b'CABOMETYXPlacebo8.3Females and Males of Reproductive Potentialor severe abdominal pain because cases of gastrointestinal LaboratoryN=125 N=62 Pregnancy Testingperforation and fistula have been reported in patients taking Abnormality AllGrade AllGrade Verify the pregnancy status of females of reproductive potentialCABOMETYX. Grades 3 or 4 Grades 3 or 4 prior to initiating CABOMETYX.Thrombotic events: Venous and arterial thrombotic events have Percentage (%) of Patients Contraceptionbeen reported. Advise patients to report signs or symptoms of Hypokalemia 18 1 3 0 CABOMETYX can cause fetal harm when administered to aan arterial thrombosis. Venous thromboembolic events including Hyponatremia 15 0 10 2 pregnant woman.pulmonary embolus have been reported. Advise patients to Hyperbilirubinemia 12 0 5 0 Femalescontact their health care provider if new onset of dyspnea, chest Hematology Advise females of reproductive potential to use effectivepain, or localized limb edema occurs.Leukocytescontraception during treatment with CABOMETYX and for 4Hypertension and hypertensive crisis: Inform patients of the decreased 38 2 7 2 months after the final dose.signs and symptoms of hypertension. Advise patients to undergo NeutrophilsInfertilityroutine blood pressure monitoring and to contact their health care decreased 31 2 5 2 Females and Malesprovider if blood pressure is elevated or if they experience signs or PlateletsBased on findings in animals, CABOMETYX may impair fertility insymptoms of hypertension. decreased 26 0 5 0 females and males of reproductive potential.Diarrhea: Advise patients to notify their healthcare provider at 1Includeslaboratoryabnormalitiesthataremorefrequentinthe8.4 Pediatric Usethe first signs of poorly formed or loose stool or an increasedCABOMETYX arm and have a between-arm difference of5% (allThe safety and effectiveness of CABOMETYX for the treatmentfrequency of bowel movements.2 grades) or2% (Grade 3-4) of differentiated thyroid cancer (DTC) have been established inPalmar-plantar erythrodysesthesia: Advise patients to contact theirSponsor-defined grades for LDH were as follows: Grade 1 ( ULN to2 ULN), Grade 2 ( 2ULN to3ULN), Grade 3 ( 3ULN). pediatric patients aged 12 years and older. healthcare provider for progressive or intolerable rash. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartateUse of CABOMETYX in pediatric patients aged 12 years andHepatotoxicity: Advise patients to contact their healthcare provider aminotransferase; GGT, gamma glutamyl transferase; LDH, blood lactateolder with DTC is supported by evidence from adequate andimmediately for jaundice, severe nausea or vomiting, or easy dehydrogenase well-controlled studies of CABOMETYX in adults with additionalbruising or bleeding. population pharmacokinetic data demonstrating that cabozantinib 7 DRUG INTERACTIONSexposure is within the same range between adults and pediatricAdrenal insufficiency: Advise patients receiving with nivolumab patients aged 12 years and older at the recommended dosages. to contact their healthcare provider immediately for signs or 7.1 Effects of Other Drugs on CABOMETYXThe safety and effectiveness of CABOMETYX in pediatric patientssymptoms of adrenal insufficiency. Strong CYP3A4 Inhibitorsless than 12 years of age have not been established.Proteinuria: Advise patients to contact their healthcare provider for Coadministration of a cabozantinib capsule formulation with asigns or symptoms of proteinuria. strong CYP3A4 inhibitor increased the exposure of cabozantinib,Juvenile Animal Toxicity Data which may increase the risk of exposure-related adverseJuvenile rats were administered cabozantinib at doses of 1 orOsteonecrosis of the jaw: Advise patients regarding good oral reactions. Avoid coadministration of CABOMETYX with strong2 mg/kg/day from Postnatal Day 12 (comparable to less than 2hygiene practices. Advise patients to immediately contact their CYP3A4 inhibitors. Reduce the dosage of CABOMETYX ifyears in humans) through Postnatal Day 35 or 70. Mortalitieshealthcare provider for signs or symptoms associated with coadministration with strong CYP3A4 inhibitors cannot beoccurred at doses 1 mg/kg/day (approximately 0.16 timesosteonecrosis of the jaw. avoided. Avoid grapefruit or grapefruit juice which may alsothe clinical dose of 60 mg/day based on body surface area).Impaired wound healing: Advise patients that CABOMETYX may increase exposure of cabozantinib.Hypoactivity was observed at both doses tested on Postnatal Dayimpair wound healing. Advise patients to inform their healthcare Strong CYP3A Inducers22. Targets were generally similar to those seen in adult animals,provider of any planned surgical procedure. Coadministration of a cabozantinib capsule formulationoccurred at both doses, and included the kidney (nephropathy,Reversible posterior leukoencephalopathy syndrome: Advise with a strong CYP3A4 inducer decreased the exposure ofglomerulonephritis), reproductive organs, gastrointestinalpatients to immediately contact their health care provider for new cabozantinib, which may reduce efficacy. Avoid coadministrationtract (cystic dilatation and hyperplasia in Brunners gland andonset or worsening neurological function. of CABOMETYX with strong CYP3A4 inducers. Increase theinflammation of duodenum; and epithelial hyperplasia of colon and dosage of CABOMETYX if coadministration with strong CYP3A4cecum), bone marrow (hypocellularity and lymphoid depletion),Thyroid dysfunction: Advise patients that CABOMETYX can inducers cannot be avoided. Avoid St. Johns wort which may alsoand liver. Tooth abnormalities and whitening as well as effectscause thyroid dysfunction and that their thyroid function should decrease exposure of cabozantinib. on bones including reduced bone mineral content and density,be monitored regularly during treatment. Advise patients to physeal hypertrophy, and decreased cortical bone also occurredimmediately contact their healthcare provider for signs or 8 USE IN SPECIFIC POPULATIONSat all dose levels. Recovery was not assessed at a dose of 2 mg/ symptoms of thyroid dysfunction. 8.1 Pregnancykg (approximately 0.32 times the clinical dose of 60 mg basedHypocalcemia: Advise patients that CABOMETYX can cause Risk Summaryon body surface area) due to high levels of mortality. At the lowlow calcium levels and that their serum calcium levels should Based on findings from animal studies and its mechanism ofdose level, effects on bone parameters were partially resolvedbe monitored regularly during treatment. Advise patients to action, CABOMETYX can cause fetal harm when administeredbut effects on the kidney and epididymis/testis persisted afterimmediately contact their healthcare provider for signs or to a pregnant woman. There are no available data in pregnanttreatment ceased.symptoms of hypocalcemia. women to inform the drug-associated risk. In animal developmental8.5 Geriatric UseEmbryo-fetal toxicity:and reproductive toxicology studies administration of cabozantinibIn CABOSUN and METEOR, 41% of 409 patients treated with Advise females of reproductive potential of the potential risk toto pregnant rats and rabbits during organogenesis resulted inCABOMETYX were age 65 years and older, and 8% were 75a fetus. Advise females to inform their healthcare provider of a embryofetal lethality and structural anomalies at exposures thatyears and older. In CELESTIAL, 49% of 467 patients treatedknown or suspected pregnancy. were below those occurring clinically at the recommended dosewith CABOMETYX were age 65 years and older, and 15% were(see Data). Advise pregnant women of the potential risk to a fetus.75 years and older. In COSMIC-311, 50% of 125 patients treated Advise females of reproductive potential to use effective In the U.S. general population, the estimated background riskwith CABOMETYX were age 65 years and older, and 12% werecontraception during treatment with CABOMETYX and for 4 of major birth defects and miscarriage in clinically recognized75 years and older. months after the final dose. pregnancies is 2-4% and 15-20%, respectively.No overall differences in safety or effectiveness were observedLactation: Advise women not to breastfeed during treatment with Databetween these patients and younger patients.CABOMETYX and for 4 months following the last dose. Animal DataOf the 320 patients randomized to CABOMETYX administeredDrug interactions: Advise patients to inform their healthcare In an embryo-fetal development study in pregnant rats, dailywith nivolumab in CHECKMATE-9ER, 41% were 65 years or olderprovider of all prescription or nonprescription medications, oral administration of cabozantinib throughout organogenesisand 9% were 75 years or older. No overall difference in safety wasvitamins or herbal products. Inform patients to avoid grapefruit, caused increased embryo-fetal lethality compared to controls atreported between elderly patients and younger patients.grapefruit juice, and St. Johns wort. a dose of 0.03 mg/kg (approximately 0.12-fold of human area8.6 Hepatic ImpairmentImportant administration information under the curve [AUC] at the recommended dose). FindingsIncreased exposure to cabozantinib has been observed in patientsInstruct patients to take CABOMETYX at least 1 hour before or at included delayed ossification and skeletal variations at a dose ofwith moderate (Child-Pugh B) hepatic impairment. Reduce theleast 2 hours after eating. 0.01 mg/kg/day (approximately 0.04-fold of human AUC at theCABOMETYX dose in patients with moderate hepatic impairment. recommended dose).Avoid CABOMETYX in patients with severe hepatic impairmentThis brief summary is based on the CABOMETYX Prescribing In pregnant rabbits, daily oral administration of cabozantinib(Child-Pugh C), since it has not been studied in this population.Information throughout organogenesis resulted in findings of visceral8.7Renal ImpairmentRevision 10/2021 malformations and variations including reduced spleen size andNo dosage adjustment is recommended in patients with mildDistributed by Exelixis, Inc. Alameda, CA 94502 missing lung lobe at 3 mg/kg (approximately 1.1-fold of the humanor moderate renal impairment. There is no experience with AUC at the recommended dose).CABOMETYX in patients with severe renal impairment. In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day10 OVERDOSAGE 20. Cabozantinib did not produce adverse maternal toxicity orOne case of overdosage was reported following administration of affect pregnancy, parturition or lactation of female rats, and didanother formulation of cabozantinib; a patient inadvertently tookCABOMETYX is a registered trademark of Exelixis, Inc.2021 not affect the survival, growth or postnatal development of thetwice the intended dose for 9 days. The patient suffered GradeExelixis, Inc.offspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum3 memory impairment, Grade 3 mental status changes, Grade 3 recommended clinical dose).cognitive disturbance, Grade 2 weight loss, and Grade 1 increasePrinted in USA 10/2021 CA-1121-48.2 Lactationin BUN. The extent of recovery was not documented. Risk Summary17 PATIENT COUNSELING INFORMATION There is no information regarding the presence of cabozantinibAdvise the patient to read the FDA-approved patient labeling or its metabolites in human milk, or their effects on the breastfed(Patient Information). child or milk production. Because of the potential for seriousHemorrhage: Instruct patients to contact their healthcare provider adverse reactions in breastfed children, advise women not toto seek immediate medical attention for signs or symptoms of breastfeed during treatment with CABOMETYX and for 4 monthsunusual severe bleeding or hemorrhage. after the final dose.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 72299_Exelixis_Cabometyx_HCP-Brief_USMedicine_7-875x10-75_r3v1jl.indd 4 11/30/21 10:03 AM'