TABRECTA

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)] Pancreatic Toxicity [see Warnings and Precautions (5.3)] Hypersensitivity reactions [see Warnings and Precautions (5.4)] The most common adverse reactions (≥ 20%) are edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, 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 a 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 Cancer The 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 = 373). Among patients who received TABRECTA, 37% were exposed for at least 6 months and 22% were exposed for at least one year. Serious adverse reactions occurred in 53% of patients who received TABRECTA. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), edema (2.4%), and vomiting (2.4%). Fatal adverse reactions occurred in 0.5% of patients who received TABRECTA, including pneumonitis (0.3%) and death, not otherwise specified (0.3%). Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 17% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of TABRECTA were ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%). Dose interruptions due to an adverse reaction occurred in 57% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in > 2% of patients who received TABRECTA included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin. Dose reductions due to an adverse reaction occurred in 26% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in > 2% of patients who received TABRECTA included edema, increased ALT and increased blood creatinine. The most common adverse reactions (≥ 20%) in patients who received TABRECTA were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite. Table 3 summarizes the adverse reactions in GEOMETRY mono-1. Table 3: Adverse Reactions (≥ 10%) in Patients Who Received TABRECTA in GEOMETRY mono-1 a Edema includes edema peripheral, generalized edema, face edema, edema, localized edema, edema genital, eyelid edema, peripheral swelling, scrotal edema, and penile edema. b Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, spinal pain. c Fatigue includes fatigue and asthenia. d Pyrexia includes pyrexia and body temperature increased. e Cough includes cough, upper airway cough syndrome, and productive cough. f Pneumonia includes pneumonia aspiration, pneumonia, pneumonia influenzal, pneumonia bacterial, lower respiratory tract infection, and lung abscess. g Rash includes rash, dermatitis acneiform, rash maculo-papular, eczema, erythema multiforme, rash macular, dermatitis, rash erythematous, rash pustular, dermatitis bullous, and rash vesicular. h Dizziness includes dizziness, vertigo, and vertigo positional. Adverse reactions TABRECTA (N = 373) Grades 1 to 4 (%) Grades 3 to 4 (%) General disorders and administration-site conditions Edema a 59 13 Musculoskeletal pain b 40 4.3 Fatigue c 34 8 Pyrexia d 14 0.8 Weight decreased 11 0.5 Gastrointestinal disorders Nausea 46 2.4 Vomiting 28 2.4 Constipation 19 0.8 Diarrhea 19 0.5 Respiratory, thoracic, and mediastinal disorders Dyspnea 25 7 Cough e 21 0.5 Pneumonia f 13 6 Metabolism and nutrition disorders Decreased appetite 21 1.1 Skin and subcutaneous tissue disorders Rash g 13 0.5 Nervous system disorders Dizziness h 13 0.5 Clinically relevant adverse reactions occurring in < 10% of patients treated with TABRECTA included pruritus (including allergic pruritus), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis. Table 4 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-1 a The denominator used to calculate the rate varied from 359 to 364 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory abnormalities TABRECTA a Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Decreased albumin 72 1.9 Increased creatinine 65 0.5 Increased alanine aminotransferase 39 9 Increased amylase 34 4.7 Increased alkaline phosphatase 32 0.6 Increased gamma-glutamyltransferase 30 6 Increased lipase 29 9 Increased aspartate aminotransferase 28 6 Decreased phosphate 26 4.4 Increased potassium 25 4.1 Decreased sodium 24 6 Decreased glucose 23 0.3 Hematology Decreased lymphocytes 45 14 Decreased leukocytes 25 1.7 Decreased hemoglobin 24 2.8 Other Clinical Trials Experience The following adverse reactions have been reported following administration of TABRECTA: hypersensitivity.

4 CONTRAINDICATIONS None. None.

11 DESCRIPTION Capmatinib is a kinase inhibitor. The chemical name is 2-Fluoro- N -methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2- b ][1,2,4]triazin-2-yl]benzamide—hydrogen chloride—water (1/2/1). The molecular formula for capmatinib dihydrochloride monohydrate is C 23 H 21 Cl 2 FN 6 O 2 . The relative molecular mass is 503.36 g/mol for the dihydrochloride monohydrate salt and 412.43 g/mol for the free base. The chemical structure for capmatinib dihydrochloride monohydrate is shown below: Capmatinib dihydrochloride monohydrate is a yellow powder with a pKa 1 of 0.9 (calculated) and pKa 2 of 4.5 (experimentally). Capmatinib dihydrochloride monohydrate is slightly soluble in acidic aqueous solutions at pH 1 and 2 and of further decreasing solubility towards neutral condition. The log of the distribution coefficient (n-octanol/acetate buffer pH 4.0) is 1.2. TABRECTA is supplied for oral use as ovaloid, curved film-coated tablets with beveled edges, unscored containing 150 mg (pale orange brown color) or 200 mg (yellow color) capmatinib (equivalent to 183.00 mg or 244.00 mg respectively of capmatinib dihydrochloride monohydrate). Each tablet strength contains colloidal silicon dioxide; crospovidone; magnesium stearate; mannitol; microcrystalline cellulose; povidone; and sodium lauryl sulfate as inactive ingredients. The 150 mg tablet coating contains ferric oxide, red; ferric oxide, yellow; ferrosoferric oxide; hypromellose; polyethylene glycol (PEG) 4000; talc; and titanium dioxide. The 200 mg tablet coating contains ferric oxide, yellow; hypromellose; polyethylene glycol (PEG) 4000; talc; and titanium dioxide. capmatinib dihydrochloride monohydrate structural formula

2 DOSAGE AND ADMINISTRATION Select patients for treatment with TABRECTA based on presence of a 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 a mutation that leads to MET exon 14 skipping in tumor or plasma specimens [see Clinical Studies (14)] . If a mutation that leads to MET exon 14 skipping is not detected in a 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 a patient misses or vomits a 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 Reactions Dose reduction Dose and schedule First 300 mg orally twice daily Second 200 mg orally twice daily Permanently 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 Reactions Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Adverse reaction Severity Dosage modification Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)] Any grade Permanently discontinue TABRECTA. Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2)] Grade 3 Withhold TABRECTA until recovery to baseline ALT/AST. If recovered to baseline within 7 days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at a reduced dose. Grade 4 Permanently 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 3 times ULN with total bilirubin greater than 2 times ULN Permanently discontinue TABRECTA. Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2)] Grade 2 Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at a reduced dose. Grade 3 Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TABRECTA at a reduced dose; otherwise permanently discontinue TABRECTA. Grade 4 Permanently discontinue TABRECTA. Increased lipase or amylase [see Warnings and Precautions (5.3)] Grade 3 Withhold TABRECTA until ≤ Grade 2 or baseline. If recovered to baseline or ≤ Grade 2 within 14 days, resume TABRECTA at a reduced dose; otherwise permanently discontinue TABRECTA. Grade 4 Permanently discontinue TABRECTA. Pancreatitis [see Warnings and Precautions (5.3)] Grade 3 or Grade 4 Permanently discontinue TABRECTA. Hypersensitivity [see Warnings and Precautions (5.4)] All Grades If hypersensitivity is suspected based on clinical judgment, withhold TABRECTA until resolution of the event. Permanently discontinue TABRECTA in patients who develop serious hypersensitivity reactions. Other adverse reactions [see Adverse Reactions (6.1)] Grade 2 Maintain dose level. If intolerable, consider withholding TABRECTA until resolved, then resume TABRECTA at a reduced dose. Grade 3 Withhold TABRECTA until resolved, then resume TABRECTA at a reduced dose. Grade 4 Permanently discontinue TABRECTA.

1 INDICATIONS AND USAGE TABRECTA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. TABRECTA is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

7 DRUG INTERACTIONS Strong and Moderate CYP3A Inducers : Avoid concomitant use. ( 7.1 ) 7.1 Effect of Other Drugs on TABRECTA Strong CYP3A Inhibitors Coadministration of TABRECTA with a 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 Inducers Coadministration of TABRECTA with a strong CYP3A inducer decreased capmatinib exposure. Coadministration of TABRECTA with a 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 Substrates Coadministration of TABRECTA increased the exposure of a 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) Substrates Coadministration of TABRECTA increased the exposure of a P-gp substrate and a 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 Substrates Coadministration 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by a 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 a 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-Response Capmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology No 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 (AUC 0-12h and C max ) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%). Absorption After administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (C max ) were reached in approximately 1 to 2 hours (T max ). The absorption of capmatinib after oral administration is estimated to be greater than 70%. Effect of Food A high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC 0-INF by 46% with no change in C max compared to under fasted conditions. A 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 (AUC 0-12h ) was similar after administration of capmatinib with food and under fasted conditions. Distribution Capmatinib 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. Elimination The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%). Metabolism Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase. Excretion Following a 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 Populations No 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 Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC 0-INF by 42% with no change in capmatinib C max . Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC 0-INF by 67% and decreased C max by 56%. Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC 0-12h by 44% and decrease C max by 34%. Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC 0-INF by 25% and decreased C max by 38%. Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC 0-INF by 134% with no change in its C max . 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) AUC 0-INF by 47% and increased C max by 74%. BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC 0-INF by 108% and increased C max by 204%. In Vitro Studies Transporter Systems: Capmatinib is a substrate of P-gp, but not a substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.

12.1 Mechanism of Action Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by a 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 a 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-Response Capmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology No 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 (AUC 0-12h and C max ) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%). Absorption After administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (C max ) were reached in approximately 1 to 2 hours (T max ). The absorption of capmatinib after oral administration is estimated to be greater than 70%. Effect of Food A high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC 0-INF by 46% with no change in C max compared to under fasted conditions. A 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 (AUC 0-12h ) was similar after administration of capmatinib with food and under fasted conditions. Distribution Capmatinib 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. Elimination The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%). Metabolism Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase. Excretion Following a 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 Populations No 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 Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC 0-INF by 42% with no change in capmatinib C max . Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC 0-INF by 67% and decreased C max by 56%. Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC 0-12h by 44% and decrease C max by 34%. Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC 0-INF by 25% and decreased C max by 38%. Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC 0-INF by 134% with no change in its C max . 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) AUC 0-INF by 47% and increased C max by 74%. BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC 0-INF by 108% and increased C max by 204%. In Vitro Studies Transporter Systems: Capmatinib is a substrate of P-gp, but not a substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.

20230712

10

3 DOSAGE FORMS AND STRENGTHS Tablets: 150 mg: pale orange brown, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘DU’ on one side and ‘NVR’ on the other side 200 mg: yellow, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘LO’ on one side and ‘NVR’ on the other side Tablets: 150 mg and 200 mg

TABRECTA capmatinib CAPMATINIB HYDROCHLORIDE CAPMATINIB SILICON DIOXIDE CROSPOVIDONE MAGNESIUM STEARATE MANNITOL CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM LAURYL SULFATE FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE HYPROMELLOSES POLYETHYLENE GLYCOL 400 TALC TITANIUM DIOXIDE Pale orange brown ovaloid, curved DU;NVR TABRECTA capmatinib CAPMATINIB HYDROCHLORIDE CAPMATINIB SILICON DIOXIDE CROSPOVIDONE MAGNESIUM STEARATE MANNITOL CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM LAURYL SULFATE FERRIC OXIDE YELLOW HYPROMELLOSES POLYETHYLENE GLYCOL 400 TALC TITANIUM DIOXIDE ovaloid, curved LO;NVR

13.2 Animal Toxicology and/or Pharmacology In rats, capmatinib administration resulted in vacuolation of white matter of the brain in both 4- and 13-week studies at doses ≥ 2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose. In some cases, the brain lesions were associated with early death and/or convulsions or tremors. Concentrations of capmatinib in the brain tissue of rats was approximately 9% of the corresponding concentrations in plasma. In vitro and in vivo assays demonstrated that capmatinib has some potential for photosensitization; however, the no-observed-adverse-effect level for in vivo photosensitization was 30 mg/kg/day (C max of 14000 ng/mL), about 2.9 times the human C max at the 400 mg twice daily clinical dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were not conducted with capmatinib. Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats. Dedicated fertility studies were not conducted with capmatinib. No effects on male and female reproductive organs occurred in general toxicology studies conducted in rats and monkeys at doses resulting in exposures of up to approximately 3.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were not conducted with capmatinib. Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats. Dedicated fertility studies were not conducted with capmatinib. No effects on male and female reproductive organs occurred in general toxicology studies conducted in rats and monkeys at doses resulting in exposures of up to approximately 3.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose. 13.2 Animal Toxicology and/or Pharmacology In rats, capmatinib administration resulted in vacuolation of white matter of the brain in both 4- and 13-week studies at doses ≥ 2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose. In some cases, the brain lesions were associated with early death and/or convulsions or tremors. Concentrations of capmatinib in the brain tissue of rats was approximately 9% of the corresponding concentrations in plasma. In vitro and in vivo assays demonstrated that capmatinib has some potential for photosensitization; however, the no-observed-adverse-effect level for in vivo photosensitization was 30 mg/kg/day (C max of 14000 ng/mL), about 2.9 times the human C max at the 400 mg twice daily clinical dose.

NDA213591

TABRECTA

capmatinib

0078-0716

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 0078-0709-56 TABRECTA ® (capmatinib) tablets 150 mg * Attention: Dispense and store Tabrecta in original container with the desiccant to protect from moisture. Rx only 56 Film-coated tablets NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0709-56 TABRECTA® (capmatinib) tablets 150 mg* Attention: Dispense and store Tabrecta in original container with the desiccant to protect from moisture. Rx only 56 Film-coated tablets NOVARTIS

Indications and Usage ( 1 ) 8/2022 Dosage and Administration ( 2.3 ) 3/2023 Warnings and Precautions, Pancreatic Toxicity ( 5.3 ) 8/2022 Warnings and Precautions, Hypersensitivity Reactions ( 5.4 ) 3/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Interstitial Lung Disease (ILD)/Pneumonitis Inform 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)] . Hepatotoxicity Inform 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)] . Pancreatic Toxicity Inform patients that they will need to undergo lab tests to monitor pancreatic function. Advise patients to immediately contact their healthcare provider for signs and symptoms of pancreatitis [see Warnings and Precautions (5.3)] . Hypersensitivity Reactions Inform patients that there is a risk of hypersensitivity reactions with TABRECTA. Advise patients to stop taking TABRECTA and immediately contact their healthcare provider for signs and symptoms of hypersensitivity [see Warnings and Precautions (5.4)] . Risk of Photosensitivity Inform patients that there is a 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 (5.5)] . Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 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 1 week after the last dose [see Use in Specific Populations (8.3)] . Drug Interactions Advise 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)] . Lactation Advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose [see Use in Specific Populations (8.2)] . Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2023-15

14 CLINICAL STUDIES Metastatic NSCLC with a Mutation that Leads to MET Exon 14 Skipping The efficacy of TABRECTA was evaluated in GEOMETRY mono-1, a multicenter, non-randomized, open-label, multi-cohort study (NCT02414139). Eligible patients were required to have NSCLC with a 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 first 97 patients enrolled in GEOMETRY mono-1 following the central confirmation of MET exon 14 skipping by a RNA-based clinical trial assay, 78 patient samples were retested with the FDA-approved FoundationOne ® CDx (22 treatment-naïve and 56 previously treated patients) to detect mutations that lead to MET exon 14 skipping. Out of 78 samples retested with FoundationOne ® CDx, 73 samples were evaluable (20 treatment-naïve and 53 previously treated patients), 72 (20 treatment-naïve and 52 previously treated patients) of which were confirmed to have a 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 a 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 60 treatment-naïve patients and 100 previously treated patients. The median age was 71 years (range: 48 to 90 years); 61% female; 77% White; 25% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 74% had ECOG PS 1; 61% never smoked; 83% had adenocarcinoma; and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy. Efficacy results are presented in Table 5. Table 5: Efficacy Results for Treatment-Naïve and Previously Treated Patients in GEOMETRY mono-1 Abbreviations: CI, confidence interval; NE, not estimable. a Blinded Independent Review Committee (BIRC) review. b Confirmed response. c Clopper and Pearson exact binomial 95% CI. d Based on Kaplan-Meier estimate. Efficacy parameters Treatment-Naïve N = 60 Previously treated N = 100 Overall response rate a,b (95% CI) c 68% (55, 80) 44% (34, 54) Complete response 5% 0 Partial response 63% 44% Duration of response (DOR) a Median (months) (95% CI) d 16.6 (8.4, 22.1) 9.7 (5.6, 13.0) Patients % with DOR ≥ 12 months 49% 36%

8.5 Geriatric Use In GEOMETRY mono-1, 61% of the 373 patients were 65 years or older and 18% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.

8.4 Pediatric Use Safety and effectiveness of TABRECTA in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] , TABRECTA can cause fetal harm when administered to a 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 a 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 Data In 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 ≥ 5 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 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] , TABRECTA can cause fetal harm when administered to a 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 a 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 Data In 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 ≥ 5 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 Summary There 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 1 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 Testing Verify pregnancy status for females of reproductive potential prior to starting treatment with TABRECTA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 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, 61% of the 373 patients were 65 years or older and 18% 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).

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied TABRECTA (capmatinib) 150 mg and 200 mg tablets Strength Description Tablets per bottle NDC number 150 mg Pale orange brown, ovaloid, curved film-coated tablet with beveled edges, unscored, debossed with ‘DU’ on one side and ‘NVR’ on the other side. 56 0078-0709-56 200 mg Yellow, ovaloid, curved film-coated tablet with beveled edges, unscored, debossed with ‘LO’ on one side and ‘NVR’ on the other side. 56 0078-0716-56 Storage Dispense in the original package with the desiccant cartridge. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Discard any unused TABRECTA remaining after 6 weeks of first opening the bottle.