Cabometyx (cabozantinib)

Cabometyx may cause serious side effects, including:

• bleeding (hemorrhage). Cabometyx can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with Cabometyx, including:
  • coughing up blood or blood clots o red or black (looks like tar) stools
  • vomiting blood or if your vomit looks like coffee-grounds
  • menstrual bleeding that is heavier than normal
  • any unusual or heavy bleeding
• a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2parts of your body (fistula). Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen).
• blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:
  • swelling or pain in your arms or legs
  • shortness of breath
  • feel lightheaded or faint
  • sweating more than usual
  • numbness or weakness of your face, arm or leg, especially on one side of your body
  • sudden confusion, trouble speaking or understanding
  • sudden trouble seeing in one or both eyes
  • sudden trouble walking
  • dizziness, loss of balance or coordination
  • a sudden severe headache
• high blood pressure (hypertension). Hypertension is common with Cabometyx and sometimes can be severe. Your healthcare provider will check your blood pressure before starting Cabometyx and during treatment with Cabometyx. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure.
• diarrhea. Diarrhea is common with Cabometyx and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.
• a skin problem called hand-foot skin reaction. Hand-foot skin reactions are common and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.
• protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet.
• severe jaw bone problems (osteonecrosis). Symptoms may include jaw pain, toothache, or sores on your gums. Your healthcare provider should examine your mouth before you start and during treatment with Cabometyx. Tell your dentist that you are taking Cabometyx. It is important for you to practice good mouth care during treatment with Cabometyx.
• wound healing problems. Wound healing problems have happened in some people who take Cabometyx. Tell your healthcare provider if you plan to have any surgery before or during treatment with Cabometyx.
  • You should stop taking Cabometyx at least 3 weeks before planned surgery.
  • Your healthcare provider should tell you when you may start taking Cabometyx again after surgery.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with Cabometyx. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.
• Cabometyx may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Cabometyx if you have certain side effects.

The most common side effects of Cabometyx include:

• tiredness
• decreased appetite
• weight loss
• nausea
• vomiting
• changes in certain blood tests

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Cabometyx. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Important Dosage Information

• Stop treatment with Cabometyx at least 3 weeks prior to scheduled surgery, including dental surgery.
• Do not substitute Cabometyx tablets with cabozantinib capsules.
• Do not administer Cabometyx with food. Administer at least 1 hour before or at least 2 hours after eating.
• Swallow Cabometyx tablets whole. Do not crush Cabometyx tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450.

Recommended Dosage For Renal Cell Carcinoma

The recommended dosage of Cabometyx as a single agent is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.

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

Table 1: Recommended Dosage of Cabometyx in Combination with Nivolumab

Recommended Dosage For Hepatocellular Carcinoma

The recommended dosage of Cabometyx is 60 mg once daily without food until disease progression or unacceptable toxicity.

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:

Table 2: Recommended Dosage Reductions for Cabometyx for Adverse Reactions

Permanently discontinue Cabometyx for any of the following:

• Severe hemorrhage
• Development of gastrointestinal (GI) perforation or Grade 4 fistula
• 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
• Reversible posterior leukoencephalopathy syndrome

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

Table 3: Recommended Specific Dosage Modifications for Hepatic Adverse Reactions for Combination

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). Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

Dosage Modifications For Coadministration With Strong 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 CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. Do not exceed a daily dose of 80 mg.

Dosage Modifications For Patients With Moderate And Severe Hepatic Impairment

• Reduce the starting dose of Cabometyx to 40 mg once daily in patients with moderate hepatic impairment (Child-Pugh B). Avoid Cabometyx in patients with severe hepatic impairment (Child-Pugh C).

Effects Of Other Drugs On Cabometyx

Strong CYP3A4 Inhibitors

• Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of Cabometyx with strong CYP3A4 inhibitors.
• Reduce the dosage of Cabometyx if coadministration with strong CYP3A4 inhibitors cannot be avoided.
• Avoid grapefruit or grapefruit juice which may also increase exposure of cabozantinib.

Strong CYP3A Inducers

• Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy.
• Avoid coadministration of Cabometyx with strong CYP3A4 inducers. Increase the dosage of Cabometyx if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John's wort which may also decrease exposure of cabozantinib.

• Based on findings from animal studies and its mechanism of action, 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.
• 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.