Cabozantinib

CABOMETYX is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC). ( 1.1 ) patients with advanced renal cell carcinoma, as a first-line treatment in combination with nivolumab ( 1.1 ) patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib ( 1.2 ) adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible ( 1.3 ) adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). ( 1.4 ) adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET). ( 1.4 )

1.1 Renal Cell Carcinoma CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

1.2 Hepatocellular Carcinoma CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

1.3 Differentiated Thyroid Cancer CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

1.4 Neuroendocrine Tumors CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET).

Tablets: 60 mg: yellow film-coated, oval shaped with no score, and debossed with "XL" on one side and "60" on the other side. 40 mg: yellow film-coated, triangle shaped with no score, and debossed with "XL" on one side and "40" on the other side. 20 mg: yellow film-coated, round with no score, and debossed with "XL" on one side and "20" on the other side. Tablets: 60 mg, 40 mg, 20 mg. ( 3 )

None. None ( 4 )

Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. ( 5.1 ) Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade 4 fistula or perforation. ( 5.2 ) Thromboembolic 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 ) Cardiac Failure: Monitor patients for signs and symptoms of cardiac failure throughout treatment. ( 5.5 ) Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to ≤Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. ( 5.6 ) Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. ( 5.7 ) Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade 3 and 4 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. ( 5.8 ) Adrenal Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. ( 5.9 ) Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to ≤ Grade 1, resume CABOMETYX at a reduced dose. Discontinue for nephrotic syndrome. ( 5.10 ) Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least 3 weeks prior to invasive dental procedures and for development of ONJ. ( 5.11 ) Impaired Wound Healing: Withhold CABOMETYX for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. ( 5.12 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue CABOMETYX. ( 5.13 ) Thyroid Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. ( 5.14 ) Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. ( 5.15 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.16 , 8.1 , 8.3 )

5.1 Hemorrhage CABOMETYX can cause severe and fatal hemorrhages. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies [see Adverse Reactions (6.1) ] . Withhold CABOMETYX for 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended [see Dosage and Administration (2.3) , Warnings and Precautions (5.11 , 5.12) ] .

5.2 Perforations and Fistulas CABOMETYX can cause gastrointestinal (GI) perforations and fistulas. Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients [see [see Adverse Reactions (6.1) ] . 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 a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.3) ] .

5.3 Thromboembolic Events CABOMETYX can cause arterial or venous thromboembolic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thromboembolic events occurred in CABOMETYX-treated patients [see Adverse Reactions (6.1) ] . 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 (2.3) ] .

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 3 and <1% Grade 4) of CABOMETYX-treated patients. In CABINET (n=195) [see Clinical Studies (14.4) ] , hypertension was reported in 65% (26% Grade 3) 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 a reduced dose [see Dosage and Administration (2.3) ] . Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis [see Dosage and Administration (2.3) ] .

5.5 Cardiac Failure CABOMETYX can cause severe and fatal cardiac failure [see Adverse Reactions (6.1) ] . Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Median time to onset of cardiac failure was 73 days (range: 44 days to 159 days). Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on the severity [see Dosage and Administration (2.3) ] .

5.6 Diarrhea CABOMETYX can cause diarrhea. Diarrhea occurred in 62% of patients treated with CABOMETYX. Grade 3 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 a reduced dose [see Dosage and Administration (2.3) ] .

5.7 Palmar-Plantar Erythrodysesthesia CABOMETYX can cause palmar-plantar erythrodysesthesia (PPE). PPE occurred in 45% of patients treated with CABOMETYX [see Adverse Reactions (6.1) ] . Grade 3 PPE occurred in 13% of patients treated with CABOMETYX. Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE [see Dosage and Administration (2.3) ] .

5.8 Hepatotoxicity CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 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 (2.3) ] . With the combination of CABOMETYX and nivolumab, Grades 3 and 4 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%). […]

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) ] Thromboembolic Events [see Warnings and Precautions (5.3) ] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4) ] Cardiac Failure [see Warnings and Precautions (5.5) ] Diarrhea [see Warnings and Precautions (5.6) ] Palmar-plantar Erythrodysesthesia [see Warnings and Precautions (5.7) ] Hepatotoxicity [see Warnings and Precautions (5.8) ] Adrenal Insufficiency [see Warnings and Precautions (5.9) ] Proteinuria [see Warnings and Precautions (5.10) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.11) ] Impaired Wound Healing [see Warnings and Precautions (5.12) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.13) ] Thyroid Dysfunction [see Warnings and Precautions (5.14) ] Hypocalcemia [see Warnings and Precautions (5.15) ] The most common (≥ 20%) adverse reactions are: as a 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.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to CABOMETYX as a single agent at 60 mg orally once daily until disease progression or unacceptable toxicity in 409 patients with RCC enrolled in a randomized, active-controlled trial (CABOSUN, METEOR), 467 patients with HCC enrolled in a randomized, placebo- controlled trial (CELESTIAL), 125 patients with DTC enrolled in a randomized, placebo- controlled trial (COSMIC-311), 195 patients with pNET or epNET enrolled in a randomized, placebo-controlled trial (CABINET), and at 40 mg CABOMETYX in combination with nivolumab 240 mg/m 2 every 2 weeks, in 320 patients with RCC enrolled in a randomized, active- controlled trial (CHECKMATE-9ER). Renal Cell Carcinoma METEOR The safety of CABOMETYX was evaluated in METEOR, a 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 Reaction CABOMETYX (n=331) One subject randomized to everolimus received cabozantinib. Everolimus (n=322) All Grades National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version

4.0 Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Gastrointestinal Diarrhea 74 11 28 2 Nausea 50 4 28 <1 Vomiting 32 2 14 <1 Stomatitis 22 2 24 2 Constipation 25 <1 19 <1 Abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower 23 4 13 2 Dyspepsia 12 <1 5 0 General Fatigue 56 9 47 7 Mucosal inflammation 19 <1 23 3 Asthenia 19 4 16 2 Metabolism and Nutrition Decreased appetite 46 3 34 <1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 42 8 6 <1 Rash Includes 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 <1 43 <1 Dry skin 11 0 10 0 Vascular Hypertension Includes the following terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation 39 16 8 3 Investigations Weight decreased 31 2 12 0 Nervous System Dysgeusia 24 0 9 0 Headache 11 <1 12 <1 Dizziness 11 0 7 0 Endocrine Hypothyroidism 21 0 <1 <1 Respiratory, Thoracic, and Mediastinal Dysphonia 20 <1 4 0 Dyspnea 19 3 29 4 Cough 18 <1 33 <1 Blood and Lymphatic Anemia 17 5 38 16 Musculoskeletal and Connective Tissue Pain in extremity 14 1 8 <1 Muscle spasms 13 0 5 0 Arthralgia 11 <1 14 1 Renal and Urinary Proteinuria 12 2 9 <1 Other clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), cardiac failure (<1%), 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 Abnormality CABOMETYX (n=331) Everolimus (n=322) All Grades Grade 3-4 All Grades Grade 3-4 Percentage (%) of Patients ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase. NCI CTCAE, Version

4.0 Chemistry Increased AST 74 3 40 <1 Increased ALT 68 3 32 <1 Increased creatinine 58 <1 71 0 Increased triglycerides 53 4 73 13 Hypophosphatemia 48 8 36 5 Hyperglycemia 37 2 59 8 Hypoalbuminemia 36 2 28 <1 Increased ALP 35 2 29 1 Hypomagnesemia 31 7 4 <1 Hyponatremia 30 8 26 6 Increased GGT 27 5 43 9 Hematology Leukopenia 35 <1 31 <1 Neutropenia 31 2 17 <1 Anemia Based on laboratory abnormalities 31 4 71 17 Lymphopenia 25 7 39 12 Thrombocytopenia 25 <1 27 <1 CABOSUN The safety of CABOMETYX was evaluated in CABOSUN, a randomized, open-label trial in patients with advanced renal cell carcinoma, in which 78 patients received CABOMETYX 60 mg once daily and 72 patients received sunitinib 50 mg once daily (4 weeks on treatment followed by 2 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. […]

Strong CYP3A4 inhibitors: Reduce the CABOMETYX dosage if coadministration cannot be avoided. ( 2.4 , 7.1 ) Strong or moderate CYP3A4 inducers: Increase the CABOMETYX dosage if coadministration cannot be avoided. ( 2.5 , 7.1 )

7.1 Effects of Other Drugs on CABOMETYX Strong CYP3A4 Inhibitors Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions [see Clinical Pharmacology (12.3) ] . Avoid coadministration of CABOMETYX with strong CYP3A4 inhibitors. Reduce the dosage of CABOMETYX if coadministration with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.4) ] . Avoid grapefruit or grapefruit juice which may also increase exposure of cabozantinib. Strong or Moderate CYP3A Inducers Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy [see Clinical Pharmacology (12.3) ] . Avoid coadministration of CABOMETYX with strong or moderate CYP3A4 inducers. Increase the dosage of CABOMETYX if coadministration with strong or moderate CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.5) ] . Avoid St. John’s wort which may also decrease exposure of cabozantinib.

Hepatic Impairment: Reduce the CABOMETYX dosage for patients with moderate hepatic impairment. Avoid in patients with severe hepatic impairment. ( 2.6 , 8.6 ) Lactation: Advise not to breastfeed. ( 8.2 ) Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. ( 8.4 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , CABOMETYX can cause fetal harm when administered to a 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 a 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. Data Animal Data In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a 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 a 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 3 mg/kg (approximately 1.1-fold of the human AUC at the recommended dose). In a 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 Summary There 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 4 months after the final dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX [see Use in Specific Populations (8.1) ] . Contraception CABOMETYX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility Females and Males Based 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) and neuroendocrine tumors (NETs) have been established in pediatric patients aged 12 years and older. Use of CABOMETYX in pediatric patients aged 12 years and older with DTC and NETs 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 (2.2 , 2.3 ), Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3 , 14.4) ] . Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Based on the limited available data of the effects of CABOMETYX on longitudinal growth, physeal and longitudinal growth monitoring is recommended in children with open growth plates. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established. Juvenile Animal Toxicity Data Juvenile rats were administered cabozantinib at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 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 Brunner’s 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 a dose of 2 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. In CABINET, 38% of 63 patients treated with CABOMETYX were age 65 years and older, and 5% were 75 years and older in the pNET cohort, and 55% of 132 patients treated with CABOMETYX were age 65 years and older, and 13% were 75 years and older in the epNET cohort [see Clinical Studies (14) ] . No overall differences in safety or effectiveness were observed between these patients and younger patients. Of the 320 patients with RCC treated with CABOMETYX in combination with nivolumab in CHECKMATE-9ER, 41% were 65 years or older and 9% were 75 years or older [see Clinical Studies (14.1) ] . No overall difference in safety was reported between older and younger patients receiving both CABOMETYX and nivolumab.

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 (2.2 , 2.6) , 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) ] .

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.