Cabometyx

Renal Cell Carcinoma

CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

Hepatocellular Carcinoma

CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Differentiated Thyroid Cancer

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

Neuroendocrine Tumors

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET).

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET).

Important Dosage Information and Recommended Evaluation and Testing Before Initiating CABOMETYX

• Do not substitute CABOMETYX tablets with cabozantinib capsules.
• Administer CABOMETYX on an empty stomach. Administer at least 1 hour before or at least 2 hours after eating [ see Clinical Pharmacology (12.3)].
• Stop treatment with CABOMETYX 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing [see Warnings and Precautions (5.1, 5.10, 5.11)].

Recommended Dosage for Renal Cell Carcinoma

The recommended dosage of CABOMETYX as a single agent is 60 mg orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.9)].

The recommended dosage of CABOMETYX in combination with nivolumab is provided in the following table:

Recommended Dosage for Hepatocellular Carcinoma

The recommended dosage of CABOMETYX as a single agent is 60 mg orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.9)].

Recommended Dosage for Differentiated Thyroid Cancer and Neuroendocrine Tumors

Table 2 provides the recommended dosage of CABOMETYX for differentiated thyroid cancer (DTC) and neuroendocrine tumors (NET).

Dosage Modifications for Adverse Reactions

Withhold CABOMETYX for:

• Intolerable Grade 2 adverse reactions
• Grade 3 or 4 adverse reactions
• Osteonecrosis of the jaw

Upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows:

The following table represents dosage modifications for the drug administered in combination that are different from those described above for CABOMETYX or in the Full Prescribing Information:

When administering CABOMETYX in combination with nivolumab for the treatment of advanced RCC, refer to the nivolumab prescribing information.

Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors

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 or from 20 mg daily to 20 mg every other day in pediatric patients 12 years of age and older with bodyweight less than 40 kg). Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Dosage Modifications for Coadministration with Strong or Moderate CYP3A4 Inducers

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 strong or moderate CYP3A4 inducer 2 to 3 days after discontinuation of the inducer. Do not exceed a daily dose of 80 mg [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Dosage Modifications for Patients with Hepatic Impairment

Reduce the starting dose of CABOMETYX 60 mg daily to 40 mg daily or 40 mg daily to 20 mg daily (for pediatric patients 12 years of age and older with bodyweight less than 40 kg) in patients with moderate hepatic impairment (Child-Pugh B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Administration

Administer CABOMETYX on an empty stomach. Administer at least 1 hour before or at least 2 hours after eating [see Clinical Pharmacology (12.3)].

• Swallow CABOMETYX tablets whole. Do not crush, chew, or split CABOMETYX tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the CABOMETYX dose for patients taking drugs known to moderately or strongly induce CYP3A4 or strongly inhibit CYP3A4 and for patients with moderate hepatic impairment [see Dosage and Administration (2.6, 2.7, 2.8), 2.9)].

Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], CABOMETYX can cause fetal harm when administered to a pregnant woman. 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 Data). Advise pregnant women of the potential risk to a fetus.

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 area under the curve [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).

Lactation

Risk Summary

There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX [see Use in Specific Populations (8.1)].

Contraception

CABOMETYX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

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)].

Pediatric Use

The safety and effectiveness of CABOMETYX for the treatment of differentiated thyroid cancer (DTC) and neuroendocrine tumors (NETs) have been established in pediatric patients aged 12 years and older.

Use of CABOMETYX in pediatric patients aged 12 years and older with DTC and NETs is supported by evidence from adequate and well-controlled studies of CABOMETYX in adults with additional population pharmacokinetic data demonstrating that cabozantinib exposure is within the same range between adults and pediatric patients aged 12 years and older at the recommended dosages [see Dosage and Administration (2.4, 2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3, 14.4)].

Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Based on the limited available data of the effects of CABOMETYX on longitudinal growth, physeal and longitudinal growth monitoring is recommended in children with open growth plates.

The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

Juvenile Animal Toxicity Data

Juvenile rats were administered cabozantinib 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 ≥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 a dose of 2 mg/kg (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.

Geriatric Use

In CABOSUN and METEOR, 41% of 409 patients treated with CABOMETYX were age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of 467 patients treated with CABOMETYX were age 65 years and older, and 15% were 75 years and older. In COSMIC-311, 50% of 125 patients treated with CABOMETYX were age 65 years and older, and 12% were 75 years and older. In CABINET, 38% of 63 patients treated with CABOMETYX were age 65 years and older, and 5% were 75 years and older in the pNET cohort, and 55% of 132 patients treated with CABOMETYX were age 65 years and older, and 13% were 75 years and older in the epNET cohort [see Clinical Studies (14)].

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 320 patients with RCC treated with CABOMETYX in combination with nivolumab in CHECKMATE-9ER, 41% were 65 years or older and 9% were 75 years or older [see Clinical Studies (14.1)].

No overall difference in safety was reported between older and younger patients receiving both CABOMETYX and nivolumab.

Hepatic Impairment

Increased exposure to cabozantinib has been observed in patients with moderate (Child-Pugh B) hepatic impairment. Reduce the CABOMETYX dose in patients with moderate hepatic impairment. Avoid CABOMETYX in patients with severe hepatic impairment (Child-Pugh C), since it has not been studied in this population [see Dosage and Administration (2.8, 2.9), Clinical Pharmacology (12.3)].

Renal Impairment

No dosage adjustment is recommended 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)].

Hemorrhage

CABOMETYX can cause severe and fatal hemorrhages. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies [see Adverse Reactions (6.1)].

Withhold CABOMETYX for 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.10, 5.11)].

Perforations and Fistulas

CABOMETYX can cause gastrointestinal (GI) perforations and fistulas.

Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients [see [see Adverse Reactions (6.1)]. GI perforations, including fatal cases, occurred in 1% of CABOMETYX- treated patients.

Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.5)].

Thromboembolic Events

CABOMETYX can cause arterial or venous thromboembolic events.

Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thrombotic events occurred in CABOMETYX-treated patients [see Adverse Reactions (6.1)].

Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention [see Dosage and Administration (2.5)].

Hypertension and Hypertensive Crisis

CABOMETYX can cause hypertension, including hypertensive crisis [see Adverse Reactions (6.1)]. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX- treated patients. In CABINET (n=195) [see Clinical Studies (14.4)], hypertension was reported in 65% (26% Grade 3) of CABOMETYX-treated patients.

Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.5)]. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis [see Dosage and Administration (2.5)].

Diarrhea

CABOMETYX can cause diarrhea. Diarrhea occurred in 62% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 10% of patients treated with CABOMETYX [see Adverse Reactions (6.1)].

Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤Grade 1, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.5)].

Palmar-Plantar Erythrodysesthesia

CABOMETYX can cause palmar-plantar erythrodysesthesia (PPE). PPE occurred in 45% of patients treated with CABOMETYX [see Adverse Reactions (6.1)]. Grade 3 PPE occurred in 13% of patients treated with CABOMETYX.

Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE [see Dosage and Administration (2.5)].

Hepatotoxicity

CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids [see Dosage and Administration (2.5)].

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Withhold and then resume CABOMETYX at a reduced dose based on severity [see Dosage and Administration (2.5)].

Adrenal Insufficiency

CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency.

Adrenal insufficiency occurred in 4.7% (15/320) of patients treated with the combination of CABOMETYX and nivolumab including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions [see Adverse Reactions (6.1)]. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity [see Dosage and Administration (2.5)].

Proteinuria

CABOMETYX can cause proteinuria.

Proteinuria was observed in 8% of patients receiving CABOMETYX [see Adverse Reactions (6.1)].

Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome [see Dosage and Administration (2.5)].

Osteonecrosis of the Jaw

CABOMETYX can cause osteonecrosis of the jaw (ONJ).

ONJ occurred in <1% of patients treated with CABOMETYX [see Adverse Reactions (6.1)].

ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of CABOMETYX and periodically during CABOMETYX. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose [see Dosage and Administration (2.5)].

Impaired Wound Healing

CABOMETYX can cause impaired wound healing [see Adverse Reactions (6.1)]. Withhold CABOMETYX for at least 3 weeks prior to elective surgery [see Dosage and Administration (2.1)]. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established [see Dosage and Administration (2.1, 2.5)].

Reversible Posterior Leukoencephalopathy Syndrome

CABOMETYX can cause reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS [see Dosage and Administration (2.5)].

Thyroid Dysfunction

CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism. Thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients [see Adverse Reactions (6.1)].

Assess patients for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated [see Dosage and Administration (2.5)].

Hypocalcemia

CABOMETYX can cause hypocalcemia. Hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients [see Adverse Reactions (6.1)]. Laboratory abnormality data were not collected in CABOSUN and CABINET.

In COSMIC-311 (n=125) [see Clinical Studies (14.3)], hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity [see Dosage and Administration (2.5)].

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].