General

Pronunciation:
ka-boe-zan-ti-nib

Trade Name(s)

• Cabometyx
• Cometriq

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

• Cabometyx:

  Advanced renal cell carcinoma (RCC).

  First-line treatment of advanced RCC (in combination with nivolumab).

  Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Cometriq: Progressive, metastatic medullary thyroid cancer (MTC).

Action

Inhibits tyrosine kinase, resulting in disruption of cellular function including tumor formation and progression.

Therapeutic Effect(s):

• Improved survival with RCC and HCC.
• Decreased spread of MTC.

Pharmacokinetics

Absorption: Well absorbed following oral administration; food significantly enhances absorption.

Distribution: Extensively distributed to tissues.

Protein Binding: >99.7%.

Metabolism and Excretion: Highly metabolized by the liver, mostly by the CYP3A4 isoenzyme. 54% excreted in feces, 27% in urine (as metabolites).

Half-life: 55 hr (Cometriq); 99 hr (Cabometyx).

TIME/ACTION PROFILE (improved survival)

Contraindication/Precautions

Contraindicated in:

• Severe hepatic impairment;
• Concurrent foods/nutritional supplements that are CYP3A4 inhibitors;
• OB:  Pregnancy (may cause fetal harm);
•  Lactation: Lactation.

Use Cautiously in:

• Concurrent use of strong CYP3A4 inhibitors/inducers should be avoided if possible; if unavoidable, dosage adjustments are necessary
• Moderate hepatic impairment (Cabometyx)
• Severe renal impairment;
• Elective surgical procedures (discontinue 28 days prior, if possible);
• Hypertension (control prior to treatment)
• Rep:   Women of reproductive potential
• Pedi:  Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CNS: POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), dizziness, fatigue, headache

CV: THROMBOTIC EVENTS, hypertension

Derm: dry skin, hair color changes, palmar-plantar erythrodysesthesia, rash, impaired wound healing

Endo: ADRENAL INSUFFICIENCY (in combination with nivolumab), hypothyroidism

F and E: hypocalcemia, hypophosphatemia, hypokalemia, hypomagnesemia, hyponatremia

GI: HEPATOTOXICITY (in combination with nivolumab), GASTROINTESTINAL PERFORATION/FISTULA, abdominal pain, altered taste, ↓ appetite, constipation, diarrhea, dyspepsia, ↑ liver enzymes, nausea, oral pain, stomatitis, vomiting, weight loss

GU: proteinuria, infertility, nephrotic syndrome

Hemat: BLEEDING, lymphocytopenia, neutropenia, thrombocytopenia, anemia

MS: arthralgia, muscle spasms, osteonecrosis of the jaw

Resp: cough, dyspnea

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Levels and risk of toxicity are ↑ by  strong CYP3A4 inhibitors, including  atazanavir,  clarithromycin,  conivaptan,  indinavir,  itraconazole,  ketoconazole,  lopinavir/ritonavir,  nefazodone,  nelfinavir,  posaconazole,  ritonavir,  saquinavir, and  voriconazole ; concurrent use should be avoided if possible. If unavoidable, cabozantinib daily dose should be ↓; routine dose may be resumed 4 days following discontinuation of inhibitor.
• Levels and effectiveness may be ↓ by chronic concurrent use of  strong CYP3A4 inducers, including  carbamazepine,  dexamethasone,  phenobarbital,  phenytoin,  rifabutin,  rifampin, and  rifapentine ; concurrent use should be avoided if possible. If unavoidable, cabozantinib daily dose should be ↑; routine dose may be resumed 2–3 days following discontinuation of inducer.
• Levels and risk of toxicity are ↑ by  MRP2 inhibitors, including  abacavir,  adefovir,  cidofovir,  furosemide,  lamivudine,  nevirapine,  ritonavir,  probenecid,  saquinavir, and  tenofovir.

Drug-Natural Products:

Levels and effectiveness may be ↓ by chronic concurrent use of  St. John's wort  ; avoid concurrent use.

Drug-Food:

Levels and risk of toxicity are ↑ by grapefruit juice; avoid concurrent use.

Route/Dosage

Capsules and tablets are not interchangeable

Cabometyx

Advanced Renal Cell Carcinoma

PO (Adults): As monotherapy– 60 mg once daily. Continue until patient no longer experiences benefit or experiences unacceptable toxicity.  With nivolumab– 40 mg once daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor (as monotherapy)–  40 mg once daily. Continue until patient no longer experiences benefit or experiences unacceptable toxicity; resume full dose 2–3 days after discontinuing inhibitor.  Concurrent use of strong CYP3A4 inhibitor (with nivolumab)–  20 mg once daily. Continue until disease progression or unacceptable toxicity; resume full dose 2–3 days after discontinuing inhibitor.  Concurrent use of strong CYP3A4 inducer (as monotherapy)–  80 mg once daily. Continue until patient no longer experiences benefit or experiences unacceptable toxicity; resume full dose 2–3 days after discontinuing inducer.  Concurrent use of strong CYP3A4 inducer (with nivolumab)–  60 mg once daily. Continue until disease progression or unacceptable toxicity; resume full dose 2–3 days after discontinuing inducer.

Hepatic Impairment 
(Adults): Moderate hepatic impairment– 40 mg once daily. Continue until patient no longer experiences benefit or experiences unacceptable toxicity.

Hepatocellular Carcinoma

PO (Adults): 60 mg once daily. Continue until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor–  40 mg once daily. Continue until disease progression or unacceptable toxicity; resume full dose 2–3 days after discontinuing inhibitor.  Concurrent use of strong CYP3A4 inducer–  80 mg once daily. Continue until disease progression or unacceptable toxicity; resume full dose 2–3 days after discontinuing inducer.

Hepatic Impairment 
(Adults): Moderate hepatic impairment– 40 mg once daily. Continue until disease progression or unacceptable toxicity.

Cometriq

PO (Adults): 140 mg once daily.  Concurrent CYP3A4 inhibitors– 100 mg once daily; resume full dose 4 days after discontinuing inhibitor.  Concurrent CYP3A4 inducers–  180 mg once daily; resume full dose 2–3 days after discontinuing inducer.

Hepatic Impairment 
(Adults): Mild or moderate hepatic impairment– 80 mg once daily.

Availability

Capsules (Cometriq): 20 mg, 80 mg

Tablets (Cabometyx): 20 mg, 40 mg, 60 mg

Assessment

• Monitor BP prior to and periodically during therapy. Hold cabozantinib if BP is not adequately controlled with medications; resume at a reduced dose. Discontinue cabozantinib for uncontrolled hypertension.
• Monitor for symptoms of perforations and fistulas, including abscess (severe abdominal pain, coughing, gagging, choking especially when eating or drinking, abscess, sepsis). Discontinue cabozantinib if symptoms occur.
• Monitor for diarrhea.  If intolerable Grade 2 diarrhea, Grade 3 diarrhea not managed with antidiarrheal treatments, or Grade 4 diarrhea occurs : hold dose until Grade 1, then resume at reduced dose.
• Monitor for signs and symptoms of palmar-plantar erythrodysesthesia (PPE) during therapy. If intolerable Grade 2 PPE or Grade 3 PPE occurs: hold dose until Grade 1, then resume at reduced dose.
• Perform an oral examination for inflammation, infection, or ulceration prior to and periodically during therapy.
• Evaluate patients with seizures, headache, visual disturbances, confusion, or altered mental status for PRES via MRI. Discontinue therapy if confirmed.
• Monitor for signs and symptoms of adrenal insufficiency.  If ≥Grade 2 adrenal insufficiency occurs,  begin symptomatic treatment and hormone replacement therapy. May require holding cabozantinib.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

Monitor urine protein periodically during therapy; discontinue therapy if nephrotic syndrome develops.

• Monitor CBC and platelet count periodically during therapy. May cause ↓ WBC, ANC, hemoglobin, lymphocytes, and platelets.
• Monitor liver enzymes prior to and periodically during therapy and more frequently when used in combination with other drugs. May cause ↑ AST, ↑ ALT, and ↑ ALP. When used with nivolumab, if ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN,  hold cabozantinib and nivolumab until recover to Grades 0 or 1. If ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, permanently discontinue both cabozantinib and nivolumab.
• May cause hypocalcemia, hypophosphatemia, hyperbilirubinemia, hypomagnesemia, hypokalemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia.

Potential Diagnoses

• Diarrhea (Adverse Reaction) 

Implementation

• Do not interchange tablets and capsules.
• Stop treatment at least 21 days before scheduled surgery, including dental surgery. Do not resume therapy for at least 14 days after major surgery and until the wound is adequately healed. Hold doses in patients with dehiscence or wound healing complications.
• Permanently discontinue if development of visceral perforation or fistula formation, severe hemorrhage, serious arterial thrombotic event (MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome occur.
• PO  Cometriq : Administer 140 mg dose as one 80-mg and 3 20-mg capsules, on an empty stomach at least 1 hr before or 2 hr after meals.  DNC: Swallow capsules whole; do not open, crush, or chew.  Avoid foods or nutritional supplements that inhibit cytochrome P450 during therapy.
  • If Grade 4 hematologic, ≥Grade 3 non-hematologic or intolerable Grade 2 adverse reactions occur:  hold cabozantinib; once baseline or Grade 1, reduce dose.  If previously receiving 140 mg daily , resume at 100 mg daily (one 80-mg and one 20-mg capsule).  If previously receiving 100 mg daily , resume at 60 mg daily (3 20-mg capsules).  If previously receiving 60 mg daily , resume at 60 mg daily if tolerated, otherwise, discontinue.
• PO  Cabometyx : Administer tablet on an empty stomach at least 1 hr before or 2 hr after meals.  DNC: Swallow tablet whole; do not break, crush, or chew. 
  • If Grade 4 hematologic and Grade 3 or intolerable Grade 2 adverse reactions not managed by dose reductions or supportive care. Upon return to baseline or resolution to Grade 1, reduce dose.  If previously receiving 60 mg daily , resume at 40 mg daily.  If previously receiving 40 mg daily , resume at 20 mg daily.  If previously receiving 20 mg daily , resume at 20 mg daily if tolerated, otherwise, discontinue.

Patient/Family Teaching

• Instruct patient to take cabozantinib as directed on an empty stomach with at least 8 oz of water. Take missed doses as soon as remembered if within 12 hrs of dose; take next dose at regularly scheduled time. If >12 hrs omit dose and text next dose at normal time; do not double doses.
• Advise patient to avoid grapefruit, grapefruit juice and any foods or supplements that contain grapefruit during therapy.
• Caution patient to notify health care professional immediately if signs and symptoms of hemorrhage (coughing up blood or blood clots, vomiting blood or coffee-ground like vomit, red or black tarry stools, menstrual bleeding heavier than usual, any unusual or heavy bleeding); perforation or fistula (abdominal pain or tenderness); stroke or heart attack (swelling or pain in hands, arms, feet, or legs; shortness of breath; unusual sweating; numbness or weakness of face, arm or leg especially on one side of body; sudden confusion, trouble speaking, or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking; dizziness, loss of balance or coordination; sudden severe headache); diarrhea; PPE (rashes, redness, pain, swelling, or blisters on palms or soles of feet); swelling in hands, arms, legs, or feet; jaw pain, toothache, or sores on gums; or reversible posterior leukoencephalopathy syndrome occur.
• Instruct patient to notify health care professional if signs and symptoms of hand-foot skin reactions (progressive or intolerable rash, redness, pain, swelling, blisters on hands or soles of feet); severe diarrhea; mouth sores, oral pain, changes in taste, nausea or vomiting severe or preventing from eating or drinking; or weight loss occur.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's Wort.
• Instruct patient to maintain good oral hygiene and regular dentist exams during therapy. If jaw pain, toothache, or sores on gums occur, notify health care professional.
• Advise patient to notify health care professional of medication regimen prior to treatment or surgery. Therapy must be stopped 28 days before planned surgery, including dental procedures.
• Rep:  Cabozantinib is teratogenic. Advise females of reproductive potential and male patients with female partners with reproductive potential to use effective contraception during and for at least 4 mo after completion of therapy and to avoid breastfeeding during and for 4 mo following last dose. May impair fertility in male and female patients.

Evaluation/Desired Outcomes

• Decreased spread of metastatic MTC.
• Improved survival with RCC and HCC.