cabozantinib

Advanced renal cell carcinoma.
First-line treatment of advanced renal cell carcinoma (in combination with nivolumab).
Hepatocellular carcinoma in patients previously treated with sorafenib.

High Alert

Cabometyx

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.
Previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors.
Previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors.

Cometriq

Progressive, metastatic medullary thyroid cancer.

Action ⬆ ⬇

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

Therapeutic effects:

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

Pharmacokinetics ⬆ ⬇

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

Distribution: Extensively distributed to tissues.

Protein Binding: >99.7%.

Metabolism/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)

ROUTE	ONSET	PEAK	DURATION
PO	within 2 mo	unknown	14.7–21.4 mo

Contraind./Precautions ⬆ ⬇

Contraindicated in:

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

Use Cautiously in:

Elective surgical procedures (discontinue 28 days prior, if possible);
Hypertension (control prior to treatment);
Severe renal impairment;
Moderate hepatic impairment (Cabometyx);
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).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension, DEEP VEIN THROMBOSIS, MI

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

GU: proteinuria, infertility, nephrotic syndrome

Hemat: lymphopenia, neutropenia, thrombocytopenia, anemia, BLEEDING

MS: arthralgia, muscle spasms, osteonecrosis of the jaw

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

Resp: cough, dyspnea, PULMONARY EMBOLISM

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including atazanavir, clarithromycin, conivaptan, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, and voriconazole, may ↑ levels and risk of toxicity; avoid concurrent use, if possible. If concurrent use necessary, ↓ cabozantinib dose.
Strong CYP3A4 inducers, including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine, may ↓ levels and effectiveness; avoid concurrent use, if possible. If concurrent use necessary, ↓ cabozantinib dose.
MRP2 inhibitors, including abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, and tenofovir, may ↑ levels and risk of toxicity.

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 and Neuroendocrine Tumors
PO (Adults and Children ≥12 yr and ≥40 kg): 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 <40 kg): 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 ⬆ ⬇

(Generic available)

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, do not initiate, or hold therapy and manage medically; once BP controlled, resume cabozantinib at ↓ dose. If uncontrollable, severe hypertension or hypertensive crisis occurs, 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. If PRES confirmed, permanently discontinue cabozantinib.
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. If nephrotic syndrome occurs, discontinue cabozantinib.
- 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. Hold; then 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 severe hemorrhage, serious arterial thrombotic event (MI, cerebral infarction), or osteonecrosis of the jaw 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.
- Dose Reduction Schedule (Cometriq)Upon resolution of adverse reactions to Grade ≤1: hold cabozantinib; resume at ↓ dose once Grade ≤1. If previous dose was 140 mg once daily, resume at 100 mg once daily. If previous dose was 100 mg once daily, resume at 60 mg once daily. If previous dose was 60 mg once daily, resume at 60 mg once 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 resolution of adverse reactions to Grade ≤1: If previous dose was 60 mg once daily,↓ to 40 mg once daily. 2nd dose reduction: ↓ to 20 mg once daily. If previous dose was 40 mg once daily,↓ to 20 mg once daily. 2nd dose reduction: ↓ to 20 mg every other day. If previous dose was 40 mg once daily (with nivolumab), ↓ to 20 mg every other day.

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 provider 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 provider 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 provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider 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 provider.
Advise patient to notify health care provider 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 men and women.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆