Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 21 April 2018

Indication(s)

1 INDICATIONS AND USAGE CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). CABOMETYX is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: Hemorrhage [see Warnings and Precautions (5.1)] GI Perforations and Fistulas [see Warnings and Precautions (5.2)] Thrombotic Events [see Warnings and Precautions (5.3)] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4)] Diarrhea [see Warnings and Precautions (5.5)] Palmar-plantar erythrodysesthesia [see Warnings and Precautions (5.6)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.7)] The most commonly reported (≥ 25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia (PPE), weight decreased, vomiting, dysgeusia and stomatitis. (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. METEOR The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received 60 mg CABOMETYX and 322 patients received 10 mg everolimus administered 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 included, in order of decreasing frequency: 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, lymphocytes decreased, anemia, hypokalemia, and GGT increased. The dose was reduced in 60% of patients receiving CABOMETYX and in 24% of patients receiving everolimus. Twenty percent (20%) of patients received 20 mg CABOMETYX 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 led to study treatment being held 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 1. 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 GradesNational Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Gastrointestinal Disorders 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 painIncludes PT terms abdominal pain, abdominal pain upper, and abdominal pain lower 23 4 13 2 Dyspepsia 12 <1 5 0 General Disorders and Administration Site Conditions Fatigue 56 9 47 7 Mucosal inflammation 19 <1 23 3 Asthenia 19 4 16 2 Metabolism and Nutrition Disorders Decreased appetite 46 3 34 <1 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 42 8 6 <1 RashIncludes PT 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 Disorders HypertensionIncludes PT terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation 39 16 8 3 Investigations Weight decreased 31 2 12 0 Nervous System Disorders Dysgeusia 24 0 9 0 Headache 11 <1 12 <1 Dizziness 11 0 7 0 Endocrine Disorders Hypothyroidism 21 0 <1 <1 Respiratory, Thoracic, and Mediastinal Disorders Dysphonia 20 <1 4 0 Dyspnea 19 3 29 4 Cough 18 <1 33 <1 Blood and Lymphatic Disorders Anemia 17 5 38 16 Musculoskeletal and Connective Tissue Disorders Pain in extremity 14 1 8 <1 Muscle spasms 13 0 5 0 Arthralgia 11 <1 14 1 Renal and Urinary Disorders Proteinuria 12 2 9 <1 Other clinically important adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis cholestatic (<1%). Table 2. Laboratory Abnormalities Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR Test CABOMETYX (n=331) Everolimus (n=322) All Grades Grade 3-4 All Grades Grade 3-4 Percentage (%) of Patients Chemistry AST increased 74 3 40 <1 ALT increased 68 3 32 <1 Creatinine increased 58 <1 71 0 Triglycerides increased 53 4 73 13 Hypophosphatemia 48 8 36 5 Hyperglycemia 37 2 59 8 Hypoalbuminemia 36 2 28 <1 ALP increased 35 2 29 1 Hypomagnesemia 31 7 4 <1 Hyponatremia 30 8 26 6 GGT increased 27 5 43 9 Hematology White blood cells decreased 35 <1 31 <1 Absolute neutrophil count decreased 31 2 17 <1 Hemoglobin decreased 31 4 71 17 Lymphocytes decreased 25 7 39 12 Platelets decreased 25 <1 27 <1 ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase. National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 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 60 mg CABOMETYX daily and 72 patients received 50 mg sunitinib taken once daily (4 weeks on treatment followed by 2 weeks off), until disease progression or unacceptable toxicity [see Clinical Studies (14)]. 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. Within 30 days of treatment, there were 4 deaths in patients treated with CABOMETYX and 6 deaths in patients treated with sunitinib. Of the 4 patients treated with CABOMETYX, two patients died due to gastrointestinal perforation, one patient had acute renal failure, and one patient died due to clinical deterioration. All Grade 3-4 adverse reactions were collected in the entire safety population. The most frequent Grade 3-4 adverse reactions (≥5%) in patients treated with CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, ALT increased, decreased appetite, stomatitis, pain, hypotension, and syncope. The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced in 46% of patients receiving CABOMETYX and in 35% of patients receiving sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in 71% of patients receiving sunitinib. Based on patient disposition, 21% of patients receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to an adverse reaction. Table 3. Grade 3-4 Adverse Reactions Occurring in ≥ 1% Patients Who Received CABOMETYX in CABOSUN CABOMETYX n = 78 Sunitinib n = 72 Grade 3-4National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 Grade 3-4 Percentage (%) of Patients Patients with any Grade 3-4 Adverse Reaction 68 65 Gastrointestinal Disorders Diarrhea 10 11 Stomatitis 5 6 Nausea 3 4 Vomiting 1 3 Constipation 1 0 General Disorders and Administration Site Conditions Fatigue 6 17 Pain 5 0 Metabolism and Nutrition Disorders HyponatremiaLaboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values 9 8 Hypophosphatemia 9 7 Decreased appetite 5 1 Dehydration 4 1 Hypocalcemia 3 0 Hypomagnesemia 3 0 Hypokalemia 1 3 Skin and Subcutaneous Skin Disorders Palmar-plantar erythrodysesthesia 8 4 Skin Ulcer 3 0 Vascular Disorders HypertensionIncludes PT term hypertension 28 21 Hypotension 5 1 Angiopathy 1 1 Investigations ALT increased 5 0 Weight decreased 4 0 AST increased 3 3 Blood creatinine increased 3 3 Lymphocyte count decreased 1 6 Platelet count decreased 1 11 Nervous System Disorders Syncope 5 0 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 1 6 Dysphonia 1 0 Blood and Lymphatic Disorders Anemia 1 3 Psychiatric Disorders Depression 4 0 Confusional state 1 1 Infections and Infestations Lung Infection 4 0 Musculoskelatal and Connective Tissue Disorders Back pain 4 0 Bone pain 3 1 Pain in extremity 3 0 Arthralgia 1 0 Renal and Urinary Disorders Renal failure acute 4 1 Proteinuria 3 1 ALT, alanine aminotransferase; AST, aspartate aminotransferase

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended Dose: 60 mg orally, once daily. (2.1) Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX. (2.1) Do NOT substitute CABOMETYX tablets with cabozantinib capsules. (2.1) 2.1 Recommended Dose Do not substitute CABOMETYX tablets with cabozantinib capsules. The recommended oral daily dose of CABOMETYX is 60 mg. Do not administer CABOMETYX with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX. Continue treatment until patient no longer experiences clinical benefit or experiences unacceptable toxicity. Swallow CABOMETYX tablets whole. Do not crush CABOMETYX tablets. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during CABOMETYX treatment [see Drug Interactions (7)]. 2.2 Dosage Adjustments For Patients Undergoing Surgery Stop treatment with CABOMETYX at least 28 days prior to scheduled surgery, including dental surgery.[see Warning and Precautions (5.1)]. For Adverse Reactions Management of Grade ≤3 adverse reactions may require dose modifications and/or supportive care. If dose reduction is required, a 20 mg decrease from the previously administered dose is recommended. If Grade ≤3 adverse reaction is intolerable, withhold CABOMETYX. Withhold CABOMETYX for NCI CTCAE Grade 4 adverse reactions. If the dose was withheld, upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows: If previously receiving 60 mg daily dose, resume treatment at 40 mg daily If previously receiving 40 mg daily dose, resume treatment at 20 mg daily If previously receiving 20 mg daily dose, resume at 20 mg if tolerated, otherwise, discontinue CABOMETYX Permanently discontinue CABOMETYX for any of the following: development of unmanageable fistula or GI perforation severe hemorrhage arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction) hypertensive crisis or severe hypertension despite optimal medical management nephrotic syndrome reversible posterior leukoencephalopathy syndrome In Patients Concurrently Taking a Strong CYP3A4 Inhibitor Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)]. In Patients Concurrently Taking a Strong CYP3A4 Inducer Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of CABOMETYX should not exceed 80 mg [see Drug Interactions (7), Clinical Pharmacology (12.3)]. In Patients with Hepatic Impairment Reduce the starting dose of CABOMETYX to 40 mg once daily in patients with mild or moderate hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Mild to Moderate Hepatic Impairment: Reduce the CABOMETYX dosage. (2.2, 8.6) Lactation: Advise not to breastfeed while taking CABOMETYX. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 Nonclinical Toxicology (13.1)]. Advise pregnant women or women of childbearing potential of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 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 infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from CABOMETYX, advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females CABOMETYX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. 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 in pediatric patients have not been established. Juvenile Animal Data Juvenile rats were administered cabozantinib daily 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 equal and greater than 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 the 2 mg/kg dose level (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 RCC studies, 41% of patients treated with CABOMETYX were age 65 years and older, and 8% of patients were 75 years and older. Grade 3-4 adverse reactions occurred in 73% of patients age 65 years and older, and in 76% of patients 75 years and older. No overall differences in safety or efficacy were observed between older and younger patients. 8.6 Hepatic Impairment Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce the CABOMETYX dose in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.2), and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Dosage adjustment is not required 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)].
Pregnancy and lactation
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 infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from CABOMETYX, advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Interactions

7 DRUG INTERACTIONS Table 4. Clinically Significant Drug Interactions Involving Drugs that Affect Cabozantinib Strong CYP3A4 Inhibitors Clinical Implications: Concomitant use of CABOMETYX with a strong CYP3A4 inhibitor increased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Increased cabozantinib exposure may increase the risk of exposure-related toxicity. Prevention or Management: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2)]. Examples: Boceprevir, clarithromycin, conivaptan, grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a "strong CYP3A inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a "moderate CYP3A inhibitor" when another preparation was used (e.g., low dose, single strength)., indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole Strong CYP3A4 Inducers Clinical Implications: Concomitant use of CABOMETYX with a strong CYP3A4 inducer decreased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Decreased cabozantinib exposure may lead to reduced efficacy. Prevention or Management: Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. Examples: Rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and St. John’s WortThe effect of St. John’s Wort varies widely and is preparation-dependent Strong CYP3A4 inhibitors: Reduce the CABOMETYX dosage. (2.2, 7) Strong CYP3A4 inducers: Increase the CABOMETYX dosage. (2.2, 7)

More information

Category Value
Authorisation number NDA208692
Agency product number DR7ST46X58
Orphan designation No
Product NDC 42388-025,42388-024,42388-023
Date Last Revised 20-12-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Exelixis, Inc.