PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Repeat daily dosing of cabozantinib capsule formulation for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to single dose administration; steady state was achieved by Day 15.AbsorptionMedian time to peak cabozantinib concentrations (Tmax) ranged from to hours post-dose. 19% increase in the Cmax of CABOMETYX compared to cabozantinib capsule formulation was observed following single 140 mg dose. less than 10% difference in the AUC was observed between CABOMETYX and cabozantinib capsule formulation [see Dosage and Administration (2.1)].Food EffectCabozantinib Cmax and AUC increased by 41% and 57%, respectively, following high-fat meal relative to fasted conditions in healthy subjects administered single oral dose of cabozantinib capsule formulation.DistributionThe oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma (>= 99.7%).EliminationThe predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.MetabolismCabozantinib is substrate of CYP3A4 in vitro.ExcretionApproximately 81% of the total administered radioactivity was recovered within 48-day collection period following single dose of radiolabeled 14C-cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following 72-hour collection.Specific PopulationsThe following patient characteristics did not result in clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR >= 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with eGFR 29 mL/min/1.73m2 as estimated by MDRD equation or requiring dialysis.Pediatric PatientsThe systemic exposures to cabozantinib in pediatric patients 12 years and older at the recommended dosages are expected to be comparable to the exposure in adults at the dose of CABOMETYX 60 mg once daily.Patients with Hepatic ImpairmentBased on population pharmacokinetic analysis of cabozantinib in healthy subjects and patients with cancer, no clinically significant differences in the mean cabozantinib exposure were observed between subjects with normal liver function (total bilirubin and AST <= ULN) and those with mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5x ULN and any AST value). In dedicated pharmacokinetic study, cabozantinib exposure (AUC0-INF) increased by 63% in patients with moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment have not been studied [see Dosage and Administration (2.8), Use in Specific Populations (8.6)].Drug Interaction StudiesClinical StudiesCYP3A4 Inhibitors:Administration of strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), with cabozantinib capsule formulation to healthy subjects increased single-dose cabozantinib exposure (AUC0-INF) by 38%.CYP3A4 Inducers:Administration of strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), with cabozantinib capsule formulation to healthy subjects decreased single-dose cabozantinib exposure (AUC0-INF) by 77%.CYP2C8 Substrates:No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) exposure (Cmax and AUC) was observed when co-administered with cabozantinib capsule formulation at steady-state concentrations.Gastric Acid Reducing Agents:No clinically-significant effect on cabozantinib exposure (AUC) was observed following co- administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for days) with single 100 mg dose of cabozantinib capsule formulation to healthy subjects.In vitro StudiesCYP Enzymes:Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by 80%. Inhibition of CYP2C9 had minimal effect on cabozantinib metabolite formation (i.e., <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.Although cabozantinib is an inhibitor of CYP2C8 in vitro, clinical study of this potential interaction concluded that concurrent use did not result in clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in clinical study, because, although clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.Transporters:Cabozantinib is an inhibitor, but not substrate, of P-gp transport activities and has the potential to increase concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.Cabozantinib is substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase concentrations of cabozantinib. The clinical relevance of this finding is unknown.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed elsewhere in the labeling:Hemorrhage [see Warnings and Precautions (5.1)] Perforations and Fistulas [see Warnings and Precautions (5.2)] Thrombotic Events [see Warnings and Precautions (5.3)] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4)] Diarrhea [see Warnings and Precautions (5.5)] Palmar-plantar Erythrodysesthesia [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7) ]Adrenal Insufficiency [see Warnings and Precautions (5.8) ]Proteinuria [see Warnings and Precautions (5.9)] Osteonecrosis of the Jaw [see Warnings and Precautions (5.10)] Impaired Wound Healing [see Warnings and Precautions (5.11)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.12)] Thyroid Dysfunction [see Warnings and Precautions (5.13)] Hypocalcemia [see Warnings and Precautions (5.14)] Hemorrhage [see Warnings and Precautions (5.1)] Perforations and Fistulas [see Warnings and Precautions (5.2)] Thrombotic Events [see Warnings and Precautions (5.3)] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4)] Diarrhea [see Warnings and Precautions (5.5)] Palmar-plantar Erythrodysesthesia [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7) ]. Adrenal Insufficiency [see Warnings and Precautions (5.8) ]. Proteinuria [see Warnings and Precautions (5.9)] Osteonecrosis of the Jaw [see Warnings and Precautions (5.10)] Impaired Wound Healing [see Warnings and Precautions (5.11)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.12)] Thyroid Dysfunction [see Warnings and Precautions (5.13)] Hypocalcemia [see Warnings and Precautions (5.14)] The most common (>= 20%) adverse reactions are:as single agent: diarrhea, fatigue, PPE, decreased appetite,hypertension, nausea, vomiting, weight decreased, constipation. (6.1)in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE,stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. as single agent: diarrhea, fatigue, PPE, decreased appetite,hypertension, nausea, vomiting, weight decreased, constipation. (6.1). in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE,stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1). 6.1 Clinical Trial Experience. The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to CABOMETYX as single agent in 409 patients with RCC enrolled in randomized, active-controlled trials (CABOSUN, METEOR), 467 patients with HCC enrolled in randomized, placebo-controlled trial (CELESTIAL), and 125 patients with DTC enrolled in randomized, placebo-controlled trial (COSMIC-311), and in combination with nivolumab 240 mg/m2 every weeks in 320 patients with RCC enrolled in randomized, active-controlled trial (CHECKMATE-9ER).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.Renal Cell CarcinomaMETEORThe safety of CABOMETYX was evaluated in METEOR, randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 mg once daily and 322 patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator [see Clinical Studies (14)]. The median duration of treatment was 7.6 months (range 0.3 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 18.9) for patients receiving everolimus.Adverse reactions which occurred in >= 25% of CABOMETYX-treated patients, in order of decreasing frequency, were: diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia (PPE), hypertension, vomiting, weight decreased, and constipation. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in >= 5% of patients were hypertension, diarrhea, fatigue, PPE, hyponatremia, hypophosphatemia, hypomagnesemia, lymphopenia, anemia, hypokalemia, and increased GGT.The dose was reduced in 60% of patients receiving CABOMETYX and in 24% of patients receiving everolimus. Twenty percent (20%) of patients received CABOMETYX 20 mg once daily as their lowest dose. The most frequent adverse reactions leading to dose reduction in patients treated with CABOMETYX were: diarrhea, PPE, fatigue, and hypertension. Adverse reactions leading to dose interruption occurred in 70% patients receiving CABOMETYX and in 59% patients receiving everolimus. Adverse reactions led to study treatment discontinuation in 10% of patients receiving CABOMETYX and in 10% of patients receiving everolimus. The most frequent adverse reactions leading to permanent discontinuation in patients treated with CABOMETYX were decreased appetite (2%) and fatigue (1%).Table 5. Adverse Reactions Occurring in >= 10% Patients Who Received CABOMETYX in METEOR Adverse ReactionCABOMETYX (n=331)One subject randomized to everolimus received cabozantinib. Everolimus (n=322)All GradesNational Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Grades 3-4All Grades Grades 3-4Percentage (%) of Patients Gastrointestinal Diarrhea7411282 Nausea50428<1 Vomiting32214<1 Stomatitis222242 Constipation25<119<1 Abdominal painIncludes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower 234132 Dyspepsia12<150 General Fatigue569477 Mucosal inflammation19<1233 Asthenia194162 Metabolism and Nutrition Decreased appetite46334<1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia4286<1 RashIncludes the following terms: rash, rash erythematous, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, genital rash, intermittent leg rash, rash on scrotum and penis, rash maculo- papular, rash pruritic, contact dermatitis, dermatitis acneiform 23<143<1 Dry skin110100 Vascular HypertensionIncludes the following terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation 391683 Investigations Weight decreased312120 Nervous System Dysgeusia24090 Headache11<112<1 Dizziness11070 Endocrine Hypothyroidism210<1<1 Respiratory, Thoracic, and Mediastinal Dysphonia20<140 Dyspnea193294 Cough18<133<1 Blood and Lymphatic Anemia1753816 Musculoskeletal and Connective Tissue Pain in extremity1418<1 Muscle spasms13050 Arthralgia11<1141 Renal and Urinary Proteinuria1229<1Other clinically important adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis cholestatic (<1%).Table 6. Laboratory Abnormalities Occurring in >= 25% Patients Who Received CABOMETYX in METEOR Laboratory AbnormalityCABOMETYX (n=331)Everolimus (n=322)All GradesGrade 3-4All GradesGrade 3-4Percentage (%) of Patients Chemistry Increased AST74340<1 Increased ALT68332<1 Increased creatinine58<1710 Increased triglycerides5347313 Hypophosphatemia488365 Hyperglycemia372598 Hypoalbuminemia36228<1 Increased ALP352291 Hypomagnesemia3174<1 Hyponatremia308266 Increased GGT275439 Hematology Leukopenia35<131<1 Neutropenia31217<1 AnemiaBased on laboratory abnormalities 3147117 Lymphopenia2573912 Thrombocytopenia25<127<1 ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase. NCI CTCAE, Version 4.0CABOSUNThe safety of CABOMETYX was evaluated in CABOSUN, randomized, open-label trial in patients with advanced renal cell carcinoma, in which 78 patients received CABOMETYX60 mg once daily and 72 patients received sunitinib 50 mg once daily (4 weeks on treatment followed by weeks off), until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. The median duration of treatment was 6.5 months (range 0.2 28.7) for patients receiving CABOMETYX and 3.1 months (range 0.2 25.5) for patients receiving sunitinib.Within 30 days of treatment, there were deaths in patients treated with CABOMETYX and deaths in patients treated with sunitinib. Of the patients treated with CABOMETYX, patients died due to gastrointestinal perforation, patient had acute renal failure, and patient died due to clinical deterioration. All Grade 3-4 adverse reactions were collected in the entire safety population. The most frequent Grade 3-4 adverse reactions (>=5%) in patients treated with CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope.The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced in 46% of patients receiving CABOMETYX and in 35% of patients receiving sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in 71% of patients receiving sunitinib. Based on patient disposition, 21% of patients receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to an adverse reaction.Table 7. Grade 3-4 Adverse Reactions Occurring in >= 1% Patients Who Received CABOMETYX in CABOSUN Adverse ReactionCABOMETYX(n 78)Sunitinib(n 72)Grade 3-4NCI CTCAE Version 4.0 Grade 3-4 Percentage (%) of Patients Patients with any Grade 3-4 Adverse Reaction6865 Gastrointestinal Diarrhea1011 Stomatitis56 Nausea34 Vomiting13 Constipation10 General Fatigue617 Pain50 Metabolism and Nutrition HyponatremiaLaboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values 98 Hypophosphatemia 97 Decreased appetite51 Dehydration41 Hypocalcemia 30 Hypomagnesemia 30 Hypokalemia 13 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia84 Skin Ulcer30 Vascular Hypertensionncludes the following term: hypertension 2821 Hypotension51 Angiopathy11 Investigations Increased ALT 50 Weight decreased40 Increased AST 33 Increased blood creatinine 33 Lymphopenia 16 Thrombocytopenia 111 Nervous System Syncope50 Respiratory, Thoracic, and Mediastinal Dyspnea16 Dysphonia10 Blood and Lymphatic Anemia13 Psychiatric Depression40 Confusional state11 Infections Lung Infection40 Musculoskelatal and Connective Tissue Back pain40 Bone pain31 Pain in extremity30 Arthralgia10 Renal and Urinary Renal failure acute41 Proteinuria31 ALT, alanine aminotransferase; AST, aspartate aminotransferaseCHECKMATE-9ERThe safety of CABOMETYX with nivolumab was evaluated in CHECKMATE-9ER, randomized, open-label study in patients with previously untreated advanced RCC [see Clinical Studies (14.1)]. Patients received CABOMETYX 40 mg orally once daily with nivolumab 240 mg over 30 minutes every weeks (n=320) or sunitinib 50 mg daily, administered orally for weeks on treatment followed by weeks off (n=320) [see Clinical Studies (14.1)]. CABOMETYX could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in CABOMETYX and nivolumab-treated patients. In this trial, 82% of patients in the CABOMETYX and nivolumab arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.Serious adverse reactions occurred in 48% of patients receiving CABOMETYX and nivolumab. The most frequent (>=2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in (0.9%) patients.Adverse reactions leading to discontinuation of either CABOMETYX or nivolumab occurred in 20% of patients: 8% CABOMETYX only, 7% nivolumab only, and 6% both drugs due to the same adverse reaction at the same time. Adverse reactions leading to dose interruption or reduction of either CABOMETYX or nivolumab occurred in 83% of patients: 46% CABOMETYX only, 3% nivolumab only, and 21% both drugs due to the same adverse reaction at the same time, and 6% both drugs sequentially.The most common adverse reactions reported in >=20% of patients treated with CABOMETYX and nivolumab were diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.Table 8. Adverse Reactions in >15% of Patients Receiving CABOMETYX and Nivolumab CHECKMATE-9ER Adverse ReactionCABOMETYX and Nivolumab(n=320)Sunitinib(n=320)Grades 1-4Grades 3-4Grades 1-4Grades 3-4Percentage (%) of Patients Gastrointestinal Diarrhea647474.4 Nausea270.6310.3 Abdominal painIncludes abdominal discomfort, abdominal pain lower, abdominal pain upper. 221.9150.3 Vomiting171.9210.3 DyspepsiaIncludes gastroesophageal reflux disease. 150220.3 General FatigueIncludes asthenia. 518508 Hepatobiliary HepatotoxicityIncludes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. 4411265 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia408418 StomatitisIncludes mucosal inflammation, aphthous ulcer, mouth ulceration. 373.4464.4 RashIncludes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. 363.1140 Pruritus190.34.40 Vascular HypertensionIncludes blood pressure increased, blood pressure systolic increased. 36133914 Endocrine HypothyroidismIncludes primary hypothyroidism. 340.3300.3 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. 333.8293.1 Arthralgia180.390.3 Metabolism and Nutrition Decreased appetite281.9201.3 Nervous System Disorders Dysgeusia240220 Headache160120.6 Respiratory, Thoracic and Mediastinal CoughIncludes productive cough. 200.3170 Dysphonia170.33.40 Infections and Infestations Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinitis. 200.380.3 Toxicity was graded per NCI CTCAE v4.Table 9. Laboratory Values Worsening from BaselineEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: CABOMETYX and nivolumab group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). Occurring in >20% of Patients Receiving CABOMETYX and Nivolumab CHECKMATE-9ER Laboratory AbnormalityCABOMETYX andNivolumabSunitinibGrades 1-4Grades 3-4Grades 1-4Grades 3-4Percentage (%) of Patients Chemistry Increased ALT799.8393.5 Increased AST777.9572.6 Hypophosphatemia69284810 Hypocalcemia541.9240.6 Hypomagnesemia471.3250.3 Hyperglycemia443.5441.7 Hyponatremia43113612 Increased lipase41143813 Increased amylase4110286 Increased alkaline phosphatase412.8371.6 Increased creatinine391.3420.6 Hyperkalemia354.7271 Hypoglycemia260.8140.4 Hematology Lymphopenia426.64510 Thrombocytopenia410.3709.7 Anemia372.5614.8 Leukopenia370.3665.1 Neutropenia353.26712Hepatocellular CarcinomaThe safety of CABOMETYX was evaluated in CELESTIAL, randomized, double-blind, placebo-controlled trial in which 704 patients with advanced hepatocellular carcinoma were randomized to receive CABOMETYX 60 mg orally once daily (n=467) or placebo (n=237) until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. The median duration of treatment was 3.8 months (range 0.1 37.3) for patients receiving CABOMETYX and 2.0 months (range 0.0 27.2) for patients receiving placebo. The population exposed to CABOMETYX was 81% male, 56% White, and had median age of 64 years.Adverse reactions occurring in >= 25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, decreased appetite, PPE, fatigue, nausea, hypertension, and vomiting. Grade 3-4 adverse reactions which occurred in >= 5% of patients were PPE, hypertension, fatigue, diarrhea, asthenia, and decreased appetite. There were adverse reactions leading to death in patients receiving CABOMETYX (hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, upper gastrointestinal hemorrhage).The median average daily dose was 35.8 mg for CABOMETYX. The dose was reduced in 62% of patients receiving CABOMETYX; 33% of patients required reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leading to dose reduction of CABOMETYX were: PPE, diarrhea, fatigue, hypertension, and increased AST. Adverse reactions leading to dose interruption occurred in 84% patients receiving CABOMETYX. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 16% of patients. The most frequent adverse reactions leading to permanent discontinuation of CABOMETYX were PPE (2%), fatigue (2%), decreased appetite (1%), diarrhea (1%), and nausea (1%).Table 10. Adverse Reactions Occurring in >= 5% of CABOMETYX-Treated Patients in CELESTIALIncludes terms with between-arm difference of >= 5% (all grades) or >= 2% (Grade 3-4) Adverse ReactionCABOMETYX (n=467)Placebo (n=237)All GradesNCI CTCAE Version 4.0 Grade 3-4All Grades Grade 3-4Percentage (%) of Patients Gastrointestinal Diarrhea5410192 Nausea312182 Vomiting26<1123 Stomatitis13220 Dyspepsia10030 General Fatigue4510304 Asthenia22782 Mucosal inflammation1422<1 Metabolism and Nutrition Decreased appetite48618<1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia461750 RashIncludes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculo- papular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected 2129<1 Vascular HypertensionIncludes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased 301662 Investigations Weight decreased17160 Nervous System Dysgeusia12020 Endocrine Hypothyroidism8<1<10 Respiratory, Thoracic, and Mediastinal Dysphonia19120 Dyspnea12310<1 Musculoskeletal and Connective Tissue Pain in extremity9<141 Muscle spasms8<120Table 11. Laboratory Abnormalities Occurring in >= 5% of CABOMETYX-Treated Patients in CELESTIALIncludes laboratory abnormalities with between-arm difference of >= 5% (all grades) or >= 2% (Grade 3-4) Laboratory AbnormalityCABOMETYX (n=467)Placebo (n=237)All GradesGrade 3-4All GradesGrade 3-4Percentage (%) of Patients Chemistry Increased LDH849292 Increased ALT7312376 Increased AST73244619 Hypoalbuminemia511321 Increased ALP438386 Hypophosphatemia25984 Hypokalemia23661 Hypomagnesemia22330 Increased amylase16292 Hypocalcemia8200 Hematology Decreased platelets5410161 Neutropenia43781 Increased hemoglobin8010 ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, blood lactate dehydrogenaseDifferentiated Thyroid CancerThe safety of CABOMETYX was evaluated in COSMIC-311, randomized, double-blind, placebo-controlled trial in which 187 patients with advanced differentiated thyroid cancer were randomized to receive CABOMETYX 60 mg orally once daily (n=125) or placebo (n=62) with supportive care until disease progression or unacceptable toxicity [see Clinical Studies (14.3)]. At the time of the primary efficacy analysis, the median duration of treatment was 4.4 months (range 0.0 15.7) for patients receiving CABOMETYX and 2.3 months (range 0.3 11.6) for patients receiving placebo. The median age was 66 years (range 32 to 85 years), 55% were female, 70% were White, 18% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib.Adverse reactions occurring in >= 25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, PPE, fatigue, hypertension, and stomatitis. Grade 3-4 adverse reactions which occurred in >= 5% of patients were PPE, hypertension, fatigue, diarrhea, and stomatitis. Serious adverse reactions occurred in 34% of patients who received CABOMETYX. Serious adverse reactions in >=2% included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal adverse reactions occurred in 1.6% of patients in the CABOMETYX arm, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%).The median average daily dose was 42.0 mg for CABOMETYX. The dose was reduced in 56% of patients receiving CABOMETYX; 22% of patients required second dose reduction. The most frequent adverse reactions (>=5%) leading to dose reduction of CABOMETYX were PPE, diarrhea, fatigue, proteinuria, and decreased appetite. Dose interruptions occurred in 72% patients receiving CABOMETYX. Adverse reactions requiring dosage interruption in >=5% of patients were PPE, diarrhea, dyspnea, hypertension, decreased appetite and proteinuria. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 5% of patients.Table 12. Adverse Reactions Occurring in >=5% of CABOMETYX-Treated Patients in COSMIC-311Includes terms that are more frequent in the CABOMETYX arm and have between-arm difference of >= 5% (all grades) or >= 2% (Grade 3-4) Adverse ReactionCABOMETYX (N=125)Placebo (N=62)All GradesNCI CTCAE Version 5.0 Grade 3-4All Grades Grade 3-4Percentage of PatientsGastrointestinal Diarrhea51730 Nausea24320 Vomiting14180 StomatitisIncludes the following terms: mucosal inflammation, stomatitis 26530 Dry mouth10120General FatigueIncludes the following terms: fatigue, asthenia 4210230Metabolism and Nutrition Decreased appetite233160Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia461000Vascular HypertensionIncludes the following terms: hypertension, blood pressure increased, hypertensive crisis 301053Investigations Weight decreased18150Nervous System Dysgeusia10000 Headache10220Respiratory, Thoracic, and Mediastinal Dysphonia10020 Pulmonary embolism5200Renal and Urinary Proteinuria15130Table 13. Laboratory Abnormalities Occurring in >= 10% of CABOMETYX-Treated Patients in COSMIC-311Includes laboratory abnormalities that are more frequent in the CABOMETYX arm and have between-arm difference of >= 5% (all grades) or >= 2% (Grade 3-4) Laboratory AbnormalityCABOMETYX (N=125)Placebo (N=62)All GradesGrade 3-4All GradesGrade 3-4Percentage of PatientsChemistry LDH increasedSponsor-defined grades for LDH were as follows: Grade (> ULN to <= x ULN), Grade (> x ULN to <= x ULN), Grade (> x ULN). 9010323 AST increased771180 ALT increased662110 Hypocalcemia369102 ALP increased340150 GGT increased262212 Hypomagnesemia25250 Hypoalbuminemia19170 Hypokalemia18130 Hyponatremia150102 Hyperbilirubinemia12050Hematology Leukocytes decreased38272 Neutrophils decreased31252 Platelets decreased26050 ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; LDH, blood lactate dehydrogenase. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of CABOMETYX. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.. 12.2 Pharmacodynamics. The exposure-response or -safety relationship for cabozantinib is unknown.Cardiac ElectrophysiologyThe effect of cabozantinib on QTc interval was evaluated in randomized, double-blinded, placebo-controlled trial in patients with medullary thyroid cancer administered cabozantinib capsule formulation. mean increase in QTcF of 10 15 ms was observed at weeks after initiation. concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No patients in this study had confirmed QTcF 500 ms nor did any patients in METEOR, CABOSUN, CELESTIAL, or CHECKMATE-9ER, or COSMIC-311.. 12.3 Pharmacokinetics. Repeat daily dosing of cabozantinib capsule formulation for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to single dose administration; steady state was achieved by Day 15.AbsorptionMedian time to peak cabozantinib concentrations (Tmax) ranged from to hours post-dose. 19% increase in the Cmax of CABOMETYX compared to cabozantinib capsule formulation was observed following single 140 mg dose. less than 10% difference in the AUC was observed between CABOMETYX and cabozantinib capsule formulation [see Dosage and Administration (2.1)].Food EffectCabozantinib Cmax and AUC increased by 41% and 57%, respectively, following high-fat meal relative to fasted conditions in healthy subjects administered single oral dose of cabozantinib capsule formulation.DistributionThe oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma (>= 99.7%).EliminationThe predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.MetabolismCabozantinib is substrate of CYP3A4 in vitro.ExcretionApproximately 81% of the total administered radioactivity was recovered within 48-day collection period following single dose of radiolabeled 14C-cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following 72-hour collection.Specific PopulationsThe following patient characteristics did not result in clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR >= 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with eGFR 29 mL/min/1.73m2 as estimated by MDRD equation or requiring dialysis.Pediatric PatientsThe systemic exposures to cabozantinib in pediatric patients 12 years and older at the recommended dosages are expected to be comparable to the exposure in adults at the dose of CABOMETYX 60 mg once daily.Patients with Hepatic ImpairmentBased on population pharmacokinetic analysis of cabozantinib in healthy subjects and patients with cancer, no clinically significant differences in the mean cabozantinib exposure were observed between subjects with normal liver function (total bilirubin and AST <= ULN) and those with mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5x ULN and any AST value). In dedicated pharmacokinetic study, cabozantinib exposure (AUC0-INF) increased by 63% in patients with moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment have not been studied [see Dosage and Administration (2.8), Use in Specific Populations (8.6)].Drug Interaction StudiesClinical StudiesCYP3A4 Inhibitors:Administration of strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), with cabozantinib capsule formulation to healthy subjects increased single-dose cabozantinib exposure (AUC0-INF) by 38%.CYP3A4 Inducers:Administration of strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), with cabozantinib capsule formulation to healthy subjects decreased single-dose cabozantinib exposure (AUC0-INF) by 77%.CYP2C8 Substrates:No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) exposure (Cmax and AUC) was observed when co-administered with cabozantinib capsule formulation at steady-state concentrations.Gastric Acid Reducing Agents:No clinically-significant effect on cabozantinib exposure (AUC) was observed following co- administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for days) with single 100 mg dose of cabozantinib capsule formulation to healthy subjects.In vitro StudiesCYP Enzymes:Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by 80%. Inhibition of CYP2C9 had minimal effect on cabozantinib metabolite formation (i.e., <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.Although cabozantinib is an inhibitor of CYP2C8 in vitro, clinical study of this potential interaction concluded that concurrent use did not result in clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in clinical study, because, although clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.Transporters:Cabozantinib is an inhibitor, but not substrate, of P-gp transport activities and has the potential to increase concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.Cabozantinib is substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase concentrations of cabozantinib. The clinical relevance of this finding is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Renal Cell Carcinoma. Previously Treated with Anti-angiogenic TherapyThe efficacy of CABOMETYX was evaluated in METEOR (NCT01865747), randomized (1:1), open-label, multicenter trial of CABOMETYX versus everolimus conducted in patients with advanced RCC who had received at least prior anti-angiogenic therapy. Patients had to have Karnofsky Performance Score (KPS) >= 70%. Patients were stratified by the number of prior VEGFR tyrosine kinase inhibitors (TKIs) and Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group.Patients were randomized to receive CABOMETYX (N=330) 60 mg orally once daily or everolimus (N=328) 10 mg orally once daily. The majority of the patients were male (75%), with median age of 62 years. Sixty-nine percent (69%) received only one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 46% favorable (0 risk factors), 42% intermediate (1 risk factor), and 13% poor (2 or risk factors). Fifty-four percent (54%) of patients had or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%).The main efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent radiology review committee among the first 375 subjects randomized. Other efficacy endpoints were objective response rate (ORR) and overall survival (OS) in the Intent-to- Treat (ITT) population. Tumor assessments were conducted every weeks for the first 12 months, then every 12 weeks thereafter. Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator.Statistically significant improvements in PFS, OS, and ORR were demonstrated for CABOMETYX compared to everolimus. Efficacy results are presented in Tables 14 and 15 and Figures and 2.Table 14: Efficacy Results in METEOR (First 375 Randomized) EndpointCABOMETYXEverolimusN 187N 188 Median PFS (95% CI), months7.4 (5.6, 9.1)3.8 (3.7, 5.4) HR (95% CI), p-valuestratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs vs or 3) as stratification factors (per IVRS data) 0.58 (0.45, 0.74), p<0.0001Figure 1: Kaplan-Meier Curves of Progression-Free Survival in METEOR (First 375 Randomized)Table 15: Efficacy Results in METEOR (ITT) EndpointCABOMETYXEverolimusN 330N 328 Median OS (95% CI), months21.4 (18.7, NE)16.5 (14.7, 18.8) HR (95% CI), p-valuestratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs vs or 3) as stratification factors (per IVRS data) 0.66 (0.53, 0.83), p=0.0003 Confirmed ORR (partial responses only) (95% CI)17% (13%, 22%)3% (2%, 6%) p-valuechi-squared test p<0.0001Figure 2: Kaplan-Meier Curve of Overall Survival in METEOR (ITT)First-line TreatmentCABOSUNThe efficacy of CABOMETYX was evaluated in CABOSUN (NCT01835158), randomized (1:1), open-label, multicenter trial of CABOMETYX versus sunitinib conducted in patients with advanced RCC who had not received prior therapy. Patients were randomized to receive CABOMETYX (N=79) 60 mg orally once daily or sunitinib (N=78) 50 mg orally once daily(4 weeks on treatment followed by weeks off) until disease progression or unacceptable toxicity. All patients were required to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no).The majority of patients were male (78%), with median age of 63 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (>=3 risk factors). Thirty-six percent (36%) patients had bone metastases. Forty-six percent (46%) of patients were ECOG 0, 41% ECOG 1, and 13% ECOG 2.The major efficacy outcome measure was progression-free survival (PFS) by retrospective blinded independent radiology review committee (BIRC).A statistically significant improvement in PFS, as assessed by blinded independent radiology review committee, was demonstrated for CABOMETYX compared to sunitinib. Efficacy results are presented in Table 16, Figure 3, and Figure 4.Table 16: Efficacy Results in CABOSUN EndpointCABOMETYXSunitinibN 79N 78 Progression-Free Survivalas assessed by retrospective blinded independent radiology review committee (BIRC) Events, n(%)43 (54)49 (63) Median PFS (95% CI), months 8.6 (6.8, 14.0)5.3 (3.0, 8.2) Hazard Ratioestimated from stratified Cox proportional hazards model with stratification factors IMDC risk group and presence of bone metastases and treatment as covariate (95% CI), p-valuetwo-sided stratified log-rank test with stratification factors IMDC risk group and presence of bone metastases 0.48 (0.31, 0.74), p=0.0008 Overall Survival Events, n(%)43 (54)47 (60) Hazard Ratio no multiplicity adjustments were made for overall survival or ORR (95% CI)0.80 (0.53, 1.21) Confirmed ORR, partial responses only (95% CI) 20% (12.0, 30.8)9% (3.7, 17.6)Figure 3: Kaplan-Meier Curve of Progression-Free Survival in CABOSUNFigure 4: Kaplan-Meier Curve of Overall Survival in CABOSUNCHECKMATE-9ERCHECKMATE-9ER (NCT03141177) was randomized, open-label study of CABOMETYX combined with nivolumab versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (>=1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).Patients were randomized to CABOMETYX 40mg orally daily and nivolumab 240mg intravenously every weeks (n=323), or sunitinib 50 mg orally daily for the first weeks of 6-week cycle (4 weeks on treatment followed by weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST- defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every weeks until Week 60, and then every 12 weeks thereafter.The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% >=65 years of age and 10% >=75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated statistically significant improvement in PFS, OS, and ORR for patients randomized to CABOMETYX and nivolumab compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. Efficacy results are shown in Table 17 and Figures and 6.Table 17: Efficacy Results in CHECKMATE-9ERCABOMETYX andNivolumab(n=323)Sunitinib(n=328)Progression-free Survival Disease progression or deaths (%)144 (45)191 (58) Median PFS (months)Based on Kaplan-Meier estimates. (95% CI)16.6 (12.5, 24.9)8.3 (7.0, 9.7) Hazard ratio (95% CI)Stratified Cox proportional hazards model. 0.51 (0.41, 0.64) p-valueBased on stratified log-rank test 2-sided p-values from stratified log-rank test. <0.0001Overall Survival Deaths (%)67 (21)99 (30) Median OS (months) (95% CI)NRNot Reached NR (22.6, NR) Hazard ratio (95% CI) 0.60 (0.40, 0.89) p-value , p-value is compared with the allocated alpha of 0.0111 for this interim analysis. 0.0010Confirmed Objective Response Rate (95% CI)CI based on the Clopper and Pearson method. 55.7% (50.1, 61.2)27.1% (22.4, 32.3) p-value2-sided p-value from Cochran-Mantel-Haenszel test. <0.0001 Complete Response (CR)26 (8%)15 (4.6%) Partial Response (PR)154 (48%)74 (23%) Median duration of response in months (95% CI) 20.2 (17.3, NR)11.5 (8.3, 18.4)Figure 5: Kaplan-Meier Curve of Progression-Free Survival in CHECKMATE-9ERFigure 6: Kaplan-Meier Curve of Overall Survival in CHECKMATE-9ER. 14.2 Hepatocellular Carcinoma. The efficacy of CABOMETYX was evaluated in CELESTIAL (NCT01908426), randomized (2:1), double-blind, placebo-controlled, multicenter trial in patients with hepatocellular carcinoma (HCC) who had previously received sorafenib and had Child Pugh Class liver impairment. Patients were randomized to receive CABOMETYX 60 mg orally once daily or placebo until disease progression or unacceptable toxicity. Randomization was stratified by etiology of disease (hepatitis virus [HBV] with or without hepatitis virus [HCV] vs. HCV [without HBV] vs. other [without HBV and HCV]), geographic region (Asia vs. other regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (yes vs. no). The primary efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and objective response rate (ORR), as assessed by investigators per RECIST 1.1. Tumor assessments were conducted every weeks.In CELESTIAL, total of 707 patients were randomized, 470 to CABOMETYX and 237 to placebo. The median age was 64 years (range 22 to 86 years), 82% were male, 56% were White and 34% were Asian. Baseline ECOG performance status was (53%) or (47%). The etiology of HCC was attributed to HBV in 38% of patients and HCV in 21%; etiology was attributed to causes other than HBV or HCV in 40%. Macroscopic vascular invasion or extra-hepatic tumor spread was present in 78% of patients and 41% had alpha-fetoprotein (AFP) levels >= 400 mcg/L. All patients received prior sorafenib and 27% received two prior systemic therapy regimens.Efficacy results are summarized in Table 18, Figure 7, and Figure 8.Table 18: Efficacy Results from CELESTIAL EndpointCABOMETYXPlaceboN 470N 237 Overall Survival Number of Deaths, (%)317 (67)167 (70) Median OS in Months (95% CI)10.2 (9.1, 12.0)8.0 (6.8, 9.4) Hazard Ratio (95% CI)estimated using the Cox proportional-hazard model 0.76 (0.63, 0.92) p-valuelog-rank test stratified by etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other), geographic region (Asia, Other Regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data) p=0.0049significance level 0.021 for 78% information (484 deaths) based on OBrien-Fleming method Progression-Free Survival Number of Events, (%)349 (74)205 (86) Progressive Disease284 (60)186 (78) Death65 (14)19 (8) Median PFS in Months (95% CI)5.2 (4.0, 5.5)1.9 (1.9, 1.9) Hazard Ratio (95% CI) 0.44 (0.36, 0.52) p-value p< 0.0001 Overall Response Rate (ORR) Confirmed ORR (partial responses only) (95% CI) 4% (2.3, 6.0)0.4% (0.0, 2.3) p-valueFishers exact test p=0.0086Figure 7: Kaplan-Meier Curve of Overall Survival in CELESTIALFigure 8: Kaplan-Meier Curve of Progression-Free Survival in CELESTIAL. 14.3 Differentiated Thyroid Cancer. The efficacy of CABOMETYX was evaluated in COSMIC-311 (NCT03690388), randomized (2:1), double-blind, placebo-controlled, multicenter trial in patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that had progressed following prior VEGFR-targeted therapy and were radioactive iodine-refractory or ineligible. Patients were randomized to receive CABOMETYX 60 mg orally once daily or placebo with supportive care until disease progression or unacceptable toxicity. Randomization was stratified by prior receipt of lenvatinib (yes vs. no) and age (<= 65 years vs 65 years). Eligible patients randomized to placebo were allowed to cross-over to CABOMETYX upon confirmation of progressive disease by blinded independent radiology review committee (BIRC). The multiple primary efficacy outcome measures were progression-free survival (PFS) in the ITT population, and overall response rate (ORR) in the first 100 randomized patients, as assessed by BIRC per RECIST 1.1. Tumor assessments were conducted every weeks. Overall survival (OS) was descriptive outcome measure.The primary analysis of PFS included 187 randomized patients. An updated analysis of PFS was performed and included 258 randomized patients. The median age was 65 years (range 31 to 85 years), 53% were female, 70% were White, 19% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib. Baseline ECOG performance status was (46%) or (54%) and 93% of patients had metastatic disease.The trial demonstrated statistically significant improvement in PFS, while it failed to demonstrate statistically significant improvement in ORR, for patients randomized to CABOMETYX compared with placebo. Efficacy results are summarized in Table 19 and Figure 9.Table 19: Efficacy Results from COSMIC-311Primary AnalysisUpdated AnalysisNo formal statistical testing was conducted at the time of the updated analysis CABOMETYX(n=125)Placebo(n=62)CABOMETYX(n=170)Placebo(n=88)Progression-Free SurvivalNumber of Events, (%)31 (25)43 (69)62 (36)69 (78)Median PFS in Months(95% CI)NR (5.7, NE)1.9 (1.8, 3.6)11.0 (7.4, 13.8)1.9 (1.9, 3.7)Hazard Ratio (95% CI)Estimated using the Cox proportional-hazard model 0.22 (0.14, 0.35)0.22 (0.15, 0.31)p-valueLog-rank test stratified by receipt of prior lenvatinib (yes vs no) and age (<= 65 years vs 65 years) 0.0001Overall Response Rate (95% CI) Overall Response, (95% CI)All responses were partial responses The analysis population overall response rate was the first 100 randomized patients (67 in the CABOMETYX arm, and 33 in the placebo arm) 15% (7%, 26%)0% (0.0%, 11%)18% (10%, 29%)0% (0.0%, 11%) p-valueFishers exact test compared to an alpha boundary of 0.01 0.0281 CI, confidence interval; NR, not reached; NE, not evaluableFigure 9: Kaplan-Meier Curve of Progression-Free Survival in COSMIC-311 (Updated Analysis, N=258).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Stop treatment with CABOMETYX at least weeks prior to scheduled surgery, including dental surgery (2.1)Do NOT substitute CABOMETYX tablets with cabozantinib capsules (2.1)Recommended Dose:60 mg orally, once daily. (2.2, 2.3)40 mg orally, once daily, in pediatric patients with BSA less than 1.2 m2 (2.4)40 mg orally, once daily, administered in combination with nivolumab 240 mg every weeks or 480 mg every weeks (2.2) Administer at least hour before or at least hours after eating. (2.1). Stop treatment with CABOMETYX at least weeks prior to scheduled surgery, including dental surgery (2.1). Do NOT substitute CABOMETYX tablets with cabozantinib capsules (2.1). Recommended Dose:60 mg orally, once daily. (2.2, 2.3)40 mg orally, once daily, in pediatric patients with BSA less than 1.2 m2 (2.4)40 mg orally, once daily, administered in combination with nivolumab 240 mg every weeks or 480 mg every weeks (2.2) 60 mg orally, once daily. (2.2, 2.3). 40 mg orally, once daily, in pediatric patients with BSA less than 1.2 m2 (2.4). 40 mg orally, once daily, administered in combination with nivolumab 240 mg every weeks or 480 mg every weeks (2.2). Administer at least hour before or at least hours after eating. (2.1). 2.1 Important Dosage Information. Stop treatment with CABOMETYX at least weeks prior to scheduled surgery, including dental surgery [see Warnings and Precautions (5.1, 5.10, 5.11)].Do not substitute CABOMETYX tablets with cabozantinib capsules.. Stop treatment with CABOMETYX at least weeks prior to scheduled surgery, including dental surgery [see Warnings and Precautions (5.1, 5.10, 5.11)].. Do not substitute CABOMETYX tablets with cabozantinib capsules.. 2.2 Recommended Dosage for Renal Cell Carcinoma. The recommended dosage of CABOMETYX as single agent is 60 mg once daily until disease progression or unacceptable toxicity administered as recommended [see Dosage and Administration (2.9)].The recommended dosage of CABOMETYX in combination with nivolumab is provided in the following table:Table 1. Recommended Dosage of CABOMETYX in Combination with NivolumabRecommended DosageDuration of TherapyCABOMETYX 40 mg once daily without fooduntil disease progression or unacceptable toxicityNivolumab 240 mg every weeks (30-minute intravenous infusion) or 480 mg every weeks (30- minute intravenous infusion)until disease progression or unacceptable toxicity for up to years. 2.3 Recommended Dosage for Hepatocellular Carcinoma The recommended dosage of CABOMETYX as single agent is 60 mg once daily until disease progression or unacceptable toxicity administered as recommended [see Dosage and Administration (2.9)]. 2.4 Recommended Dosage for Differentiated Thyroid Cancer The recommended dosage of CABOMETYX as single agent for adult and pediatric patients 12 years of age and older with BSA greater than or equal to 1.2 m2 is 60 mg once daily until disease progression or unacceptable toxicity administered as recommended [see Dosage and Administration (2.9), Clinical Pharmacology (12.3) ]. The recommended dosage of CABOMETYX as single agent in pediatric patients 12 years of age and older with BSA less than 1.2 m2 is 40 mg once daily until disease progression or unacceptable toxicity administered as recommended [see [see Dosage and Administration (2.9), Clinical Pharmacology (12.3) ]. 2.5 Dosage Modifications for Adverse Reactions. Withhold CABOMETYX for:Intolerable Grade adverse reactionsGrade or adverse reactionsOsteonecrosis of the jawUpon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows:Table 2. Recommended Dosage Reductions for CABOMETYX for Adverse ReactionsRecommended DosageFirst Dosage Reduction ToSecond Dosage Reduction ToCABOMETYX 60 mg daily in adult and pediatric patients with BSA greater than or equal to 1.2 m2 40 mg daily20 mg dailyIf previously receiving lowest dose, resume at same dose. If lowest dose not tolerated, discontinue CABOMETYX. CABOMETYX 40 mg daily in pediatric patients with BSA less than 1.2 m2 20 mg daily20 mg every other day CABOMETYX 40 mg daily in combination with nivolumab20 mg daily20 mg every other day Table 3. Recommended Dosage Modifications for CABOMETYX Adverse ReactionsAdverse ReactionSeverityGraded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) CABOMETYX Dosage ModificationHemorrhage [see Warnings and Precautions (5.1)] Grade or 4Permanently discontinue CABOMETYXPerforations and Fistulas [see Warnings and Precautions (5.2)] Any grade gastrointestinal perforation or Grade fistulaPermanently discontinue CABOMETYXThrombotic Events [see Warnings and Precautions (5.3)] Any grade acute myocardial infarction or Grade or higher cerebral infarction or Grade or arterial thromboembolic events or Grade venous thromboembolic eventsPermanently discontinue CABOMETYXHypertension and Hypertensive Crisis [see Warnings and Precautions (5.4)] Grade 3Withhold CABOMETYX until hypertension is adequately controlled to <=Grade 2Resume at reduced dosePermanently discontinue CABOMETYX for hypertension that cannot be controlledGrade 4Permanently discontinue CABOMETYXDiarrhea [see Warnings and Precautions (5.5)] Grade 2, Grade, or Grade 4Withhold CABOMETYX until <=Grade 1Resume at reduced dosePalmar-Plantar Erythrodysesthesia [see Warnings and Precautions (5.6)] Intolerable Grade or Grade 3Withhold CABOMETYX until <=Grade 1Resume at reduced doseProteinuria [see Warnings and Precautions (5.9)] Grade or 3Withhold CABOMETYX until improvement to <= Grade proteinuriaResume at reduced dosePermanently discontinue CABOMETYX for nephrotic syndromeOsteonecrosis of the jaw (ONJ) [see Warnings and Precautions (5.10)] Any gradeWithhold CABOMETYX for development of ONJ until complete resolutionResume at reduced doseReversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.12)] Any gradePermanently discontinue CABOMETYXOther Adverse Reactions [see Adverse Reactions (6.1)] Intolerable Grade 2, or Grade 3, or Grade 4Withhold CABOMETYX until improvement to baseline or <=Grade 1Resume at reduced doseThe following table represents dosage modifications for the drug administered in combination that are different from those described above for CABOMETYX or in the Full Prescribing Information:Table 4. Recommended Specific Dosage Modifications for Hepatic Adverse Reactions for CombinationCABOMETYX in combination with nivolumabALT or AST >3 times ULN but <=10 times ULN with concurrent total bilirubin <2 times ULNWithholdConsider corticosteroid therapy for hepatic adverse reactions if CABOMETYX is withheld or discontinued when administered in combination with nivolumab both CABOMETYX and nivolumab until adverse reactions recoverAfter recovery, rechallenge with one or both of CABOMETYX and nivolumab may be considered. If rechallenging with nivolumab with or without CABOMETYX, refer to nivolumab Prescribing Information. to Grades or 1ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin >=2 times ULNPermanently discontinue both CABOMETYX and nivolumabWhen administering CABOMETYX in combination with nivolumab for the treatment of advanced RCC, refer to the nivolumab prescribing information.. Intolerable Grade adverse reactions. Grade or adverse reactions. Osteonecrosis of the jaw. Permanently discontinue CABOMETYX. Permanently discontinue CABOMETYX. Permanently discontinue CABOMETYX. Withhold CABOMETYX until hypertension is adequately controlled to <=Grade 2. Resume at reduced dose. Permanently discontinue CABOMETYX for hypertension that cannot be controlled. Permanently discontinue CABOMETYX. Withhold CABOMETYX until <=Grade 1. Resume at reduced dose. Withhold CABOMETYX until <=Grade 1. Resume at reduced dose. Withhold CABOMETYX until improvement to <= Grade proteinuria. Resume at reduced dose. Permanently discontinue CABOMETYX for nephrotic syndrome. Withhold CABOMETYX for development of ONJ until complete resolution. Resume at reduced dose. Permanently discontinue CABOMETYX. Withhold CABOMETYX until improvement to baseline or <=Grade 1. Resume at reduced dose. 2.6 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors. Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily or from 20 mg daily to 20 mg every other day in pediatric patients with BSA less than 1.2 m2). Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor to days after discontinuation of the strong inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 2.7 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. Resume the dose that was used prior to initiating the strong CYP3A4 inducer to days after discontinuation of the strong inducer. Do not exceed daily dose of 80 mg [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 2.8 Dosage Modifications for Patients with Moderate and Severe Hepatic Impairment Reduce the starting dose of CABOMETYX 60 mg daily to 40 mg daily or 40 mg daily to 20 mg daily (for pediatric patients with BSA less than 1.2 m2) in patients with moderate hepatic impairment (Child-Pugh B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 2.9 Administration Do not administer CABOMETYX with food. Administer at least hour before or at least hours after eating [see Clinical Pharmacology (12.3)]. Swallow CABOMETYX tablets whole. Do not crush CABOMETYX tablets.Do not take missed dose within 12 hours of the next dose.Modify the CABOMETYX dose for patients taking drugs known to strongly induce or inhibit CYP3A4 and for patients with moderate hepatic impairment [see Dosage and Administration (2.6, 2.7, 2.8)].. Swallow CABOMETYX tablets whole. Do not crush CABOMETYX tablets.. Do not take missed dose within 12 hours of the next dose.. Modify the CABOMETYX dose for patients taking drugs known to strongly induce or inhibit CYP3A4 and for patients with moderate hepatic impairment [see Dosage and Administration (2.6, 2.7, 2.8)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.1)].Perforations and fistulas: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during CABOMETYX treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking CABOMETYX [see Warnings and Precautions (5.2)].Thrombotic Events: Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs [see Warnings and Precautions (5.3)].Hypertension and hypertensive crisis: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4)].Diarrhea: Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements [see Warnings and Precautions (5.5)].Palmar-plantar erythrodysesthesia: Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.6)].Hepatotoxicity: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.7)].Adrenal insufficiency: Advise patients receiving with nivolumab to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency [see Warnings and Precautions (5.8)].Proteinuria: Advise patients to contact their healthcare provider for signs or symptoms of proteinuria [see Warnings and Precautions (5.9)].Osteonecrosis of the jaw: Advise patients regarding good oral hygiene practices. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.10)].Impaired wound healing: Advise patients that CABOMETYX may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Dosage and Administration (2.1), Warnings and Precautions (5.11)].Reversible posterior leukoencephalopathy syndrome: Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.12)].Thyroid dysfunction: Advise patients that CABOMETYX can cause thyroid dysfunction and that their thyroid function should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of thyroid dysfunction [see Warnings and Precautions (5.13)].Hypocalcemia: Advise patients that CABOMETYX can cause low calcium levels and that their serum calcium levels should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of hypocalcemia [see Warnings and Precautions (5.14)].Embryo-fetal toxicity:Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for months after the final dose [Use in Specific Populations (8.3)].Lactation: Advise women not to breastfeed during treatment with CABOMETYX and for months following the last dose [Use in Specific Populations (8.2)].Drug interactions: Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. Johns wort [see Drug Interactions (7.1)].Important administration informationInstruct patients to take CABOMETYX at least hour before or at least 2hours after eating.Manufactured for Exelixis, Inc. Alameda, CA 94502. Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.1)].. Perforations and fistulas: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during CABOMETYX treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking CABOMETYX [see Warnings and Precautions (5.2)].. Thrombotic Events: Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs [see Warnings and Precautions (5.3)].. Hypertension and hypertensive crisis: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4)].. Diarrhea: Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements [see Warnings and Precautions (5.5)].. Palmar-plantar erythrodysesthesia: Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.6)].. Hepatotoxicity: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.7)].. Adrenal insufficiency: Advise patients receiving with nivolumab to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency [see Warnings and Precautions (5.8)].. Proteinuria: Advise patients to contact their healthcare provider for signs or symptoms of proteinuria [see Warnings and Precautions (5.9)].. Osteonecrosis of the jaw: Advise patients regarding good oral hygiene practices. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.10)].. Impaired wound healing: Advise patients that CABOMETYX may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Dosage and Administration (2.1), Warnings and Precautions (5.11)].. Reversible posterior leukoencephalopathy syndrome: Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.12)].. Thyroid dysfunction: Advise patients that CABOMETYX can cause thyroid dysfunction and that their thyroid function should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of thyroid dysfunction [see Warnings and Precautions (5.13)].. Hypocalcemia: Advise patients that CABOMETYX can cause low calcium levels and that their serum calcium levels should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of hypocalcemia [see Warnings and Precautions (5.14)].. Embryo-fetal toxicity:Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for months after the final dose [Use in Specific Populations (8.3)].. Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for months after the final dose [Use in Specific Populations (8.3)].. Lactation: Advise women not to breastfeed during treatment with CABOMETYX and for months following the last dose [Use in Specific Populations (8.2)].. Drug interactions: Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. Johns wort [see Drug Interactions (7.1)].. Instruct patients to take CABOMETYX at least hour before or at least 2hours after eating.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONCABOMETYX(R) (Ka-boe-met-iks)cabozantinib tabletsIf your healthcare provider prescribes CABOMETYX in combination with nivolumab, also read the Medication Guide that comes with nivolumab.What is CABOMETYXCABOMETYX is prescription medicine used to treat:people with advanced kidney cancer (renal cell carcinoma). CABOMETYX may be used:alone to treat people with renal cell carcinoma (RCC) that has spread (advanced RCC).in combination with nivolumab when your cancer has spread (advanced RCC), and you have notalready had treatment for your advanced RCC. people with liver cancer (hepatocellular carcinoma) who have been previously treated with themedicine sorafenib.adults and children 12 years of age and older who have type of thyroid cancer called differentiated thyroid cancer (DTC), that has spread (locally advanced or metastatic), and,has progressed after treatment with VEGFR-targeted treatment, and your DTC can no longer be treated with radioactive iodine, or you are not able to receiveradioactive iodine treatment It is not known if CABOMETYX is safe and effective in children younger than 12 years of age.Before you take CABOMETYX, tell your healthcare provider about all of your medical conditions, including if you:have had liver problem other than liver cancerhave recent history of bleeding, including coughing up or vomiting blood, or black tarry stools.have an open or healing woundhave high blood pressurehave low calcium level in your blood (hypocalcemia)plan to have any surgery, dental procedure, or have had recent surgery. You should stop taking CABOMETYX at least weeks before planned surgery. See What are the possible side effects of CABOMETYXare pregnant, or plan to become pregnant. CABOMETYX can harm your unborn baby.If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOMETYX.Females who are able to become pregnant should use effective birth control (contraception) during treatment and for months after your final dose of CABOMETYX.Talk to your healthcare provider about birth control methods that may be right for you.If you become pregnant or think you are pregnant, tell your healthcare provider right away. are breastfeeding or plan to breastfeed. It is not known if CABOMETYX passes into your breast milk. Do not breastfeed during treatment and for months after your final dose of CABOMETYX. Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. CABOMETYX and certain other medicines may affect each other causing side effects.How should take CABOMETYXTake CABOMETYX exactly as your healthcare provider tells you to take it.Do not take CABOMETYX with food. Take CABOMETYX at least hour before or at least hours after eating.Swallow CABOMETYX tablets whole.Do not crush CABOMETYX tablets.If you miss dose and your next scheduled dose is in:less than 12 hours, take your next dose at the normal time. Do not make up the missed dose. What should avoid while taking CABOMETYXAvoid drinking grapefruit juice, eating grapefruit or taking supplements that contain grapefruit or St. Johns wort during treatment with CABOMETYX.What are the possible side effects of CABOMETYXCABOMETYX may cause serious side effects, including:bleeding (hemorrhage). CABOMETYX can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with CABOMETYX, including:coughing up blood or blood clotsvomiting blood or if your vomit looks like coffee-groundsred or black (looks like tar) stoolsmenstrual bleeding that is heavier than normalany unusual or heavy bleeding tear in your stomach or intestinal wall (perforation) or an abnormal connection between parts of your body (fistula). Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:swelling or pain in your arms or legs shortness of breathfeel lightheaded or faintsweating more than usualnumbness or weakness of your face, arm or leg, especially on one side of your bodysudden confusion, trouble speaking or understandingsudden trouble seeing in one or both eyessudden trouble walkingdizziness, loss of balance or coordinationa sudden severe headache high blood pressure (hypertension). Hypertension is common with CABOMETYX and sometimes can be severe. Your healthcare provider will check your blood pressure before starting CABOMETYX and regularly during treatment with CABOMETYX. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.diarrhea. Diarrhea is common with CABOMETYX and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.a skin problem called hand-foot skin reaction. Hand-foot skin reactions are common with CABOMETYX and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.liver problems. Liver problems may happen during treatment with CABOMETYX. When CABOMETYX is taken in combination with nivolumab, severe changes in liver function tests may happen more often than if you take CABOMETYX alone. Your healthcare provider will do blood tests to check your liver function before and during treatment with CABOMETYX. Tell your healthcare provider right away if you develop symptoms of liver problems including: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach-area (abdomen), dark urine, bleeding or bruising more easily than normal.adrenal gland problems. Your healthcare provider will monitor you for this problem. Your healthcare provider may prescribe hormone replacement therapy or corticosteroid medicines if needed. Tell your healthcare provider right away if you develop any of the following signs or symptoms: extreme tiredness, dizziness or fainting, weakness, nausea, or vomiting.protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet. Your healthcare provider will check you for this problem during treatment with CABOMETYX.severe jaw bone problems (osteonecrosis). Your healthcare provider should examine your mouth before you start and during treatment with CABOMETYX. Tell your dentist that you are taking CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX. Tell your healthcare provider right away if you develop any symptoms of jaw problems, including: jaw pain, toothache, or sores on your gums.wound healing problems. Wound healing problems have happened in some people who take CABOMETYX. Tell your healthcare provider if you plan to have any surgery before or during treatment with CABOMETYX.You should stop taking CABOMETYX at least weeks before planned surgery.Your healthcare provider should tell you when you may start taking CABOMETYX again after surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with CABOMETYX. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.change in thyroid function. CABOMETYX can cause changes in your thyroid function, including changes to thyroid hormone levels in your blood. Your healthcare provider will do blood tests to check your thyroid function before and during treatment with CABOMETYX.decreased calcium level in your blood (hypocalcemia). CABOMETYX can cause you to have decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. Tell your healthcare provider right away if you get any of the following signs or symptoms:muscle stiffness or muscle spasmsnumbness or tingling in your fingers, toes, or around your mouthseizuressudden weight gainswelling of your arms, hands, legs, and anklesYour healthcare provider may change your dose, temporarily stop, or permanently stop treatment with CABOMETYX if you have certain side effects.The most common side effects of CABOMETYX include:tirednessdecreased appetitenausea and vomitingweight lossconstipationThe most common side effects of CABOMETYX when used in combination with nivolumab include:tirednessmouth soresrashlow thyroid hormone levels (hypothyroidism)pain in muscles, bones, and jointsdecreased appetitenauseachanges in the way things tastestomach-area (abdominal) paincoughupper respiratory tract infectionCABOMETYX may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.These are not all of the possible side effects of CABOMETYX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store CABOMETYXStore CABOMETYX at room temperature between 68F to 77F (20C to 25C).Keep CABOMETYX and all medicines out of the reach of children.General information about the safe and effective use of CABOMETYX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use CABOMETYX for condition for which it was not prescribed. Do not give CABOMETYX 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 CABOMETYX that is written for health professionals.What are the ingredients in CABOMETYXActive ingredient: cabozantinib Inactive ingredients: microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow. Manufactured for Exelixis, Inc. Alameda, CA 94502For more information, go to www.cabometyx.com or call 1-855-292-3935.This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 09/2021. people with advanced kidney cancer (renal cell carcinoma). CABOMETYX may be used:alone to treat people with renal cell carcinoma (RCC) that has spread (advanced RCC).in combination with nivolumab when your cancer has spread (advanced RCC), and you have notalready had treatment for your advanced RCC. alone to treat people with renal cell carcinoma (RCC) that has spread (advanced RCC).. in combination with nivolumab when your cancer has spread (advanced RCC), and you have notalready had treatment for your advanced RCC.. people with liver cancer (hepatocellular carcinoma) who have been previously treated with themedicine sorafenib.. adults and children 12 years of age and older who have type of thyroid cancer called differentiated thyroid cancer (DTC), that has spread (locally advanced or metastatic), and,has progressed after treatment with VEGFR-targeted treatment, and your DTC can no longer be treated with radioactive iodine, or you are not able to receiveradioactive iodine treatment has progressed after treatment with VEGFR-targeted treatment, and your DTC can no longer be treated with radioactive iodine, or you are not able to receiveradioactive iodine treatment. have had liver problem other than liver cancer. have recent history of bleeding, including coughing up or vomiting blood, or black tarry stools.. have an open or healing wound. have high blood pressure. have low calcium level in your blood (hypocalcemia). plan to have any surgery, dental procedure, or have had recent surgery. You should stop taking CABOMETYX at least weeks before planned surgery. See What are the possible side effects of CABOMETYX. are pregnant, or plan to become pregnant. CABOMETYX can harm your unborn baby.If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOMETYX.Females who are able to become pregnant should use effective birth control (contraception) during treatment and for months after your final dose of CABOMETYX.Talk to your healthcare provider about birth control methods that may be right for you.If you become pregnant or think you are pregnant, tell your healthcare provider right away. If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOMETYX.. Females who are able to become pregnant should use effective birth control (contraception) during treatment and for months after your final dose of CABOMETYX.. Talk to your healthcare provider about birth control methods that may be right for you.. If you become pregnant or think you are pregnant, tell your healthcare provider right away.. are breastfeeding or plan to breastfeed. It is not known if CABOMETYX passes into your breast milk. Do not breastfeed during treatment and for months after your final dose of CABOMETYX.. Take CABOMETYX exactly as your healthcare provider tells you to take it.. Do not take CABOMETYX with food. Take CABOMETYX at least hour before or at least hours after eating.. Swallow CABOMETYX tablets whole.. Do not crush CABOMETYX tablets.. If you miss dose and your next scheduled dose is in:less than 12 hours, take your next dose at the normal time. Do not make up the missed dose. less than 12 hours, take your next dose at the normal time. Do not make up the missed dose.. bleeding (hemorrhage). CABOMETYX can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with CABOMETYX, including:coughing up blood or blood clotsvomiting blood or if your vomit looks like coffee-groundsred or black (looks like tar) stoolsmenstrual bleeding that is heavier than normalany unusual or heavy bleeding coughing up blood or blood clots. vomiting blood or if your vomit looks like coffee-grounds. red or black (looks like tar) stools. menstrual bleeding that is heavier than normal. any unusual or heavy bleeding. tear in your stomach or intestinal wall (perforation) or an abnormal connection between parts of your body (fistula). Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.. blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:swelling or pain in your arms or legs shortness of breathfeel lightheaded or faintsweating more than usualnumbness or weakness of your face, arm or leg, especially on one side of your bodysudden confusion, trouble speaking or understandingsudden trouble seeing in one or both eyessudden trouble walkingdizziness, loss of balance or coordinationa sudden severe headache swelling or pain in your arms or legs shortness of breath. feel lightheaded or faint. sweating more than usual. numbness or weakness of your face, arm or leg, especially on one side of your body. sudden confusion, trouble speaking or understanding. sudden trouble seeing in one or both eyes. sudden trouble walking. dizziness, loss of balance or coordination. sudden severe headache. high blood pressure (hypertension). Hypertension is common with CABOMETYX and sometimes can be severe. Your healthcare provider will check your blood pressure before starting CABOMETYX and regularly during treatment with CABOMETYX. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.. diarrhea. Diarrhea is common with CABOMETYX and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.. skin problem called hand-foot skin reaction. Hand-foot skin reactions are common with CABOMETYX and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.. liver problems. Liver problems may happen during treatment with CABOMETYX. When CABOMETYX is taken in combination with nivolumab, severe changes in liver function tests may happen more often than if you take CABOMETYX alone. Your healthcare provider will do blood tests to check your liver function before and during treatment with CABOMETYX. Tell your healthcare provider right away if you develop symptoms of liver problems including: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach-area (abdomen), dark urine, bleeding or bruising more easily than normal.. adrenal gland problems. Your healthcare provider will monitor you for this problem. Your healthcare provider may prescribe hormone replacement therapy or corticosteroid medicines if needed. Tell your healthcare provider right away if you develop any of the following signs or symptoms: extreme tiredness, dizziness or fainting, weakness, nausea, or vomiting.. protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet. Your healthcare provider will check you for this problem during treatment with CABOMETYX.. severe jaw bone problems (osteonecrosis). Your healthcare provider should examine your mouth before you start and during treatment with CABOMETYX. Tell your dentist that you are taking CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX. Tell your healthcare provider right away if you develop any symptoms of jaw problems, including: jaw pain, toothache, or sores on your gums.. wound healing problems. Wound healing problems have happened in some people who take CABOMETYX. Tell your healthcare provider if you plan to have any surgery before or during treatment with CABOMETYX.You should stop taking CABOMETYX at least weeks before planned surgery.Your healthcare provider should tell you when you may start taking CABOMETYX again after surgery. You should stop taking CABOMETYX at least weeks before planned surgery.. Your healthcare provider should tell you when you may start taking CABOMETYX again after surgery.. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with CABOMETYX. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.. change in thyroid function. CABOMETYX can cause changes in your thyroid function, including changes to thyroid hormone levels in your blood. Your healthcare provider will do blood tests to check your thyroid function before and during treatment with CABOMETYX.. decreased calcium level in your blood (hypocalcemia). CABOMETYX can cause you to have decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. Tell your healthcare provider right away if you get any of the following signs or symptoms:muscle stiffness or muscle spasmsnumbness or tingling in your fingers, toes, or around your mouthseizuressudden weight gainswelling of your arms, hands, legs, and ankles. muscle stiffness or muscle spasms. numbness or tingling in your fingers, toes, or around your mouth. seizures. sudden weight gain. swelling of your arms, hands, legs, and ankles. tiredness. decreased appetite. nausea and vomiting. weight loss. constipation. tiredness. mouth sores. rash. low thyroid hormone levels (hypothyroidism). pain in muscles, bones, and joints. decreased appetite. nausea. changes in the way things taste. stomach-area (abdominal) pain. cough. upper respiratory tract infection. Store CABOMETYX at room temperature between 68F to 77F (20C to 25C).. image of chemical structure of CABOMETYX. image of Kaplan-Meier Curves of Progression-Free Survival in METEOR (First 375 Randomized). image of Kaplan-Meier Curve of Overall Survival in METEOR (ITT). image of Kaplan-Meier Curve of Progression-Free Survival in CABOSUN. image of Kaplan-Meier Curve of Overall Survival in CABOSUN. image of Kaplan-Meier Curve of Progression-Free Survival in CHECKMATE-9ER. image of Kaplan-Meier Curve of Overall Survival in CHECKMATE-9ER. image of Kaplan-Meier Curve of Overall Survival in CELESTIAL. image of Kaplan-Meier Curve of Progression-Free Survival in CELESTIAL. image of Kaplan-Meier Curve of Progression-Free Survival in COSMIC-311 Updated Analysis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic Impairment: Reduce the CABOMETYX dosage for patients with moderate hepatic impairment. Avoid in patients with severe hepatic impairment. (2.8, 8.6)Lactation: Advise not to breastfeed. (8.2). Hepatic Impairment: Reduce the CABOMETYX dosage for patients with moderate hepatic impairment. Avoid in patients with severe hepatic impairment. (2.8, 8.6). 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)], CABOMETYX can cause fetal harm when administered to pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended 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 2-4% and 15-20%, respectively.DataAnimal DataIn an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at dose of 0.03 mg/kg (approximately 0.12-fold of human area under the curve [AUC] at the recommended dose). Findings included delayed ossification and skeletal variations at dose of 0.01 mg/kg/day (approximately 0.04-fold of human AUC at the recommended dose).In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at mg/kg (approximately 1.1-fold of the human AUC at the recommended dose).In pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum recommended clinical dose).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with CABOMETYX and for months after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX [see Use in Specific Populations (8.1)].ContraceptionCABOMETYX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].FemalesAdvise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for months after the final dose.InfertilityFemales and MalesBased on findings in animals, CABOMETYX may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of CABOMETYX for the treatment of differentiated thyroid cancer (DTC) have been established in pediatric patients aged 12 years and older.Use of CABOMETYX in pediatric patients aged 12 years and older with DTC is supported by evidence from adequate and well-controlled studies of CABOMETYX in adults with additional population pharmacokinetic data demonstrating that cabozantinib exposure is within the same range between adults and pediatric patients aged 12 years and older at the recommended dosages [see Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)].The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.Juvenile Animal Toxicity DataJuvenile rats were administered cabozantinib at doses of or mg/kg/day from Postnatal Day 12 (comparable to less than years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses >=1 mg/kg/day (approximately 0.16 times the clinical dose of 60 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunners gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at dose of mg/kg (approximately 0.32 times the clinical dose of 60 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.. 8.5 Geriatric Use. In CABOSUN and METEOR, 41% of 409 patients treated with CABOMETYX were age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of 467 patients treated with CABOMETYX were age 65 years and older, and 15% were 75 years and older. In COSMIC-311, 50% of 125 patients treated with CABOMETYX were age 65 years and older, and 12% were 75 years and older [see Clinical Studies (14)].No overall differences in safety or effectiveness were observed between these patients and younger patients.Of the 320 patients randomized to CABOMETYX administered with nivolumab in CHECKMATE-9ER, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.. 8.6 Hepatic Impairment. Increased exposure to cabozantinib has been observed in patients with moderate (Child-Pugh B) hepatic impairment. Reduce the CABOMETYX dose in patients with moderate hepatic impairment. Avoid CABOMETYX in patients with severe hepatic impairment (Child-Pugh C), since it has not been studied in this population [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].. 8.7 Renal Impairment. No dosage adjustment is recommended in patients with mild or moderate renal impairment. There is no experience with CABOMETYX in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. (5.1)Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade fistula or perforation. (5.2)Thrombotic Events: Discontinue CABOMETYX for myocardial infarction or serious venous or arterial thromboembolic events. (5.3)Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. (5.4)Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to <=Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. (5.5)Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. (5.6)Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade and ALT and AST elevation may occur than with CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. (5.7)Adrenal Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. (5.8)Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to <= Grade 1, resume CABOMETYX at reduced dose. Discontinue for nephrotic syndrome. (5.9)Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least weeks prior to invasive dental procedures and for development of ONJ. (5.10)Impaired Wound Healing: Withhold CABOMETYX for at least weeks before elective surgery. Do not administer for at least weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. (5.11)Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue CABOMETYX. (5.12)Thyroid Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. (5.13)Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. (5.14)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.15, 8.1, 8.3). Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. (5.1). Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade fistula or perforation. (5.2). Thrombotic Events: Discontinue CABOMETYX for myocardial infarction or serious venous or arterial thromboembolic events. (5.3). Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. (5.4). Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to <=Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. (5.5). Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. (5.6). Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade and ALT and AST elevation may occur than with CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. (5.7). Adrenal Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. (5.8). Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to <= Grade 1, resume CABOMETYX at reduced dose. Discontinue for nephrotic syndrome. (5.9). Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least weeks prior to invasive dental procedures and for development of ONJ. (5.10). Impaired Wound Healing: Withhold CABOMETYX for at least weeks before elective surgery. Do not administer for at least weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. (5.11). Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue CABOMETYX. (5.12). Thyroid Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. (5.13). Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. (5.14). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.15, 8.1, 8.3). 5.1 Hemorrhage. Severe and fatal hemorrhages occurred with CABOMETYX [see Adverse Reactions (6.1)]. The incidence of Grade to hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade or hemorrhage and prior to surgery as recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.10, 5.11)]. Do not administer CABOMETYX to patients who have recent history of hemorrhage, including hemoptysis, hematemesis, or melena. 5.2 Perforations and Fistulas. Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients [see Adverse Reactions (6.1)]. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience Grade fistula or GI perforation [see Dosage and Administration (2.5)].. 5.3 Thrombotic Events. CABOMETYX increased the risk of thrombotic events [see Adverse Reactions (6.1)]. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thrombotic events occurred in CABOMETYX-treated patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention [see Dosage and Administration (2.5)]. 5.4 Hypertension and Hypertensive Crisis. CABOMETYX can cause hypertension, including hypertensive crisis [see Adverse Reactions (6.1)]. Hypertension was reported in 37% (16% Grade and <1% Grade 4) of CABOMETYX- treated patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at reduced dose [see Dosage and Administration (2.5)]. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis [see Dosage and Administration (2.5)]. 5.5 Diarrhea. Diarrhea occurred in 62% of patients treated with CABOMETYX. Grade diarrhea occurred in 10% of patients treated with CABOMETYX [see Adverse Reactions (6.1)]. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to <= Grade 1, resume CABOMETYX at reduced dose [see Dosage and Administration (2.5)].. 5.6 Palmar-Plantar Erythrodysesthesia. Palmar-plantar erythrodysesthesia (PPE) occurred in 45% of patients treated with CABOMETYX [see Adverse Reactions (6.1)]. Grade PPE occurred in 13% of patients treated with CABOMETYX. Withhold CABOMETYX until improvement to Grade and resume CABOMETYX at reduced dose for intolerable Grade PPE or Grade PPE [see Dosage and Administration (2.5)]. 5.7 Hepatotoxicity. CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades and ALT and AST elevations compared to CABOMETYX alone.Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids [see Dosage and Administration (2.5)].With the combination of CABOMETYX and nivolumab, Grades and increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST 3 times ULN (Grade >=2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade >=2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as single agent or with both (n=24), recurrence of Grade >=2 increased ALT or AST was observed in patients receiving CABOMETYX, patients receiving nivolumab, and patients receiving both CABOMETYX and nivolumab. Withhold and resume at reduced dose based on severity [see Dosage and Administration (2.5)].. 5.8 Adrenal Insufficiency. CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at reduced dose depending on severity [see Dosage and Administration (2.5)].Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade (2.2%), and Grade (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and had recurrence of adrenal insufficiency.. 5.9 Proteinuria Proteinuria was observed in 8% of patients receiving CABOMETYX [see Adverse Reactions (6.1)].Monitor urine protein regularly during CABOMETYX treatment. For Grade or proteinuria, withhold CABOMETYX until improvement to <= Grade proteinuria, resume CABOMETYX at reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome [see Dosage and Administration (2.5)].. 5.10 Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with CABOMETYX [see Adverse Reactions (6.1)]. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of CABOMETYX and periodically during CABOMETYX. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at reduced dose [see Dosage and Administration (2.5)]. 5.11 Impaired Wound Healing. Wound complications occurred with CABOMETYX [see Adverse Reactions (6.1)]. Withhold CABOMETYX for at least weeks prior to elective surgery [see Dosage and Administration (2.1)]. Do not administer CABOMETYX for at least weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established [see Dosage and Administration (2.5)]. 5.12 Reversible Posterior Leukoencephalopathy Syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS), syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS [see Dosage and Administration (2.5)].. 5.13 Thyroid Dysfunction. Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population [see Adverse Reactions (6.1)], thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade in 0.4% of patients.Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated [see Dosage and Administration (2.5)].. 5.14 Hypocalcemia. CABOMETYX can cause hypocalcemia. Based on the safety population [see Adverse Reactions (6.1)], hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade in 2% and Grade in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.In COSMIC-311 [see Clinical Studies (14.3)], hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade in 6% and Grade in 3% of patients.Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity [see Dosage and Administration (2.5)].. 5.15 Embryo-Fetal Toxicity. Based on data from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].