b'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 PLEASE SEE THE CABOMETYX PACKAGE INSERT FOReither CABOMETYX (n=9) or nivolumab (n=11) as a single agentpregnant woman. Cabozantinib administration to pregnant animals FULL PRESCRIBING INFORMATION.or with both (n=24), recurrence of Grade 2 increased ALT or ASTduring organogenesis resulted in embryolethality at exposures INITIAL U.S. APPROVAL: 2012 was observed in 2 patients receiving CABOMETYX, 2 patientsbelow those occurring clinically at the recommended dose, and receiving nivolumab, and 7 patients receiving both CABOMETYXin increased incidences of skeletal variations in rats and visceral 1 INDICATIONS AND USAGEand nivolumab. Withhold and resume at a reduced dose basedvariations 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 for theor secondary adrenal insufficiency. For Grade 2 or higher adrenallast dose. first-line treatment of patients with advanced RCC.insufficiency, initiate symptomatic treatment, including hormone6 ADVERSE REACTIONS replacement as clinically indicated. Withhold CABOMETYX and/ The following clinically significant adverse reactions are discussed 1.2 Hepatocellular Carcinomaor nivolumab and resume CABOMETYX at a reduced doseelsewhere in the labeling: Hemorrhage, Perforations and Fistulas, CABOMETYX is indicated for the treatment of patients withdepending on severity.Thrombotic Events, Hypertension and Hypertensive Crisis, Diarrhea, hepatocellular carcinoma (HCC) who have been previously treatedAdrenal insufficiency occurred in 4.7% (15/320) of patients withPalmar-plantar Erythrodysesthesia, Hepatotoxicity, Adrenal with sorafenib.RCC who received CABOMETYX with nivolumab, includingInsufficiency, Proteinuria, Osteonecrosis of the Jaw, Impaired 1.3 Differentiated Thyroid CancerGrade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. AdrenalWound Healing, Reversible Posterior Leukoencephalopathy CABOMETYX is indicated for the treatment of adult and pediatricinsufficiency led to permanent discontinuation of CABOMETYXSyndrome, Thyroid Dysfunction and Hypocalcemia. patients 12 years of age and older with locally advanced orand nivolumab in 0.9% and withholding of CABOMETYX and6.1 Clinical Trial Experience metastatic differentiated thyroid cancer (DTC) that has progressednivolumab in 2.8% of patients with RCC.The data described in the WARNINGS AND PRECAUTIONS following prior VEGFR-targeted therapy and who are radioactiveApproximately 80% (12/15) of patients with adrenal insufficiencysection and below reflect exposure to CABOMETYX as a single iodine-refractory or ineligible.received hormone replacement therapy, including systemicagent in 409 patients with RCC enrolled in randomized, active-4 CONTRAINDICATIONScorticosteroids. Adrenal insufficiency resolved in 27% (n=4) ofcontrolled trials (CABOSUN, METEOR), 467 patients with HCC None.the 15 patients. Of the 9 patients in whom CABOMETYX withenrolled in a randomized, placebo-controlled trial (CELESTIAL), nivolumab was withheld for adrenal insufficiency, 6 reinstatedin 125 patients with DTC enrolled in a randomized, placebo-5 WARNINGS AND PRECAUTIONStreatment after symptom improvement; of these, all (n=6) receivedcontrolled trial (COSMIC-311), and in combination with nivolumab 5.1 Hemorrhagehormone replacement therapy and 2 had recurrence of adrenal240 mg/m 2every 2 weeks in 320 patients with RCC enrolled in a Severe and fatal hemorrhages occurred with CABOMETYX.insufficiency.randomized, active-controlled trial (CHECKMATE-9ER). The incidence of Grade 3 to 5 hemorrhagic events was 5% in5.9 ProteinuriaBecause clinical trials are conducted under widely varying CABOMETYX patients in the RCC, HCC, and DTC studies.Proteinuria was observed in 8% of patients receivingconditions, adverse reaction rates observed in the clinical trials of Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and priorCABOMETYX.a drug cannot be directly compared to rates in the clinical trials of to surgery as recommended. Do not administer CABOMETYXMonitor urine protein regularly during CABOMETYX treatment.another drug and may not reflect the rates observed in practice. to patients who have a recent history of hemorrhage, includingFor Grade 2 or 3 proteinuria, withhold CABOMETYX untilRenal Cell Carcinoma hemoptysis, hematemesis, or melena.improvement toGrade 1 proteinuria, resume CABOMETYX at a 5.2 Perforations and Fistulasreduced dose. Discontinue CABOMETYX in patients who developMETEOR Fistulas, including fatal cases, occurred in 1% of CABOMETYX- nephrotic syndrome.The safety of CABOMETYX was evaluated in METEOR, a treated patients. Gastrointestinal (GI) perforations, including fatal5.10Osteonecrosis of the Jawrandomized, open-label trial in which 331 patients with advanced cases, occurred in 1% of CABOMETYX-treated patients.Osteonecrosis of the jaw (ONJ) occurred in 1% of patientsrenal cell carcinoma received CABOMETYX 60 mg once daily and 322 patients received everolimus 10 mg once daily until Monitor patients for signs and symptoms of fistulas andtreated with CABOMETYX.disease progression or unacceptable toxicity. Patients on both perforations, including abscess and sepsis. DiscontinueONJ can manifest as jaw pain, osteomyelitis, osteitis, bonearms who had disease progression could continue treatment CABOMETYX in patients who experience a Grade 4 fistula erosion, tooth or periodontal infection, toothache, gingivalat the discretion of the investigator. The median duration of or a GI perforation.ulceration or erosion, persistent jaw pain or slow healing of thetreatment was 7.6 months (range 0.320.5) for patients receiving 5.3 Thrombotic Eventsmouth or jaw after dental surgery. Perform an oral examinationCABOMETYX and 4.4 months (range 0.2118.9) for patients CABOMETYX increased the risk of thrombotic events. Venousprior to initiation of CABOMETYX and periodically duringreceiving everolimus. thromboembolism occurred in 7% (including 4% pulmonaryCABOMETYX. Advise patients regarding good oral hygieneAdverse reactions which occurred in25% of CABOMETYX-embolism) and arterial thromboembolism occurred in 2% ofpractices. Withhold CABOMETYX for at least 3 weeks priortreated patients, in order of decreasing frequency, were: CABOMETYX-treated patients. Fatal thrombotic events occurredto scheduled dental surgery or invasive dental procedures, ifdiarrhea, fatigue, nausea, decreased appetite, palmar-plantar in CABOMETYX-treated patients. possible. Withhold CABOMETYX for development of ONJ untilerythrodysesthesia (PPE), hypertension, vomiting, weight Discontinue CABOMETYX in patients who develop an acutecomplete resolution, resume at a reduced dose.decreased, and constipation. Grade 3-4 adverse reactions and myocardial infarction or serious arterial or venous thromboembolic5.11 Impaired Wound Healinglaboratory abnormalities which occurred in5% of patients events that require medical intervention.Wound complications occurred with CABOMETYX. Withholdwere hypertension, diarrhea, fatigue, PPE, hyponatremia, CABOMETYX for at least 3 weeks prior to elective surgery. Do nothypophosphatemia, hypomagnesemia, lymphopenia, anemia, 5.4 Hypertension and Hypertensive Crisisadminister CABOMETYX for at least 2 weeks after major surgeryhypokalemia, and increased GGT. CABOMETYX can cause hypertension, including hypertensiveand until adequate wound healing. The safety of resumption ofThe dose was reduced in 60% of patients receiving CABOMETYX crisis. Hypertension was reported in 37% (16% Grade 3 and 1%CABOMETYX after resolution of wound healing complications hasand in 24% of patients receiving everolimus. Twenty percent Grade 4) of CABOMETYX-treated patients.not been established.(20%) of patients received CABOMETYX 20 mg once daily as Do not initiate CABOMETYX in patients with uncontrolled5.12Reversible Posterior Leukoencephalopathy Syndrometheir lowest dose. The most frequent adverse reactions leading hypertension. Monitor blood pressure regularly duringReversible Posterior Leukoencephalopathy Syndrome (RPLS),to dose reduction in patients treated with CABOMETYX were: CABOMETYX treatment. Withhold CABOMETYX for hypertensiona syndrome of subcortical vasogenic edema diagnosed bydiarrhea, PPE, fatigue, and hypertension. Adverse reactions that is not adequately controlled with medical management; whencharacteristic finding on MRI, can occur with CABOMETYX.leading to dose interruption occurred in 70% patients receiving controlled, resume CABOMETYX at a reduced dose. PermanentlyPerform an evaluation for RPLS in any patient presenting withCABOMETYX and in 59% patients receiving everolimus. Adverse discontinue CABOMETYX for severe hypertension that cannot beseizures, headache, visual disturbances, confusion or alteredreactions led to study treatment discontinuation in 10% of controlled with anti-hypertensive therapy or for hypertensive crisis.mental function. Discontinue CABOMETYX in patients whopatients receiving CABOMETYX and in 10% of patients receiving 5.5 Diarrheadevelop RPLS.everolimus. The most frequent adverse reactions leading to Diarrhea occurred in 62% of patients treated with CABOMETYX.permanent discontinuation in patients treated with CABOMETYX Grade 3 diarrhea occurred in 10% of patients treated with5.13Thyroid Dysfunctionwere decreased appetite (2%) and fatigue (1%).CABOMETYX.Thyroid dysfunction, primarily hypothyroidism, has beenTable 1. Adverse Reactions Occurring in10% Patients Who Monitor and manage patients using antidiarrheals as indicated.observed with CABOMETYX. Based on the safety population,Received CABOMETYX in METEORWithhold CABOMETYX until improvement toGrade 1, resumethyroid dysfunction occurred in 19% of patients treated with CABOMETYX at a reduced dose. CABOMETYX, including Grade 3 in 0.4% of patients. CABOMETYXEverolimusPatients should be assessed for signs of thyroid dysfunction prior(n=331)1 (n=322)5.6 Palmar-Plantar Erythrodysesthesiato the initiation of CABOMETYX and monitored for signs andAdverse Reaction All GradeAllGrade Palmar-plantar erythrodysesthesia (PPE) occurred in 45% ofsymptoms of thyroid dysfunction during CABOMETYX treatment.Grades 2 3-4 Grades 2 3-4patients treated with CABOMETYX. Grade 3 PPE occurred in 13%Thyroid function testing and management of dysfunction shouldPercentage (%) of Patientsof patients treated with CABOMETYX.be performed as clinically indicated.GastrointestinalWithhold CABOMETYX until improvement to Grade 1 and resume5.14Hypocalcemia CABOMETYX at a reduced dose for intolerable Grade 2 PPE orCABOMETYX can cause hypocalcemia. Based on the safetyDiarrhea 74 11 28 2Grade 3 PPE.population, hypocalcemia occurred in 13% of patients treatedNausea 50 4 28 15.7 Hepatotoxicitywith CABOMETYX, including Grade 3 in 2% and Grade 4 in 1%Vomiting32 2 14 1CABOMETYX in combination with nivolumab can cause hepaticof patients. Laboratory abnormality data were not collected inStomatitis 22 2 24 2toxicity with higher frequencies of Grades 3 and 4 ALT andCABOSUN. Constipation 25 1 19 1AST elevations compared to CABOMETYX alone. Monitor liverIn COSMIC-311, hypocalcemia occurred in 36% of patientsAbdominal pain 3 23 4 13 2enzymes before initiation of and periodically throughout treatment.treated with CABOMETYX, including Grade 3 in 6% and Grade 4Dyspepsia 12 1 5 0Consider more frequent monitoring of liver enzymes as comparedin 3% of patients. Generalto when the drugs are administered as single agents. For elevatedMonitor blood calcium levels and replace calcium as necessaryFatigue 56 9 47 7liver enzymes, interrupt CABOMETYX and nivolumab andduring treatment. Withhold and resume at reduced dose uponMucosal inflammation 19 1 23 3consider administering corticosteroids.recovery or permanently discontinue CABOMETYX dependingAsthenia 19 4 16 2With the combination of CABOMETYX and nivolumab, Grades 3on severity.Metabolism and Nutritionand 4 increased ALT or AST were seen in 11% of patients. ALT or AST 3 times ULN (Grade 2) was reported in 83 patients, ofDecreased appetite 46 3 34 172299_Exelixis_Cabometyx_HCP-Brief_USMedicine_7-875x10-75_r3v1jl.indd 1 11/30/21 10:03 AM'