Usual Adult Dose for Thyroid Cancer

Capsules: 140 mg orally once a day until patient no longer experiences clinical benefit or unacceptable toxicity occurs
Tablets: BSA greater than or equal to 1.2 m(2): 60 mg once a day until disease progression or unacceptable toxicity

Comments:

• Do not substitute tablets with the capsules.
• Stop treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Uses:

• For progressive metastatic medullary thyroid cancer (MTC)
• For the treatment of adult 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

Usual Adult Dose for Renal Cell Carcinoma

Tablets:

• As a single agent: 60 mg orally once a day until patient no longer experiences clinical benefit or unacceptable toxicity occurs
• In combination with nivolumab: 40 mg once a day until disease progression or unacceptable toxicity

Comments:

• When administering this drug in combination with nivolumab, refer to the nivolumab prescribing information.
• Do not substitute tablets with the capsules.
• Stop treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Uses:

• For patients with advanced renal cell carcinoma (RCC)
• In combination with nivolumab, indicated for the first-line treatment of patients with advanced RCC

Usual Adult Dose for Hepatocellular Carcinoma

Tablets: 60 mg orally once a day until patient no longer experiences clinical benefit or unacceptable toxicity occurs

Comments:

• Do not substitute tablets with the capsules.
• Stop treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Use: For patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Usual Pediatric Dose for Thyroid Cancer

Tablets: BSA greater than or equal to 1.2 m(2): 60 mg once a day until disease progression or unacceptable toxicity
Tablets: BSA less than 1.2 m(2): 40 mg once a day until disease progression or unacceptable toxicity

Comments:

• Do not substitute tablets with the capsules.
• Stop treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Use: For the treatment of 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

Renal Dose Adjustments

Capsules/Tablets:

• Mild to moderate renal dysfunction: No adjustment recommended.
• Severe renal dysfunction: Data not available

Liver Dose Adjustments

Capsule formulation (MTC):

• Mild to moderate hepatic dysfunction: 80 mg orally once a day
• Severe hepatic dysfunction: Use is not recommended.

Tablet formulation (MTC):

• Mild hepatic dysfunction: No adjustment recommended.
• Moderate hepatic dysfunction: 40 mg daily OR 40 mg daily to 20 mg daily [for pediatric patients with BSA less than 1.2 m(2)].
• Severe hepatic dysfunction: Use is not recommended.

Tablet formulation (RCC):

• Mild to moderate hepatic dysfunction: 40 mg orally once a day
• Severe hepatic dysfunction: Use is not recommended.

• In combination with nivolumab
• If ALT or AST greater then 3 times upper limit of normal (ULN) but up to 10 times ULN with concurrent total bilirubin less than 2 times ULN: Withhold this drug and nivolumab until adverse reactions recover to Grades 0 or 1 and consider corticosteroid therapy as appropriate. Might rechallenge with one or both drugs after recovery.
• If ALT or AST greater than 10 times ULN or greater than 3 times ULN with concurrent total bilirubin of at least 2 times ULN: Permanently discontinue this drug and nivolumab. Corticosteroid therapy may be considered if immune-mediated reaction is suspected.

Dose Adjustments

CAPSULE FORMULATION (MTC):

• Adverse Reactions (Grade 4, Grade 3, or intolerable Grade 2): Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If previous dose 140 mg/day: Reduce dose to 100 mg/day
• If previous dose 100 mg/day: Reduce dose to 60 mg/day
• If previous dose 60 mg/day: Do not dose reduce; resume at 60 mg/day if tolerated or discontinue therapy.
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 40 mg (e.g., from 140 mg/day to 100 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended. If concomitant use is necessary, increase the dose of this drug by 40 mg (e.g., from 140 mg/day to 180 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the CYP450 3A4 inducer. Do not exceed 180 mg/day.
• Permanently discontinue therapy for development of perforation or fistula formation, severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, severe hypertension despite optimal medical management, osteonecrosis of the jaw, or reversible posterior leukoencephalopathy syndrome.

TABLET FORMULATION (RCC):

• Scheduled Surgery: Stop treatment at least 28 days prior to scheduled surgery, including dental surgery.
• Adverse Reactions (Grade 4, Grade 3, or Intolerable Grade 2) or osteonecrosis of the jaw: Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If previous dose 60 mg/day: Reduce dose to 40 mg/day
• If previous dose 40 mg/day: Reduce dose to 20 mg/day
• If previous dose 20 mg/day: Do not dose reduce; resume at 20 mg/day if tolerated or discontinue therapy
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 20 mg (e.g., from 60 mg/day to 40 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended if alternative therapy is available. If concomitant use is necessary, increase the dose of this drug by 20 mg (e.g., from 60 mg/day to 80 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the 3A4 inducer. Do not exceed 80 mg/day.
• Permanently discontinue therapy for 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, or reversible posterior leukoencephalopathy syndrome.

TABLET FORMULATION (RCC):

• Adverse Reactions (Grade 4, Grade 3, or intolerable Grade 2): Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If previous dose 60 mg daily in adult and pediatric patients with BSA greater than or equal to 1.2 m(2): Reduce dose to 40 mg/day OR if previous dose 20 mg every other day; do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy
• If previous dose 40 mg daily in pediatric patients with BSA less than 1.2 m(2): Reduce dose to 20 mg/day OR if previous dose 20 mg every other day, do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy

TABLET FORMULATION (RCC) IN COMBINATION WITH NIVOLUMAB:

• Scheduled Surgery: Stop treatment at least 3 weeks prior to scheduled surgery, including dental surgery.
• Adverse Reactions (Grade 4, Grade 3, or Intolerable Grade 2) or osteonecrosis of the jaw: Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If previous dose 40 mg/day: Reduce dose to 20 mg once a day
• If previous dose 20 mg/day: Reduce dose to 20 mg every other day
• If previous dose 20 mg every other day: Do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 20 mg (e.g., from 60 mg/day to 40 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended if alternative therapy is available. If concomitant use is necessary, increase the dose of this drug by 20 mg (e.g., from 60 mg/day to 80 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the 3A4 inducer. Do not exceed 80 mg/day.
• Permanently discontinue therapy for development of gastrointestinal perforation or Grade 4 fistula, severe hemorrhage, acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention, severe hypertension that cannot be controlled with anti-hypertensive therapy or hypertensive crisis, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 12 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration Advice:

• Tablets and capsules are not interchangeable.
• This drug should be taken on an empty stomach at least 2 hours before or 1 hour after a meal.
• Do not open/break/crush/chew tablets or capsules; swallow whole with a full glass of water.
• Do not take a missed dose if it is less than 12 hours before the next dose.
• Do not ingest foods (e.g., grapefruit) or nutritional supplements (e.g., St. John's Wort) that are known to inhibit or induce CYP450 activity while taking this drug.

Storage Requirements:

• Store at 20C to 25C (68F to 77F).
• Keep in the original package to protect from moisture.

Monitoring:

• Cardiovascular: Blood pressure (prior to and regularly during therapy)
• Musculoskeletal: Oral exam (prior to and periodically during therapy due to ONJ risk)
• Renal: Urine protein (regularly during therapy)
• Endocrine: Thyroid (prior to and regularly during therapy)
• Metabolic: Serum calcium (regularly during therapy)

Patient Advice:

• This drug may cause side effects such as dizziness that can affect your ability to perform certain activities; avoid driving and activities such as operating machinery until you know how this drug affects you.
• Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.
• Advise patients to contact their healthcare provider immediately for signs or symptoms of thyroid dysfunction.
• Advise patients to contact their healthcare provider immediately for signs or symptoms of hypocalcemia.
• Advise patients to contact their healthcare provider for signs or symptoms of proteinuria.
• Advise patients receiving this drug with nivolumab to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency.

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