Cabometyx

Indications and Usage, Neuroendocrine Tumors (

Tablets:

• 60 mg: yellow film-coated, oval shaped with no score, and debossed with "XL" on one side and "60" on the other side.
• 40 mg: yellow film-coated, triangle shaped with no score, and debossed with "XL" on one side and "40" on the other side.
• 20 mg: yellow film-coated, round with no score, and debossed with "XL" on one side and "20" on the other side.

• Hepatic Impairment: Reduce the CABOMETYX dosage for patients with moderate hepatic impairment. Avoid in patients with severe hepatic impairment. (
  2.6 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)]

  .
  ,
  8.6 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 (2.2, 2.6), Clinical Pharmacology (12.3)]

  .
  )
• Lactation: Advise not to breastfeed. (
  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 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.
  )
• Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. (
  8.4 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 (2.2, 2.3), 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.
  )

• Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. (
  5.1 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 (2.3), Warnings and Precautions (5.11, 5.12)]

  .
  )
• Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade 4 fistula or perforation. (
  5.2 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 (2.3)]

  .
  )
• Thromboembolic Events: Discontinue CABOMETYX for myocardial infarction or serious venous or arterial thromboembolic events. (
  5.3 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 thromboembolic 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 (2.3)]

  .
  )
• Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. (
  5.4 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 (2.3)]

  . Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis

  [see Dosage and Administration (2.3)]

  .
  )
• Cardiac Failure: Monitor patients for signs and symptoms of cardiac failure throughout treatment. (
  5.5 Cardiac Failure

  CABOMETYX can cause severe and fatal cardiac failure

  [see Adverse Reactions (6.1)]

  . Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Median time to onset of cardiac failure was 73 days (range: 44 days to 159 days).

  Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on the severity

  [see Dosage and Administration (2.3)]

  .
  )
• Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to ≤Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. (
  5.6 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 (2.3)]

  .
  )
• Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. (
  5.7 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 (2.3)]

  .
  )
• Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade 3 and 4 ALT and AST elevation may occur than with CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. (
  5.8 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 (2.3)]

  .

  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 (2.3)]

  .
  )
• Adrenal Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. (
  5.9 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 (2.3)]

  .
  )
• Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to ≤ Grade 1, resume CABOMETYX at a reduced dose. Discontinue for nephrotic syndrome. (
  5.10 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 (2.3)]

  .
  )
• Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least 3 weeks prior to invasive dental procedures and for development of ONJ. (
  5.11 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 (2.3)]

  .
  )
• Impaired Wound Healing: Withhold CABOMETYX for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. (
  5.12 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, 2.3)]

  .
  )
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue CABOMETYX. (
  5.13 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 (2.3)]

  .
  )
• Thyroid Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. (
  5.14 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 (2.3)]

  .
  )
• Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. (
  5.15 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 (2.3)]

  .
  )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.16 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)]

  .
  ,
  8.1 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).
  ,
  8.3 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)]

  .
  )

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Hemorrhage
  [see

  5.1 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 (2.3), Warnings and Precautions (5.11, 5.12)]

  .

  ]
• Perforations and Fistulas
  [see

  5.2 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 (2.3)]

  .

  ]
• Thromboembolic Events
  [see

  5.3 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 thromboembolic 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 (2.3)]

  .

  ]
• Hypertension and Hypertensive Crisis
  [see

  5.4 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 (2.3)]

  . Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis

  [see Dosage and Administration (2.3)]

  .

  ]
• Cardiac Failure
  [see

  5.5 Cardiac Failure

  CABOMETYX can cause severe and fatal cardiac failure

  [see Adverse Reactions (6.1)]

  . Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Median time to onset of cardiac failure was 73 days (range: 44 days to 159 days).

  Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on the severity

  [see Dosage and Administration (2.3)]

  .

  ]
• Diarrhea
  [see

  5.6 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 (2.3)]

  .

  ]
• Palmar-plantar Erythrodysesthesia
  [see

  5.7 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 (2.3)]

  .

  ]
• Hepatotoxicity
  [see

  5.8 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 (2.3)]

  .

  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 (2.3)]

  .
  ]
• Adrenal Insufficiency
  [see

  5.9 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 (2.3)]

  .
  ]
• Proteinuria
  [see

  5.10 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 (2.3)]

  .

  ]
• Osteonecrosis of the Jaw
  [see

  5.11 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 (2.3)]

  .

  ]
• Impaired Wound Healing
  [see

  5.12 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, 2.3)]

  .

  ]
• Reversible Posterior Leukoencephalopathy Syndrome
  [see

  5.13 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 (2.3)]

  .

  ]
• Thyroid Dysfunction
  [see

  5.14 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 (2.3)]

  .

  ]
• Hypocalcemia
  [see

  5.15 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 (2.3)]

  .

  ]