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Cabozantinib

Pronunciation

(ka boe ZAN ti nib)

Index Terms

  • BMS-907351
  • Cabozantinib (S)-malate
  • Cabozantinib s-Malate
  • Cabozantinib s-malate
  • XL184

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, oral [each package contains four blister cards; each card contains the following]:

Cometriq: 60 mg daily-dose: 20 mg (21s)

Cometriq: 100 mg daily-dose: 80 mg (7s) and 20 mg (7s)

Cometriq: 140 mg daily-dose: 80 mg (7s) and 20 mg (21s)

Tablet, oral:

Cabometyx: 20 mg, 40 mg, 60 mg

Brand Names: U.S.

  • Cabometyx
  • Cometriq

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Cabozantinib is a potent inhibitor of proinvasive receptor tyrosine kinases (RTKs), including AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3; induces apoptosis of cancer cells and suppresses tumor growth, metastasis, and angiogenesis (Yakes, 2011).

Distribution

Vd: ~319 to 349 L

Metabolism

Hepatic via CYP3A4

Excretion

Feces (~54%; 43% as unchanged drug); urine (~27%)

Time to Peak

2 to 5 hours

Half-Life Elimination

~55 hours (Cometriq); ~99 hours (Cabometyx)

Protein Binding

≥99.7% to plasma proteins

Special Populations: Hepatic Function Impairment

Cabozantinib exposure was increased by 81% and 63%, respectively, in patients with mild or moderate hepatic impairment.

Use: Labeled Indications

Renal cell carcinoma, advanced (Cabometyx): Treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy

Thyroid cancer, medullary (Cometriq): Treatment of progressive, metastatic medullary thyroid cancer (MTC)

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Note: Do not substitute cabozantinib tablets and capsules.

Renal cell carcinoma, advanced: Cabometyx: Oral: 60 mg once daily, continue as long as benefiting clinically or until unacceptable toxicity occurs (Choueiri 2015)

Thyroid cancer, medullary, metastatic: Cometriq: Oral: 140 mg once daily until disease progression or unacceptable toxicity occurs; do not exceed 180 mg daily

Missed doses: Do not take a missed dose within 12 hours of the next dose.

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

Strong CYP3A4 inhibitors:

Cabometyx: Reduce the daily dose of cabozantinib by 20 mg (from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). If the strong inhibitor is discontinued, allow ~2 to 3 days to elapse prior to adjusting the cabozantinib dose upwards to the dose used prior to the initiation of the strong inhibitor.

Cometriq: Avoid concomitant use; if concomitant use is required, reduce the daily dose of cabozantinib by 40 mg (ie, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). If the strong inhibitor is discontinued, allow ~2 to 3 days to elapse prior to adjusting the cabozantinib dose upwards to the dose used prior to the initiation of the strong inhibitor.

Strong CYP3A4 inducers:

Cabometyx: Increase the daily dose of cabozantinib by 20 mg (from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated; do not exceed 80 mg daily. If the strong inducer is discontinued, allow ~2 to 3 days to elapse prior to reducing the cabozantinib dose to the dose used prior to the initiation of the strong inducer.

Cometriq: Avoid concomitant use; if concomitant use is required, increase the daily dose of cabozantinib by 40 mg (ie, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily). If the strong inducer is discontinued, allow ~2 to 3 days to elapse prior to reducing the cabozantinib dose to the dose used prior to the initiation of the strong inducer.

Dosage adjustment for surgery: Withhold treatment for at least 28 days prior to scheduled surgery (including dental surgery). Resume therapy based on clinical judgment of adequate wound healing.

Dosing: Renal Impairment

Note: The estimated glomerular filtration rate (eGFR) is estimated using MDRD (modification of diet in renal disease) equation.

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2 or dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh classes A and B):

Cabometyx: Reduce the initial dose to 40 mg once daily.

Cometriq: Reduce the initial dose to 80 mg once daily.

Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Dosing: Adjustment for Toxicity

Cabometyx: Withhold therapy for grade 4 adverse reactions, and for grade 3 or intolerable grade 2 reactions that cannot be managed with dosage reduction or supportive care. Upon return to baseline or improvement to grade 1, resume therapy with a reduction in dose. If previously receiving 60 mg daily, resume therapy at 40 mg daily. If previously receiving 40 mg daily, resume therapy at 20 mg daily. If previously receiving 20 mg daily, resume at 20 mg daily if tolerated; if not tolerated, discontinue therapy.

Permanently discontinue for:

Development of unmanageable fistula or gastrointestinal perforation

Hypertensive crisis, severe uncontrolled hypertension despite optimal therapy

Nephrotic syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS)

Serious arterial thromboembolic event (eg, MI or cerebral infarction)

Severe hemorrhage

Cometriq:

Hematologic: Withhold therapy for grade 4 hematologic adverse reactions. Upon return to baseline or improvement to grade 1, reduce the dose to 100 mg daily. If previously receiving 100 mg daily, resume therapy at 60 mg daily. If previously receiving 60 mg daily, resume at 60 mg daily if tolerated; otherwise, discontinue therapy.

Other toxicity: Grade 3 or higher nonhematologic toxicity or intolerable grade 2 toxicity: Upon return to baseline or improvement to grade 1, reduce the dose to 100 mg daily. If previously receiving 100 mg daily, resume therapy at 60 mg daily. If previously receiving 60 mg daily, resume at 60 mg daily if tolerated; otherwise, discontinue therapy.

Permanently discontinue for:

Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal therapy

Nephrotic syndrome

Osteonecrosis of the jaw

Reversible posterior leukoencephalopathy syndrome (RPLS)

Serious arterial thromboembolic event (eg, MI or cerebral infarction)

Severe hemorrhage

Visceral perforation or fistula formation

Administration

Administer orally on an empty stomach (1 hour before or 2 hours after eating). Swallow whole; do not open capsules or crush tablets. Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single-gloving for administration of an intact capsule or tablet (NIOSH 2014).

Dietary Considerations

Avoid grapefruit and grapefruit juice throughout therapy.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Cabozantinib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

MRP2 Inhibitors: May increase the serum concentration of Cabozantinib. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Cabozantinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Elevated blood pressure (≤39% to 96%), hypertension (33% to 61%; grades 3/4: 8% to ≤16%)

Central nervous system: Fatigue (41% to 56%), mouth pain (36%), voice disorder (20%), headache (11% to 18%), dizziness (11% to 14%)

Dermatologic: Palmar-plantar erythrodysesthesia (42% to 50%; grades 3/4: 8% to 13%), hair discoloration (34%), skin rash (19% to 23%), xeroderma (11% to 19%), alopecia (16%), erythema (11%)

Endocrine & metabolic: Increased serum triglycerides (53%), hypocalcemia (52%), weight loss (31% to 48%), hypophosphatemia (28% to 48%), hyperglycemia (37%), hypoalbuminemia (36%), hypomagnesemia (19% to 31%), hyponatremia (10% to 30%), increased gamma-glutamyl transferase (27%), hypothyroidism (21%), hypokalemia (18%)

Gastrointestinal: Diarrhea (63% to 74%; grade ≥3: 11% to 16%), stomatitis (22% to 51%), decreased appetite (46%), nausea (43% to 50%), dysgeusia (24% to 34%), abdominal pain (23% to 27%), constipation (25% to 27%), vomiting (24% to 32%), mucosal inflammation (19%), dysphagia (13%), dyspepsia (11% to 12%)

Hematologic & oncologic: Lymphocytopenia (53%; grades 3/4: 16%), thrombocytopenia (35%), neutropenia (35%; grades 3/4: 3%), decreased white blood cell count (35%; grades 3/4: <1%), decreased hemoglobin (31%; grades 3/4: 4%), decrease in absolute neutrophil count (31%; grades 3/4: 2%), anemia (17%; grades 3/4: 5%)

Hepatic: Increased serum ALT (68% to 86%), increased serum AST (74% to 86%), increased serum alkaline phosphatase (35% to 52%), hyperbilirubinemia (25%)

Neuromuscular & skeletal: Weakness (19% to 21%), arthralgia (11% to 14%), limb pain (14%), muscle spasm (12% to 13%)

Renal: Increased serum creatinine (58%)

Respiratory: Dyspnea (19%), cough (18%)

1% to 10%:

Cardiovascular: Hypotension (7%), venous thromboembolism (6% to 7%), pulmonary embolism (4%), arterial thromboembolism (≤2%)

Central nervous system: Anxiety (9%), paresthesia (7%), peripheral sensory neuropathy (7%), peripheral neuropathy (5%)

Dermatologic: Hyperkeratosis (7%)

Endocrine & metabolic: Dehydration (7%)

Gastrointestinal: Hemorrhoids (9%), gastrointestinal perforation (≤3%), gastrointestinal fistula (1%)

Genitourinary: Proteinuria (2%)

Hematologic & oncologic: Hemorrhage (≥grade 3: 2% to 3%)

Neuromuscular & skeletal: Musculoskeletal chest pain (9%), osteonecrosis of the jaw (1%)

Miscellaneous: Fistula (nongastrointestinal: 4%)

<1% (Limited to important or life-threatening): Reversible posterior leukoencephalopathy syndrome, wound healing impaired

ALERT: U.S. Boxed Warning

Perforations and fistulas (Cometriq):

GI perforations occurred in 3% and fistula formation in 1% of cabozantinib-treated patients. Discontinue cabozantinib for perforation or for fistula formation.

Hemorrhage (Cometriq):

Severe and sometimes fatal hemorrhage, including hemoptysis and GI hemorrhage, occurred in 3% of cabozantinib-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer cabozantinib to patients with severe hemorrhage.

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Palmar-plantar erythrodysesthesia syndrome (PPES) was commonly observed in clinical trials; severe PPES (≥grade 3) also occurred frequently. May require dosage reduction and/or discontinuation.

• Gastrointestinal toxicity: Diarrhea was commonly observed in cabozantinib-treated patients in clinical trials. May require therapy interruption and/or dosage reduction. [US Boxed Warning]: Cometriq: Serious gastrointestinal (GI) perforations and fistulas have been reported when used for medullary thyroid cancer; discontinue for GI perforation or fistula formation. May be fatal. Tracheal/esophageal fistulas were also noted; some cases were fatal. GI fistula/perforation were also reported in patients with renal cell cancer. Monitor for signs/symptoms of perforations and fistulas. May require therapy discontinuation.

• Hemorrhage: [US Boxed Warning]: Cometriq: Serious and occasionally fatal hemorrhage (including hemoptysis and gastrointestinal) has occurred with cabozantinib when used for medullary thyroid cancer. Monitor for signs/symptoms of bleeding and do not administer to patients with severe hemorrhage or a recent history of hemorrhage or hemoptysis. Severe hemorrhage has also been reported in patients with renal cell cancer, including grade 3 or higher events. Do not administer to patients with or at risk for severe hemorrhage.

• Hypertension: Treatment emergent hypertension was commonly seen in clinical trials (including grade 3 or higher toxicity). Monitor blood pressure prior to therapy initiation and regularly thereafter; withhold for hypertension that is uncontrolled with appropriate medical management. May require cabozantinib dosage reduction and/or therapy discontinuation.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) occurred rarely; oral examinations should be performed prior to and periodically throughout therapy. Patients should maintain proper oral hygiene practices; if possible, withhold therapy for at least 28 days prior to scheduled invasive dental procedures. Discontinue cabozantinib if ONJ develops.

• Proteinuria: Proteinuria occurred in a small number of patients receiving cabozantinib in clinical trials; nephrotic syndrome was also reported (rare). Monitor urine protein regularly and discontinue therapy if nephrotic syndrome develops.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS), also referred to as posterior reversible leukoencephalopathy syndrome (PRES), occurred rarely in clinical studies. Monitor for signs/symptoms of RPLS (seizures, headache, visual disturbances, confusion or altered mental function); if diagnosis confirmed, discontinue therapy.

• Thromboembolic events: An increased incidence of thrombotic events (venous thromboembolism, including pulmonary embolism and arterial thromboembolism) was seen in cabozantinib-treated patients in clinical trials; discontinue therapy in patients who develop an acute myocardial infarction, cerebral infarction, or other clinically significant arterial thromboembolic event.

• Wound healing impairment: Cabozantinib inhibits vascular endothelial growth factor receptors 1, 2, and 3; wound complications have been reported with therapy. Hold treatment at least 28 days prior to scheduled surgery (including dental surgery); resume based on judgment of adequate wound healing post surgery. Withhold treatment in patients with dehiscence or other wound healing complications requiring intervention.

Disease-related concerns:

• Hepatic impairment: Cabozantinib exposure is increased in patients with hepatic impairment. Reduced initial doses are recommended for patients with mild or moderate impairment; use is not recommended in patients with severe impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid the use of concomitant strong CYP3A4 inducers and/or strong CYP3A4 inhibitors with Cometriq. Dosage adjustments are required if concurrent therapy is unavoidable.

Dosage form specific issues:

• Formulations: Cabozantinib is available in tablets (Cabometyx) and capsules (Cometriq) which are NOT interchangeable; do NOT substitute.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Renal function, liver function, CBC with differential and platelets, serum electrolytes; blood pressure (prior to initiation and regularly during therapy); monitor for perforations, fistulas, signs/symptoms of bleeding, palmar-plantar erythrodysesthesia syndrome (PPES), reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria (regularly during therapy), osteonecrosis of the jaw (perform oral examination prior to initiation and periodically during therapy), wound healing complications, diarrhea, stomatitis

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Based on its mechanism of action, adverse effects on pregnancy would be expected. Patients (male and female) should use effective contraception during therapy and for 4 months after therapy completion. Cabozantinib may impair fertility in females and males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, hair loss, change in taste, constipation, lack of appetite, hair discoloration, joint pain, muscle spasms, anxiety, altered voice, or dry skin. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe bleeding or persistent bleeding), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), sweating a lot, abnormal gait, severe headache, severe dizziness, passing out, vision changes, shortness of breath, severe abdominal pain, gagging, choking, severe diarrhea, severe loss of strength and energy, excessive weight loss, healing impairment, jaw pain, mouth sores, urinary retention, change in amount of urine passed, redness or irritation of hands or soles of feet, difficulty swallowing, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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