cabozantinib

ka-boe-ZAN-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

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.
Locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor (VEGF) receptor-targeted therapy in patients who are refractory to or ineligible to receive radioactive iodine.

Cometriq

Progressive, metastatic medullary thyroid cancer.

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

Therapeutic effects:

Improved survival with RCC and HCC.
Decreased spread of medullary thyroid cancer.
Improved progression free survival with differentiated thyroid cancer.

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.

(improved survival)

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

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).

CV: hypertension, THROMBOTIC EVENTS

Derm: dry skin, hair color changes, palmar-plantar erythrodysesthesia, 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, ↓appetite, constipation, diarrhea, dyspepsia, hepatotoxicity(in combination with nivolumab), ↑liver enzymes, nausea, oral pain, stomatitis, vomiting, weight loss, GI PERFORATION/FISTULA

GU: proteinuria, infertility, nephrotic syndrome

Hemat: lymphocytopenia, neutropenia, thrombocytopenia, anemia, BLEEDING

MS: arthralgia, muscle spasms, osteonecrosis of the jaw

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

Resp: cough, dyspnea

Drug-drug:

Levels and risk of toxicity are ↑ by strong CYP3A4 inhibitors, including atazanavir, clarithromycin, conivaptan, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, 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, and tenofovir.

Drug-Natural Products:

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

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

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.

Capsules (Cometriq): 20 mg; 80 mg
Tablets (Cabometyx): 20 mg; 40 mg; 60 mg

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.
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 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 ↑ 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 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.
- Monitor thyroid function periodically during therapy and manage dysfunction as needed.
- Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue Cabometyx depending on severity

Do not confuse Cometriq with coenzyme Q10.
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 three 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.
- Dose Reduction Schedule
  Upon return to baseline or resolution to Grade 1If previously receiving 60 mg daily,reduce to 40 mg/day. Second dose reduction, reduce to 20 mg/day. If previously receiving 40 mg daily, resume at 20 mg daily. Second dose reduction, reduce to 20 mg every other day.If previously receiving 20 mg daily, resume at 20 mg daily if tolerated, otherwise, discontinue.
- If Grade 4 hematologic, ≥Grade 3 nonhematologic 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 (three 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.

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 hr of dose; take next dose at regularly scheduled time. If >12 hr, 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 may cause fetal harm. Advise females of reproductive potential and male patients with female partners of 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.

Decreased spread of metastatic medullary thyroid cancer.
Improved survival with RCC and HCC.
Improved progression free survival with differentiated thyroid cancer.

Cabometyx, Cometriq

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