal harm when administered to pregnant woman. There are no available data on TABRECTA use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice 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.DataAnimal DataIn rats, maternal toxicity (reduced body weight gain and food consumption) occurred at 30 mg/kg/day (approximately 1.4 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of/reduced flexion at the humerus/ulna joints, and narrowed or small tongue) at doses of >= 10 mg/kg/day (approximately 0.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose).In rabbits, no maternal effects were detected at doses up to 60 mg/kg/day (approximately 1.5 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included small lung lobe at >= mg/kg/day (approximately 0.016 times the human exposure based on AUC at the 400 mg twice daily clinical dose), and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations (e.g., abnormal flexure/malrotation of hindpaws/forepaws, thinness of forelimbs/hindlimbs, lack of/reduced flexion at the humerus/ulna joints, small lung lobes, narrowed or small tongue) at the dose of 60 mg/kg/day.. 8.2 Lactation. Risk SummaryThere are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TABRECTA and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on animal data, TABRECTA can cause malformations at doses less than the human exposure based on AUC at the 400 mg twice daily clinical dose [see Use in Specific Populations (8.1)].Pregnancy TestingVerify pregnancy status for females of reproductive potential prior to starting treatment with TABRECTA.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose.. 8.4 Pediatric Use. Safety and effectiveness of TABRECTA in pediatric patients have not been established.. 8.5 Geriatric Use. In GEOMETRY mono-1, 57% of the 334 patients were 65 years or older and 16% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.. 8.6 Renal Impairment. No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min) [see Clinical Pharmacology (12.3)]. TABRECTA has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue TABRECTA in patients with ILD/pneumonitis. (2.3, 5.1)Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TABRECTA based on severity. (2.3, 5.2)Risk of Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue TABRECTA in patients with ILD/pneumonitis. (2.3, 5.1). Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TABRECTA based on severity. (2.3, 5.2). Risk of Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). 5.1 Interstitial Lung Disease (ILD)/Pneumonitis. ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 4.5% of patients treated with TABRECTA in GEOMETRY mono-1, with 1.8% of patients experiencing Grade ILD/pneumonitis and one patient experiencing death (0.3%). Eight patients (2.4%) discontinued TABRECTA due to ILD/pneumonitis. The median time-to-onset of Grade or higher ILD/pneumonitis was 1.4 months (range: 0.2 months to 1.2 years).Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TABRECTA 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)].. 5.2 Hepatotoxicity. Hepatotoxicity occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 13% of patients treated with TABRECTA in GEOMETRY mono-1. Grade or increased ALT/AST occurred in 6% of patients. Three patients (0.9%) discontinued TABRECTA due to increased ALT/AST. The median time-to-onset of Grade or higher increased ALT/AST was 1.4 months (range: 0.5 to 4.1 months).Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TABRECTA, 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 TABRECTA [see Dosage and Administration (2.3)].. 5.3 Risk of Photosensitivity. Based on findings from animal studies, there is potential risk of photosensitivity reactions with TABRECTA [see Nonclinical Toxicology (13.2)]. In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure such as use of sunscreen or protective clothing during treatment with TABRECTA. Advise patients to limit direct ultraviolet exposure during treatment with TABRECTA.. 5.4 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, TABRECTA can cause fetal harm when administered to pregnant woman. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at exposures less than the human exposure based on area under the curve (AUC) at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for week after the last dose [see Use in Specific Populations (8.1, 8.3)].