b'BLEED: 8.375"w TRIM: 7.875"w SAFETY: 6.875"w CABOMETYX (cabozantinib) TABLETSwhom 23 (28%) received systemic corticosteroids; ALT or AST5.15Embryo-Fetal Toxicity BRIEF SUMMARY OF PRESCRIBING INFORMATION.resolved to Grades 0-1 in 74 (89%). Among the 44 patients withBased on data from animal studies and its mechanism of action, Grade 2 increased ALT or AST who were rechallenged withCABOMETYX can cause fetal harm when administered to a CODE_CABOMETYX_RCC_3PG_Efficacy In Balance JournalAd_7.875" x 10.5_A-Size_Page PLEASE SEE THE CABOMETYX PACKAGE INSERT FOReither CABOMETYX (n=9) or nivolumab (n=11) as a single agentpregnant woman. Cabozantinib administration to pregnantSAFETY: 9.5"hTRIM: 10.5"hBLEED: 11.25"h FULL PRESCRIBING INFORMATION.or with both (n=24), recurrence of Grade 2 increased ALT or ASTanimals during organogenesis resulted in embryolethality at INITIAL U.S. APPROVAL: 2012 was observed in 2 patients receiving CABOMETYX, 2 patientsexposures below those occurring clinically at the recommended 1 INDICATIONS AND USAGEreceiving nivolumab, and 7 patients receiving both CABOMETYXdose, and in increased incidences of skeletal variations in rats and and nivolumab. Withhold and resume at a reduced dose basedvisceral variations and malformations in rabbits. 1.1 Renal Cell Carcinomaon severity.Advise pregnant women of the potential risk to a fetus. Advise CABOMETYX is indicated for the treatment of patients with5.8 Adrenal Insufficiencyfemales of reproductive potential to use effective contraception advanced renal cell carcinoma (RCC).CABOMETYX in combination with nivolumab can cause primaryduring treatment with CABOMETYX and for 4 months after the CABOMETYX, in combination with nivolumab, is indicated foror secondary adrenal insufficiency. For Grade 2 or higher adrenallast dose. the first-line treatment of patients with advanced RCC.insufficiency, initiate symptomatic treatment, including hormone6 ADVERSE REACTIONS 1.2 Hepatocellular Carcinomareplacement as clinically indicated. Withhold CABOMETYXThe following clinically significant adverse reactions are discussed CABOMETYX is indicated for the treatment of patients withand/or nivolumab and resume CABOMETYX at a reduced doseelsewhere in the labeling: Hemorrhage, Perforations and hepatocellular carcinoma (HCC) who have been previouslydepending on severity.Fistulas, Thrombotic Events, Hypertension and Hypertensive treated with sorafenib.Adrenal insufficiency occurred in 4.7% (15/320) of patients withCrisis, Diarrhea, Palmar-plantar Erythrodysesthesia, 1.3 Differentiated Thyroid CancerRCC who received CABOMETYX with nivolumab, includingHepatotoxicity, Adrenal Insufficiency, Proteinuria, Osteonecrosis CABOMETYX is indicated for the treatment of adult and pediatricGrade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenalof the Jaw, Impaired Wound Healing, Reversible Posterior patients 12 years of age and older with locally advanced orinsufficiency led to permanent discontinuation of CABOMETYXLeukoencephalopathy Syndrome, Thyroid Dysfunction and metastatic differentiated thyroid cancer (DTC) that has progressedand nivolumab in 0.9% and withholding of CABOMETYX andHypocalcemia. following prior VEGFR-targeted therapy and who are radioactivenivolumab in 2.8% of patients with RCC.6.1 Clinical Trial Experience iodine-refractory or ineligible.Approximately 80% (12/15) of patients with adrenal insufficiencyThe data described in the WARNINGS AND PRECAUTIONS 4 CONTRAINDICATIONSreceived hormone replacement therapy, including systemicsection and below reflect exposure to CABOMETYX as a single None.corticosteroids. Adrenal insufficiency resolved in 27% (n=4) ofagent in 409 patients with RCC enrolled in randomized, active-the 15 patients. Of the 9 patients in whom CABOMETYX withcontrolled trials (CABOSUN, METEOR), 467 patients with HCC 5 WARNINGS AND PRECAUTIONSnivolumab was withheld for adrenal insufficiency, 6 reinstatedenrolled in a randomized, placebo-controlled trial (CELESTIAL), 5.1 Hemorrhagetreatment after symptom improvement; of these, all (n=6) receivedin 125 patients with DTC enrolled in a randomized, placebo-Severe and fatal hemorrhages occurred with CABOMETYX.hormone replacement therapy and 2 had recurrence of adrenalcontrolled trial (COSMIC-311), and in combination with nivolumab The incidence of Grade 3 to 5 hemorrhagic events was 5% ininsufficiency.240 mg/m 2every 2 weeks in 320 patients with RCC enrolled in a CABOMETYX patients in the RCC, HCC, and DTC studies.5.9 Proteinuriarandomized, active-controlled trial (CHECKMATE-9ER). Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and priorProteinuria was observed in 8% of patients receivingBecause clinical trials are conducted under widely varying to surgery as recommended. Do not administer CABOMETYXCABOMETYX.conditions, adverse reaction rates observed in the clinical trials of to patients who have a recent history of hemorrhage, includingMonitor urine protein regularly during CABOMETYX treatment.a drug cannot be directly compared to rates in the clinical trials of hemoptysis, hematemesis, or melena.For Grade 2 or 3 proteinuria, withhold CABOMETYX untilanother drug and may not reflect the rates observed in practice. 5.2 Perforations and Fistulasimprovement toGrade 1 proteinuria, resume CABOMETYXRenal Cell Carcinoma Fistulas, including fatal cases, occurred in 1% of CABOMETYX- at a reduced dose. Discontinue CABOMETYX in patients whoMETEOR treated patients. Gastrointestinal (GI) perforations, including fataldevelop nephrotic syndrome.The safety of CABOMETYX was evaluated in METEOR, a cases, occurred in 1% of CABOMETYX-treated patients.5.10Osteonecrosis of the Jawrandomized, open-label trial in which 331 patients with advanced Monitor patients for signs and symptoms of fistulas andOsteonecrosis of the jaw (ONJ) occurred in 1% of patientsrenal cell carcinoma received CABOMETYX 60 mg once daily and perforations, including abscess and sepsis. Discontinuetreated with CABOMETYX.322 patients received everolimus 10 mg once daily until disease CABOMETYX in patients who experience a Grade 4 fistulaONJ can manifest as jaw pain, osteomyelitis, osteitis, boneprogression or unacceptable toxicity. Patients on both arms who or a GI perforation.erosion, tooth or periodontal infection, toothache, gingivalhad disease progression could continue treatment at the discretion 5.3 Thrombotic Eventsulceration or erosion, persistent jaw pain or slow healing of theof the investigator. The median duration of treatment was 7.6 CABOMETYX increased the risk of thrombotic events. Venousmouth or jaw after dental surgery. Perform an oral examinationmonths (range 0.320.5) for patients receiving CABOMETYX and thromboembolism occurred in 7% (including 4% pulmonaryprior to initiation of CABOMETYX and periodically during4.4 months (range 0.2118.9) for patients receiving everolimus. embolism) and arterial thromboembolism occurred in 2% ofCABOMETYX. Advise patients regarding good oral hygieneAdverse reactions which occurred in25% of CABOMETYX-CABOMETYX-treated patients. Fatal thrombotic events occurredpractices. Withhold CABOMETYX for at least 3 weeks priortreated patients, in order of decreasing frequency, were: in CABOMETYX-treated patients. to scheduled dental surgery or invasive dental procedures, ifdiarrhea, fatigue, nausea, decreased appetite, palmar-plantar Discontinue CABOMETYX in patients who develop an acutepossible. Withhold CABOMETYX for development of ONJ untilerythrodysesthesia (PPE), hypertension, vomiting, weight myocardial infarction or serious arterial or venous thromboemboliccomplete resolution, resume at a reduced dose.decreased, and constipation. Grade 3-4 adverse reactions and events that require medical intervention.5.11Impaired Wound Healinglaboratory abnormalities which occurred in5% of patients 5.4 Hypertension and Hypertensive CrisisWound complications occurred with CABOMETYX. Withholdwere hypertension, diarrhea, fatigue, PPE, hyponatremia, CABOMETYX can cause hypertension, including hypertensiveCABOMETYX for at least 3 weeks prior to elective surgery. Do nothypophosphatemia, hypomagnesemia, lymphopenia, anemia, crisis. Hypertension was reported in 37% (16% Grade 3 and 1%administer CABOMETYX for at least 2 weeks after major surgeryhypokalemia, and increased GGT. Grade 4) of CABOMETYX-treated patients.and until adequate wound healing. The safety of resumption ofThe dose was reduced in 60% of patients receiving CABOMETYX Do not initiate CABOMETYX in patients with uncontrolledCABOMETYX after resolution of wound healing complications hasand in 24% of patients receiving everolimus. Twenty percent hypertension. Monitor blood pressure regularly duringnot been established.(20%) of patients received CABOMETYX 20 mg once daily as CABOMETYX treatment. Withhold CABOMETYX for hypertension5.12Reversible Posterior Leukoencephalopathy Syndrometheir lowest dose. The most frequent adverse reactions leading that is not adequately controlled with medical management; whenReversible Posterior Leukoencephalopathy Syndrome (RPLS),to dose reduction in patients treated with CABOMETYX were: controlled, resume CABOMETYX at a reduced dose. Permanentlya syndrome of subcortical vasogenic edema diagnosed bydiarrhea, PPE, fatigue, and hypertension. Adverse reactions discontinue CABOMETYX for severe hypertension that cannot becharacteristic finding on MRI, can occur with CABOMETYX.leading to dose interruption occurred in 70% patients receiving controlled with anti-hypertensive therapy or for hypertensive crisis.Perform an evaluation for RPLS in any patient presenting withCABOMETYX and in 59% patients receiving everolimus. Adverse seizures, headache, visual disturbances, confusion or alteredreactions led to study treatment discontinuation in 10% of 5.5 Diarrheamental function. Discontinue CABOMETYX in patients whopatients receiving CABOMETYX and in 10% of patients receiving Diarrhea occurred in 62% of patients treated with CABOMETYX.develop RPLS.everolimus. The most frequent adverse reactions leading to Grade 3 diarrhea occurred in 10% of patients treated withpermanent discontinuation in patients treated with CABOMETYX CABOMETYX.5.13Thyroid Dysfunctionwere decreased appetite (2%) and fatigue (1%).Monitor and manage patients using antidiarrheals as indicated.Thyroid dysfunction, primarily hypothyroidism, has been Withhold CABOMETYX until improvement toGrade 1, resumeobserved with CABOMETYX. Based on the safety population,Table 1. Adverse Reactions Occurring in10% Patients Who CABOMETYX at a reduced dose. thyroid dysfunction occurred in 19% of patients treated withReceived CABOMETYX in METEOR5.6 Palmar-Plantar ErythrodysesthesiaCABOMETYX, including Grade 3 in 0.4% of patients. CABOMETYXEverolimusPalmar-plantar erythrodysesthesia (PPE) occurred in 45% ofPatients should be assessed for signs of thyroid dysfunction prior(n=331)1 (n=322)patients treated with CABOMETYX. Grade 3 PPE occurred into the initiation of CABOMETYX and monitored for signs andAdverse Reaction13% of patients treated with CABOMETYX.symptoms of thyroid dysfunction during CABOMETYX treatment.All 2 GradeAll2 Grade Thyroid function testing and management of dysfunction shouldGrades 3-4 Grades 3-4Withhold CABOMETYX until improvement to Grade 1 and resumebe performed as clinically indicated.Percentage (%) of PatientsCABOMETYX at a reduced dose for intolerable Grade 2 PPE or5.14HypocalcemiaGastrointestinalGrade 3 PPE.CABOMETYX can cause hypocalcemia. Based on the safetyDiarrhea 74 11 28 25.7 Hepatotoxicitypopulation, hypocalcemia occurred in 13% of patients treatedNausea 50 4 28 1CABOMETYX in combination with nivolumab can cause hepaticwith CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% toxicity with higher frequencies of Grades 3 and 4 ALT andof patients. Laboratory abnormality data were not collected inVomiting32 2 14 1AST elevations compared to CABOMETYX alone. Monitor liverCABOSUN. Stomatitis 22 2 24 2enzymes before initiation of and periodically throughout treatment.In COSMIC-311, hypocalcemia occurred in 36% of patientsConstipation 3 25 1 19 1Consider more frequent monitoring of liver enzymes as comparedtreated with CABOMETYX, including Grade 3 in 6% and Grade 4Abdominal pain 23 4 13 2to when the drugs are administered as single agents. For elevatedin 3% of patients. Dyspepsia 12 1 5 0liver enzymes, interrupt CABOMETYX and nivolumab andMonitor blood calcium levels and replace calcium as necessaryGeneralconsider administering corticosteroids.during treatment. Withhold and resume at reduced dose uponFatigue 56 9 47 7With the combination of CABOMETYX and nivolumab, Grades 3recovery or permanently discontinue CABOMETYX dependingMucosal inflammation 19 1 23 3and 4 increased ALT or AST were seen in 11% of patients. ALTon severity.Asthenia 19 4 16 2or AST 3 times ULN (Grade 2) was reported in 83 patients, of 72582_CA-1121-5_Exelixis_Cabometyx_HCP-Brief_7-75x10-75_r1v1jl.indd 1 8/5/22 12:29 PM'