b'BLEED: 8.375"w TRIM: 7.875"w SAFETY: 6.875"w Table 9. Laboratory Abnormalities Occurring in 10% ofoffspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum17 PATIENT COUNSELING INFORMATION CABOMETYX-Treated Patients in COSMIC-311 1 recommended clinical dose).Advise the patient to read the FDA-approved patient labeling CABOMETYXPlacebo8.2 Lactation(Patient Information). CODE_CABOMETYX_RCC_3PG_Efficacy In Balance JournalAd_7.875" x 10.5_A-Size_Page LaboratoryN=125 N=62 Risk SummaryHemorrhage: Instruct patients to contact their healthcare providerSAFETY: 9.5"hTRIM: 10.5"hBLEED: 11.25"h Abnormality AllGrade AllGrade There is no information regarding the presence of cabozantinibto seek immediate medical attention for signs or symptoms of Grades 3 or 4 Grades 3 or 4 or its metabolites in human milk, or their effects on the breastfedunusual severe bleeding or hemorrhage. Percentage (%) of Patients child or milk production. Because of the potential for seriousPerforations and fistulas: Advise patients that gastrointestinal Chemistry adverse reactions in breastfed children, advise women not todisorders such as diarrhea, nausea, vomiting, and constipation LDH increased 2 90 10 32 3 breastfeed during treatment with CABOMETYX and for 4 monthsmay develop during CABOMETYX treatment and to seek AST increased77 1 18 0 after the final dose.immediate medical attention if they experience persistent or severe ALT increased66 2 11 0 8.3Females and Males of Reproductive Potentialabdominal pain because cases of gastrointestinal perforation and Hypocalcemia 36 9 10 2 Pregnancy Testingfistula have been reported in patients taking CABOMETYX. ALP increased34 0 15 0 Verify the pregnancy status of females of reproductive potentialThrombotic events: Venous and arterial thrombotic events have GGT increased26 2 21 2 prior to initiating CABOMETYX.been reported. Advise patients to report signs or symptoms of Hypomagnesemia 25 2 5 0 Contraceptionan arterial thrombosis. Venous thromboembolic events including Hypoalbuminemia 19 1 7 0 CABOMETYX can cause fetal harm when administered to apulmonary embolus have been reported. Advise patients to Hypokalemia 18 1 3 0 pregnant woman.contact their health care provider if new onset of dyspnea, chest Hyponatremia 15 0 10 2 Femalespain, or localized limb edema occurs.Hyperbilirubinemia 12 0 5 0 Advise females of reproductive potential to use effectiveHypertension and hypertensive crisis: Inform patients of the Hematology contraception during treatment with CABOMETYX and for 4signs and symptoms of hypertension. Advise patients to undergo Leukocytesmonths after the final dose.routine blood pressure monitoring and to contact their health care decreased 38 2 7 2 Infertilityprovider if blood pressure is elevated or if they experience signs NeutrophilsFemales and Malesor symptoms of hypertension. decreased 31 2 5 2 Based on findings in animals, CABOMETYX may impair fertility inDiarrhea: Advise patients to notify their healthcare provider at Plateletsfemales and males of reproductive potential.the first signs of poorly formed or loose stool or an increased decreased 26 0 5 0 8.4 Pediatric Usefrequency of bowel movements.1Includes laboratory abnormalities that are more frequent in theThe safety and effectiveness of CABOMETYX for the treatmentPalmar-plantar erythrodysesthesia: Advise patients to contact theirCABOMETYX arm and have a between-arm difference of5% (allof differentiated thyroid cancer (DTC) have been established inhealthcare provider for progressive or intolerable rash. grades) or2% (Grade 3-4) pediatric patients aged 12 years and older.2Sponsor-defined grades for LDH were as follows: Grade 1 ( ULN toHepatotoxicity: Advise patients to contact their healthcare provider Use of CABOMETYX in pediatric patients aged 12 years and2ULN), Grade 2 ( 2ULN to3ULN), Grade 3 ( 3ULN). older with DTC is supported by evidence from adequate andimmediately for jaundice, severe nausea or vomiting, or easy ALP,alkalinephosphatase; ALT,alanineaminotransferase; AST,bruising or bleeding. aspartate aminotransferase; GGT, gamma glutamyl transferase; LDH,well-controlled studies of CABOMETYX in adults with additional blood lactate dehydrogenase population pharmacokinetic data demonstrating that cabozantinibAdrenal insufficiency: Advise patients receiving with nivolumab exposure is within the same range between adults and pediatricto contact their healthcare provider immediately for signs or 7 DRUG INTERACTIONSpatients aged 12 years and older at the recommended dosages. symptoms of adrenal insufficiency. The safety and effectiveness of CABOMETYX in pediatric patientsProteinuria: Advise patients to contact their healthcare provider for 7.1 Effects of Other Drugs on CABOMETYXless than 12 years of age have not been established.signs or symptoms of proteinuria. Strong CYP3A4 InhibitorsJuvenile Animal Toxicity DataOsteonecrosis of the jaw: Advise patients regarding good oral Coadministration of a cabozantinib capsule formulation with aJuvenile rats were administered cabozantinib at doses of 1 or 2hygiene practices. Advise patients to immediately contact their strong CYP3A4 inhibitor increased the exposure of cabozantinib,mg/kg/day from Postnatal Day 12 (comparable to less than 2 yearshealthcare provider for signs or symptoms associated with which may increase the risk of exposure-related adversein humans) through Postnatal Day 35 or 70. Mortalities occurredosteonecrosis of the jaw. reactions. Avoid coadministration of CABOMETYX with strongat doses 1 mg/kg/day (approximately 0.16 times the clinical CYP3A4 inhibitors. Reduce the dosage of CABOMETYX ifdose of 60 mg/day based on body surface area). Hypoactivity wasImpaired wound healing: Advise patients that CABOMETYX may coadministration with strong CYP3A4 inhibitors cannot beobserved at both doses tested on Postnatal Day 22. Targets wereimpair wound healing. Advise patients to inform their healthcare avoided. Avoid grapefruit or grapefruit juice which may alsogenerally similar to those seen in adult animals, occurred at bothprovider of any planned surgical procedure. increase exposure of cabozantinib.doses, and included the kidney (nephropathy, glomerulonephritis),Reversible posterior leukoencephalopathy syndrome: Advise Strong CYP3A Inducersreproductive organs, gastrointestinal tract (cystic dilatation andpatients to immediately contact their health care provider for new Coadministration of a cabozantinib capsule formulationhyperplasia in Brunners gland and inflammation of duodenum;onset or worsening neurological function. with a strong CYP3A4 inducer decreased the exposure ofand epithelial hyperplasia of colon and cecum), bone marrowThyroid dysfunction: Advise patients that CABOMETYX can cabozantinib, which may reduce efficacy. Avoid coadministration(hypocellularity and lymphoid depletion), and liver. Toothcause thyroid dysfunction and that their thyroid function should of CABOMETYX with strong CYP3A4 inducers. Increase theabnormalities and whitening as well as effects on bones includingbe monitored regularly during treatment. Advise patients to dosage of CABOMETYX if coadministration with strong CYP3A4reduced bone mineral content and density, physeal hypertrophy,immediately contact their healthcare provider for signs or inducers cannot be avoided. Avoid St. Johns wort which may alsoand decreased cortical bone also occurred at all dose levels.symptoms of thyroid dysfunction. decrease exposure of cabozantinib. Recovery was not assessed at a dose of 2 mg/kg (approximatelyHypocalcemia: Advise patients that CABOMETYX can cause 8 USE IN SPECIFIC POPULATIONS0.32 times the clinical dose of 60 mg based on body surface area)low calcium levels and that their serum calcium levels should 8.1 Pregnancydue to high levels of mortality. At the low dose level, effects onbe monitored regularly during treatment. Advise patients to Risk Summarybone parameters were partially resolved but effects on the kidneyimmediately contact their healthcare provider for signs or Based on findings from animal studies and its mechanism ofand epididymis/testis persisted after treatment ceased.symptoms of hypocalcemia. action, CABOMETYX can cause fetal harm when administered8.5 Geriatric UseEmbryo-fetal toxicity:to a pregnant woman. There are no available data in pregnantIn CABOSUN and METEOR, 41% of 409 patients treated with Advise females of reproductive potential of the potential risk to women to inform the drug-associated risk. In animal developmentalCABOMETYX were age 65 years and older, and 8% were 75 and reproductive toxicology studies administration of cabozantinibyears and older. In CELESTIAL, 49% of 467 patients treateda fetus. Advise females to inform their healthcare provider of a to pregnant rats and rabbits during organogenesis resulted inwith CABOMETYX were age 65 years and older, and 15% wereknown or suspected pregnancy. embryofetal lethality and structural anomalies at exposures that75 years and older. In COSMIC-311, 50% of 125 patients treated Advise females of reproductive potential to use effectivewere below those occurring clinically at the recommended dosewith CABOMETYX were age 65 years and older, and 12% werecontraception during treatment with CABOMETYX and for 4 (see Data). Advise pregnant women of the potential risk to a fetus.75 years and older. months after the final dose. In the U.S. general population, the estimated background riskNo overall differences in safety or effectiveness were observedLactation: Advise women not to breastfeed during treatment with of major birth defects and miscarriage in clinically recognizedbetween these patients and younger patients.CABOMETYX and for 4 months following the last dose. pregnancies is 2-4% and 15-20%, respectively.Of the 320 patients randomized to CABOMETYX administeredDrug interactions: Advise patients to inform their healthcare Datawith nivolumab in CHECKMATE-9ER, 41% were 65 years or olderprovider of all prescription or nonprescription medications, Animal Dataand 9% were 75 years or older. No overall difference in safety wasvitamins or herbal products. Inform patients to avoid grapefruit, In an embryo-fetal development study in pregnant rats, dailyreported between elderly patients and younger patients.grapefruit juice, and St. Johns wort. oral administration of cabozantinib throughout organogenesis8.6 Hepatic ImpairmentImportant administration information caused increased embryo-fetal lethality compared to controls atIncreased exposure to cabozantinib has been observed in patientsInstruct patients to take CABOMETYX at least 1 hour before or at a dose of 0.03 mg/kg (approximately 0.12-fold of human areawith moderate (Child-Pugh B) hepatic impairment. Reduce theleast 2 hours after eating. under the curve [AUC] at the recommended dose). FindingsCABOMETYX dose in patients with moderate hepatic impairment. included delayed ossification and skeletal variations at a dose ofAvoid CABOMETYX in patients with severe hepatic impairmentThis brief summary is based on the CABOMETYX Prescribing 0.01 mg/kg/day (approximately 0.04-fold of human AUC at the(Child-Pugh C), since it has not been studied in this population.Information recommended dose).8.7Renal ImpairmentRevision 07/2022 In pregnant rabbits, daily oral administration of cabozantinibNo dosage adjustment is recommended in patients with mild throughout organogenesis resulted in findings of visceralor moderate renal impairment. There is no experience withDistributed by Exelixis, Inc. Alameda, CA 94502 malformations and variations including reduced spleen size andCABOMETYX in patients with severe renal impairment. missing lung lobe at 3 mg/kg (approximately 1.1-fold of the human10 OVERDOSAGE AUC at the recommended dose).One case of overdosage was reported following administration of In a pre- and postnatal study in rats, cabozantinib wasanother formulation of cabozantinib; a patient inadvertently took administered orally from gestation day 10 through postnatal daytwice the intended dose for 9 days. The patient suffered GradeCABOMETYX is a registered trademark of Exelixis, Inc.20. Cabozantinib did not produce adverse maternal toxicity or3 memory impairment, Grade 3 mental status changes, Grade 3 2022 Exelixis, Inc.affect pregnancy, parturition or lactation of female rats, and didcognitive disturbance, Grade 2 weight loss, and Grade 1 increase not affect the survival, growth or postnatal development of thein BUN. The extent of recovery was not documented.Printed in USA 07/2022 CA-1121-572582_CA-1121-5_Exelixis_Cabometyx_HCP-Brief_7-75x10-75_r1v1jl.indd 4 8/5/22 12:29 PM'