cabozantinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Pronunciation:
ka-boe-zan-ti-nib


Trade Name(s)

  • Cabometyx
  • Cometriq

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Cabometyx:
    • Advanced renal cell carcinoma.
    • First-line treatment of advanced renal cell carcinoma (in combination with nivolumab).
    • Hepatocellular carcinoma in patients previously treated with sorafenib.
  • Locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor receptor-targeted therapy in patients who are refractory to or ineligible to receive radioactive iodine.
  • Cometriq: Progressive, metastatic medullary thyroid cancer.

Action

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

Therapeutic Effect(s):

  • Improved survival with renal cell carcinoma and hepatocellular carcinoma.
  • Decreased spread of medullary thyroid cancer.
  • Improved progression-free survival with differentiated thyroid cancer.

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: Cometriq: 55 hr;  Cabometyx: 99 hr.

TIME/ACTION PROFILE (improved survival)

ROUTEONSETPEAKDURATION
POwithin 2 mounknown14.7–21.4 mo

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment;
  • OB:  Pregnancy;
  • Lactation: Lactation.

Use Cautiously in:

  • Severe renal impairment;
  • Moderate hepatic impairment (Cabometyx);
  • 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 <12 yr (differentiated thyroid cancer) or children <18 yr (all other indications).

Adverse Reactions/Side Effects

CV: hypertension, THROMBOTIC EVENTS

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

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

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

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

GU: proteinuria, infertility, nephrotic syndrome

Hemat: lymphocytopenia, neutropenia, thrombocytopenia, anemia, BLEEDING

Metabolic: ↓ appetite, weight loss

MS: arthralgia, muscle spasms, osteonecrosis of the jaw

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

Resp: cough, dyspnea

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

Interactions

Drug-Drug

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage

Capsules and tablets are not interchangeable

Cabometyx

Advanced Renal Cell Carcinoma

PO (Adults): As monotherapy: 60 mg once daily until disease progression or unacceptable toxicity.  With nivolumab: 40 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor (as monotherapy):  40 mg once daily until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inhibitor).  Concurrent use of strong CYP3A4 inhibitor (with nivolumab):  20 mg once daily 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 until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inducer).  Concurrent use of strong CYP3A4 inducer (with nivolumab):  60 mg once daily until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inducer).

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

Hepatocellular Carcinoma

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

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

Differentiated Thyroid Cancer

PO (Adults and Children  ≥12 yr and body surface area [BSA] ≥1.2 m2): 60 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor: 40 mg once daily 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 until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inducer).

PO (Adults and Children  ≥12 yr and BSA <1.2 m2): 40 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor: 20 mg once daily until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inhibitor).  Concurrent use of strong CYP3A4 inducer:  60 mg once daily until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inducer).

Hepatic Impairment 
PO (Adults and Children  ≥12 yr and BSA ≥1.2 m2): 40 mg once daily until disease progression or unacceptable toxicity.

Hepatic Impairment 
PO (Adults and Children  ≥12 yr and BSA <1.2 m2): 20 mg once daily until disease progression or unacceptable toxicity.

Cometriq

PO (Adults): 140 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor: 100 mg once daily until disease progression or unacceptable toxicity (resume full dose 4 days after discontinuing inhibitor).  Concurrent use of strong CYP3A4 inducer:  180 mg once daily until disease progression or unacceptable toxicity (resume full dose 2–3 days after discontinuing inducer).

Hepatic Impairment 
PO (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.  If hypertension occurs,  hold cabozantinib and manage medically; once BP controlled, resume cabozantinib at ↓ dose.  If uncontrollable, severe hypertension or hypertensive crisis occur,  permanently discontinue cabozantinib.
  • Monitor for symptoms of perforations and fistulas, including abscess (severe abdominal pain, coughing, gagging, choking especially when eating or drinking, abscess, sepsis).  If symptoms occur,  permanently discontinue cabozantinib.
  • Monitor for diarrhea.  If intolerable Grade 2, Grade 3 not managed with treatment, or Grade 4 diarrhea occur,  hold cabozantinib until Grade 1; then resume at ↓ dose.
  • Monitor for signs and symptoms of PPE.  If intolerable Grade 2 or Grade 3 PPE occurs,  hold cabozantinib until Grade 1; then resume at ↓ 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.
  • Pedi:  Physeal and longitudinal growth monitoring is recommended in children with open growth plates.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Monitor urine protein periodically during therapy; discontinue cabozantinib if nephrotic syndrome develops.
  • Monitor CBC with differential periodically during therapy. May ↓ 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 ↑ AST, ALT, and alkaline phosphatase. When used with nivolumab:  If ALT or AST >3 times upper limit of normal (ULN) but ≤10 times ULN with concurrent total bilirubin <2 times ULN,  hold cabozantinib and nivolumab until recovery to Grade ≤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 hypophosphatemia, hyperbilirubinemia, hypomagnesemia, hypokalemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia.
  • Monitor thyroid function periodically during therapy and manage dysfunction as needed.
  • Monitor calcium levels and replace calcium as necessary during treatment. Withhold and resume at ↓ dose upon recovery or permanently discontinue cabozantinib depending on severity.

Implementation

  • Do not confuse Cometriq with coenzyme Q10.
  • Do not interchange tablets and capsules.
  • Stop treatment ≥21 days before scheduled surgery, including dental surgery. Do not resume therapy for ≥14 days after major surgery and until the wound is adequately healed. Hold doses in patients with dehiscence or wound-healing complications.
  • Permanently discontinue cabozantinib 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, or reversible posterior leukoencephalopathy syndrome occur.
  • PO  Cometriq : Administer 140 mg dose as one 80-mg and three 20-mg capsules on an empty stomach ≥1 hr before or 2 hr after meals.  DNC: Swallow capsules whole; do not open, crush, or chew. 
    • If Grade 4 hematologic, Grade ≥3 nonhematologic, or intolerable Grade 2 adverse reactions occur with Cometriq,  hold cabozantinib; resume at ↓ dose once baseline or Grade 1.  If previously receiving 140 mg daily , resume at 100 mg daily.  If previously receiving 100 mg daily , resume at 60 mg daily.  If previously receiving 60 mg daily , resume at 60 mg daily as tolerated or discontinue.
  • PO  Cabometyx : Administer tablet on an empty stomach with ≥8 ounces of water ≥1 hr before or 2 hr after meals.  DNC: Swallow tablet whole; do not break, crush, or chew. 
    •  Dose Reduction Schedule (Cabometyx): Upon return to baseline or resolution to Grade 1:  If previously receiving 60 mg daily,  ↓ to 40 mg daily. Second dose reduction: ↓ to 20 mg daily.  If previously receiving 40 mg daily,  ↓ to 20 mg daily. Second dose reduction: ↓ to 20 mg every other day.  If previously receiving 20 mg daily , ↓ to 20 mg/day as tolerated or discontinue cabozantinib.

Patient/Family Teaching

  • Explain purpose and side effects of medication. Advise patient to read  Patient Information  before starting therapy. Take missed doses as soon as remembered if within 12 hr of dose; then take next dose at regularly scheduled time. If >12 hr, omit dose and take 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 or 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 (rash, 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 PRES 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; severe nausea or vomiting, preventing 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:  May cause fetal harm. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during therapy and for ≥4 mo after completion of therapy and to avoid breastfeeding during therapy and for 4 mo following last dose. May impair fertility in male and female patients.

Evaluation/Desired Outcomes

  • ↓ spread of metastatic medullary thyroid cancer.
  • Improved survival with renal cell carcinoma and hepatocellular carcinoma.
  • Improved progression-free survival with differentiated thyroid cancer.