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Dosing in CABOMETYX® (cabozantinib) HCC monotherapy

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Available in 3 strengths to help you find the right dose for your patients when needed1

RECOMMENDED
STARTING DOSE*		 FIRST
REDUCTION		 SECOND
REDUCTION

60 mg
once daily
40 mg
once daily
20 mg
once daily†
RECOMMENDED STARTING DOSE* 60 mg once daily
FIRST REDUCTION 40 mg once daily
SECOND REDUCTION 20 mg once daily†

Tablets shown are not actual size.

*

Until disease progression or unacceptable toxicity, administer as recommended.1

†

If previously receiving lowest dose, resume at same dose. If lowest dose not tolerated, discontinue CABOMETYX.1

In the CELESTIAL trial, the mean average daily dose was 37 mg2
Reduce dose of CABOMETYX for patients with hepatic impairment1

Child-Pugh B: Reduce the starting dose of CABOMETYX to 40 mg once daily in patients with moderate hepatic impairment.

  • Avoid CABOMETYX in patients with severe hepatic impairment (Child-Pugh C)

How to administer CABOMETYX1

Administer on an empty stomach

Administer CABOMETYX at least 1 hour before or at least 2 hours after eating

Swallow CABOMETYX tablet whole

Do not crush, chew, or split CABOMETYX tablets

  • Withhold CABOMETYX for at least 3 weeks prior to elective surgery, including dental surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed, to reduce the risk of hemorrhage1
  • Do not substitute CABOMETYX tablets with cabozantinib capsules1
  • Do not take a missed dose within 12 hours of the next dose1
  • Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to moderately or strongly induce or strongly inhibit CYP3A41

Pharmacokinetics

The predicted terminal half-life of CABOMETYX is approximately 99 hours.1

Dose modifications1

You may need to adjust the CABOMETYX dose based on individual patient safety and tolerability. If ARs occur, consider supportive care and/or adjust the dose.

For intolerable Grade 2 ARs, Grade 3-4 ARs, and ONJ

Withhold CABOMETYX

Wait until improvement or resolution (return to baseline or resolution to Grade 1)

Reduce the dose by 20 mg
If previously receiving 20 mg once daily, resume at same dose.
If not tolerated, discontinue CABOMETYX

Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage, development of a GI perforation or Grade 4 fistula, acute myocardial infarction or Grade 2 or higher cerebral infarction, Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events, Grade 4 hypertension/hypertensive crisis or Grade 3 hypertension/hypertensive crisis that cannot be controlled, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.1

Median time to dose reductions3,4

 

When strong CYP3A4 inhibitors cannot be avoided1

Reduce the daily dose of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided.

Resume CABOMETYX at the dose used prior to initiating the strong CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

Examples of strong CYP3A4 inhibitors‡:

  • Boceprevir
  • Clarithromycin
  • Conivaptan
  • Grapefruit juice
  • Indinavir/ritonavir
  • Itraconazole
  • Ketoconazole
  • Lopinavir/ritonavir 
  • Nefazodone
  • Nelfinavir
  • Posaconazole
  • Ritonavir
  • Saquinavir/ritonavir
  • Voriconazole

 

When strong or moderate CYP3A4 inducers cannot be avoided1

Increase the daily dose of CABOMETYX if concomitant use with strong or moderate CYP3A4 inducers cannot be avoided.

Resume CABOMETYX at the dose used prior to initiating the strong or moderate CYP3A4 inducer 2-3 days after discontinuation of the strong or moderate inducer.

  • Do not exceed a daily dose of 80 mg
Examples of strong CYP3A4 inducers‡:
  • Rifampin
  • Phenytoin
  • Carbamazepine
  • St. John’s wort
Examples of moderate CYP3A4 inducers‡:
  • Bosentan 
  • Phenobarbital
  • Etravirine 
  • Dabrafenib

‡Examples listed may not be comprehensive.

For eligible patients who have been prescribed CABOMETYX: Dose Exchange Program

Provides a free 15-tablet supply in the lower dose to help patients who require a dose reduction§||

§

Additional restrictions and eligibility rules apply.  

||

Patients are required to return any unused product.

Learn More

This description of the Exelixis Access Services® (EASE) program is for informational purposes only. Exelixis® makes no representation or guarantee concerning reimbursement or coverage for any service or item. Information provided through the Exelixis Access Services program does not constitute medical or legal advice and is not intended to be a substitute for a consultation with a licensed health care provider, legal counsel, or applicable third-party payer(s). Exelixis reserves the right to modify the program at any time without notice.

Download the CABOMETYX Dosing and Administration Guide

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Download the CABOMETYX Treatment Management Guide

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AR=adverse reaction; CYP3A4=cytochrome P450 family 3 subfamily A member 4; GI=gastrointestinal; HCC=hepatocellular carcinoma; ONJ=osteonecrosis of the jaw.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  2. Data on file. Exelixis, Inc.
  3. European Medicines Agency: Committee for Medicinal Products for Human Use (CHMP). Assessment report: CABOMETYX. September 2018. Accessed 2019.
  4. Schwartz G, Darling JO, Mindo M, Damicis L. Management of adverse events associated with cabozantinib treatment in patients with advanced hepatocellular carcinoma. Target Oncol. 2020;15(4):549-565. doi:10.1007/s11523-020-00736-8

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thrombotic Events: CABOMETYX can cause arterial or venous thromboembolic event. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of CABOMETYX 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; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. 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.

Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer 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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4).

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

Please see full Prescribing Information.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Indications

CABOMETYX® (cabozantinib) 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 extrapancreatic neuroendocrine tumors (epNET)​. 

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). 

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

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

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.

CABOMETYX® (cabozantinib) 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 extrapancreatic neuroendocrine tumors (epNET)​. 

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). 

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

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

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.

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