Cabozantinib: Drug information

For additional information see "Cabozantinib: Patient drug information" and "Cabozantinib: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table

Brand Names: US

Cabometyx;
Cometriq (100 MG Daily Dose);
Cometriq (140 MG Daily Dose);
Cometriq (60 MG Daily Dose)

Brand Names: Canada

Cabometyx

Pharmacologic Category

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

Dosing: Adult

Dosage guidance:

Safety: Withhold cabozantinib treatment for at least 3 weeks prior to scheduled surgery (including dental surgery or invasive dental procedures); do not administer cabozantinib for at least 2 weeks after major surgery and until adequate wound healing. Do not use cabozantinib in patients with a recent history of hemorrhage (including hemoptysis, hematemesis, or melena). Do not initiate cabozantinib in patients with uncontrolled hypertension.

Dosage forms information: Do not substitute cabozantinib tablets (Cabometyx) and capsules (Cometriq).

Clinical considerations: Cabozantinib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea/vomiting (Ref).

Hepatocellular carcinoma, advanced

Hepatocellular carcinoma, advanced (previously treated) (Cabometyx): Oral: 60 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Neuroendocrine tumors, locally advanced or metastatic, unresectable

Neuroendocrine tumors, locally advanced or metastatic, unresectable (previously treated) (Cabometyx):

Extra-pancreatic neuroendocrine tumors: Oral: 60 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Pancreatic neuroendocrine tumors: Oral: 60 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Renal cell carcinoma, advanced, first-line combination therapy

Renal cell carcinoma, advanced, first-line combination therapy (Cabometyx):

Note: May be used in combination with nivolumab regardless of risk stratification (Ref).

Oral: 40 mg once daily (in combination with nivolumab); continue until disease progression or unacceptable toxicity (Ref).

Renal cell carcinoma, advanced, single-agent therapy

Renal cell carcinoma, advanced, single-agent therapy (Cabometyx):

Note: May be used in patients who are ineligible for (or who decline) initial treatment with immunotherapy-based combinations, as well as in those with progression after initial immunotherapy-based options or other VEGFR tyrosine kinase inhibitors (Ref).

Oral: 60 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Thyroid cancer, differentiated, locally advanced or metastatic

Thyroid cancer, differentiated, locally advanced or metastatic (previously treated) (Cabometyx): Oral: 60 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Thyroid cancer, medullary, metastatic

Thyroid cancer, medullary, metastatic (Cometriq): Oral: 140 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Kidney impairment prior to treatment initiation :

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).

Kidney toxicity during treatment:

Proteinuria, grade 2 or 3: Withhold cabozantinib until improvement to ≤ grade 1 proteinuria, then resume at a reduced dose.

Nephrotic syndrome: Permanently discontinue cabozantinib.

Dosing: Liver Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild impairment (Child-Turcotte-Pugh class A):

Cabometyx: No dosage adjustment is necessary.

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

Moderate impairment (Child-Turcotte-Pugh class B):

Cabometyx:

Initial dose 60 mg once daily: Reduce dose to 40 mg once daily.

Initial dose 40 mg once daily: Reduce dose to 20 mg once daily.

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

Severe impairment (Child-Turcotte-Pugh class C): Avoid use (has not been studied).

Acute hepatotoxicity during treatment (when used in combination with nivolumab [Cabometyx]):

ALT or AST >3 to ≤10 times ULN with concurrent total bilirubin <2 times ULN: Withhold both cabozantinib and nivolumab; consider corticosteroid therapy. Upon recovery to grade 0 or 1, may consider rechallenging with cabozantinib (at a reduced dose based on the severity) and/or nivolumab.

ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN: Permanently discontinue both cabozantinib and nivolumab; consider corticosteroid therapy.

Dosing: Adjustment for Toxicity: Adult

**Cabozantinib Dose Reduction Levels for Adverse Reactions**
Initial dose	First dose reduction	Second dose reduction
^aIf previously receiving the lowest dose, resume at the same dose. If lowest dose is not tolerated, discontinue cabozantinib.
Cabometyx
60 mg once daily	40 mg once daily	20 mg once daily^a
40 mg once daily (in combination with nivolumab)	20 mg once daily	20 mg every other day^a
Cometriq
140 mg once daily	100 mg once daily	60 mg once daily^a

**Cabozantinib** **Recommended Dosage Modifications for Adverse Reactions**
Adverse reaction	Severity	Cabobetyx dosage modification
^aIf cabozantinib is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (ESC [Lyon 2022]).
Adrenal insufficiency (when used in combination with nivolumab)	≥ grade 2	Initiate symptomatic treatment (including hormone replacement therapy as clinically indicated). Withhold cabozantinib (and/or nivolumab); resume cabozantinib at a reduced dose depending on the severity.
GI toxicity: Diarrhea	Any grade	Manage with antidiarrheals as indicated.
GI toxicity: Diarrhea	Grade 2, 3, or 4	Withhold cabozantinib until ≤ grade 1, then resume at a reduced dose.
GI toxicity: Perforation or fistulas	GI perforation (any grade) or grade 4 fistula	Permanently discontinue cabozantinib.
Hematologic toxicity (Cometriq)	Grade 4	Withhold cabozantinib; upon return to baseline or improvement to grade 1, resume at a reduced dose.
Hemorrhage	Grade 3 or 4	Permanently discontinue cabozantinib.
Hypertension	If indicated, initiate appropriate antihypertensive therapy^a to reduce the risk for cardiovascular complications (ASCO [Armenian 2017]; ESC [Lyon 2022]).
	Grade 3	Withhold cabozantinib until hypertension is adequately controlled to ≤ grade 2, then resume at a reduced dose. Permanently discontinue cabozantinib for hypertension that cannot be controlled.
	Grade 4	Permanently discontinue cabozantinib.
	Hypertensive crisis	Permanently discontinue cabozantinib.
Hypocalcemia	Any	Replace calcium as necessary during treatment. Depending on the severity, withhold cabozantinib and resume at a reduced dose upon recovery or permanently discontinue.
Osteonecrosis of the jaw	Any grade	Withhold cabozantinib until complete resolution, then resume at a reduced dose.
Palmar-plantar erythrodysesthesia	Grade 2 (intolerable) or grade 3	Withhold cabozantinib until ≤ grade 1, then resume at a reduced dose.
Reversible posterior leukoencephalopathy syndrome	Any grade	Permanently discontinue cabozantinib.
Thromboembolic events	Acute myocardial infarction (any grade), cerebral infarction (≥ grade 2), arterial thromboembolic events (grade 3 or 4), venous thromboembolic events (grade 4)	Permanently discontinue cabozantinib.
Thyroid dysfunction	Any	Manage thyroid dysfunction as clinically indicated.
Wound healing complications	Any	Withhold cabozantinib treatment for at least 3 weeks prior to scheduled surgery (including dental surgery or invasive dental procedures); do not administer cabozantinib for at least 2 weeks after major surgery and until adequate wound healing. The safety of resuming cabozantinib after resolution of wound healing complications has not been established.
Other adverse reactions	Grade 2 (intolerable), 3, or 4	Withhold cabozantinib until ≤ grade 1 or baseline, then resume at a reduced dose.

Dosing: Pediatric

(For additional information see "Cabozantinib: Pediatric drug information")

Dosage guidance:

Dosage form information: Do not substitute cabozantinib tablets (Cabometyx) and capsules (Cometriq).

Clinical considerations: Antiemetics are recommended as clinically appropriate for the prophylaxis and treatment of nausea and vomiting (Ref). Withhold cabozantinib treatment for at least 3 weeks prior to scheduled surgery (including dental surgery or invasive dental procedures); do not administer cabozantinib for at least 2 weeks after major surgery and until adequate wound healing. Do not use cabozantinib in patients with a recent history of hemorrhage (including hemoptysis, hematemesis, or melena).

Neuroendocrine tumors, pancreatic or extra-pancreatic

Neuroendocrine tumors, pancreatic (pNET) or extra-pancreatic (epNET ):

Children ≥12 years and Adolescents: Cabometyx:

<40 kg: Oral: 40 mg once daily until disease progression or unacceptable toxicity.

≥40 kg: Oral: 60 mg once daily until disease progression or unacceptable toxicity.

Thyroid cancer, differentiated, locally advanced or metastatic

Thyroid cancer, differentiated, locally advanced or metastatic:

Children ≥12 years and Adolescents: Cabometyx:

<40 kg: Oral: 40 mg once daily until disease progression or unacceptable toxicity.

≥40 kg: Oral: 60 mg once daily until disease progression or unacceptable toxicity.

Dosage adjustment for toxicity: Cabometyx:

**Cabozantinib (Cabometyx) Dose Reduction Levels for Adverse Reactions**
Initial Dosage	First Dosage Reduction	Second Dosage Reduction
^a If previously receiving the lowest dose, resume at the same dose. If lowest dose is not tolerated, discontinue cabozantinib.
40 mg once daily	20 mg once daily	20 mg every other day^a
60 mg once daily	40 mg once daily	20 mg once daily^a

**Cabozantinib (Cabometyx) Recommended Dosage Modifications for Adverse Reactions**
Adverse Reaction	Severity	Cabometyx Dosage Modification
GI toxicity: Diarrhea	Any grade	Manage with antidiarrheals as indicated.
GI toxicity: Diarrhea	Grades 2, 3, or 4	Withhold cabozantinib until ≤ grade 1, then resume at a reduced dose.
GI toxicity: Perforation or fistulas	GI perforation (any grade) or grade 4 fistula	Permanently discontinue cabozantinib.
Hemorrhage	Grade 3 or 4	Permanently discontinue cabozantinib.
Hypertension	Grade 3	Withhold cabozantinib until hypertension is adequately controlled to ≤ grade 2, then resume at a reduced dose. Permanently discontinue cabozantinib for hypertension that cannot be controlled.
	Grade 4	Permanently discontinue cabozantinib.
	Hypertensive crisis	Permanently discontinue cabozantinib.
Hypocalcemia	Any	Replace calcium as necessary during treatment. Depending on the severity, withhold cabozantinib and resume at a reduced dose upon recovery or permanently discontinue.
Osteonecrosis of the jaw	Any grade	Withhold cabozantinib until complete resolution, then resume at a reduced dose.
Palmar-plantar erythrodysesthesia	Grade 2 (intolerable) or grade 3	Withhold cabozantinib until ≤ grade 1, then resume at a reduced dose.
Reversible posterior leukoencephalopathy syndrome	Any grade	Permanently discontinue cabozantinib.
Thromboembolic events	Acute myocardial infarction (any grade), cerebral infarction (≥ grade 2), arterial thromboembolic events (grade 3 or 4), venous thromboembolic events (grade 4)	Permanently discontinue cabozantinib.
Thyroid dysfunction	Any	Manage thyroid dysfunction as clinically indicated.
Wound healing complications	Any	Withhold cabozantinib treatment for at least 3 weeks prior to scheduled surgery (including dental surgery or invasive dental procedures); do not administer cabozantinib for at least 2 weeks after major surgery and until adequate wound healing. The safety of resuming cabozantinib after resolution of wound healing complications has not been established.
Other adverse reactions	Grade 2 (intolerable), grade 3 or 4	Withhold cabozantinib until ≤ grade 1 or baseline, then resume at a reduced dose.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Renal impairment prior to treatment initiation :

Children ≥12 years and Adolescents: Cabometyx: Oral:

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).

Renal toxicity during treatment:

Proteinuria, grade 2 or 3: Withhold cabozantinib until improvement to ≤ grade 1 proteinuria, then resume at a reduced dose.

Nephrotic syndrome: Permanently discontinue cabozantinib.

Dosing: Liver Impairment: Pediatric

Baseline liver impairment: Children ≥12 years and Adolescents: Cabometyx: Oral:

Mild impairment: No dosage adjustment necessary.

Moderate impairment:

<40 kg: Reduce initial dose to 20 mg once daily.

≥40 kg: Reduce initial dose to 40 mg once daily.

Severe impairment: Avoid use (has not been studied).

Adverse Reactions (Significant): Considerations

Dermatologic toxicity

Dermatologic toxicity may occur with cabozantinib therapy, notably palmar-plantar erythrodysesthesia (PPES). PPES occurred in cabozantinib clinical studies, including grade ≥3 events. PPES manifests as tender, callus-like hyperkeratosis on the soles or palms with surrounding erythema, edema, and occasional bullae formation (Ref); significant impact on patient quality of life has been observed (Ref). PPES often resolves following cessation of therapy (Ref). Additional dermatologic toxicities, including pigment dilution, hair discoloration, xerosis, scrotal erythema, and subungual splinter hemorrhage have been reported in cabozantinib-treated patients (Ref). Delayed radiation recall phenomenon with grade 4 skin ulceration has also been reported with cabozantinib (Ref).

Mechanism: Not clearly established; impaired vascular repair in high friction areas (hands and feet) secondary to combined vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGFR) inhibition has been proposed (Ref). Alternatively, dermatologic toxicity may be related to epidermal cell apoptosis (Ref), and toxic drug concentrations in eccrine sweat glands and areas of mechanical stress secondary to capillary microtrauma (Ref).

Onset: Intermediate; median time to first occurrence of first PPES event or PPES-associated symptoms: 3.4 to 4 weeks (range: 1.9 to 23.6 weeks) (Ref). Median onset of pigment dilution/hair depigmentation, xerosis, and scrotal ulcer/erythema/edema: 11.4 weeks, 5.1 weeks, and 5.3 weeks, respectively (Ref).

Risk factors:

• Higher cabozantinib exposure (Ref)

• Tumor type: Medullary thyroid cancer, hepatocellular carcinoma (Ref)

Diarrhea

Diarrhea occurred in over half of patients receiving cabozantinib in clinical trials; grade 3 and 4 events have been reported. Diarrhea was the most common reason for dose reduction in patients with renal cell carcinoma (RCC) treated with single agent cabozantinib (Ref); cabozantinib (as a single agent or in combination with nivolumab) was associated with the highest mean risk of diarrhea (any grade) when compared to other tyrosine kinase inhibitors for the management of RCC (Ref). Similarly, cabozantinib was associated with a greater risk of diarrhea compared to other second-line treatment options for the management of hepatocellular carcinoma (Ref). Higher rates of diarrhea are observed in multikinase inhibitors, such as cabozantinib, when compared to pure vascular endothelial growth factor (VEGF) inhibitors (Ref). Symptoms generally resolve within 1 week with the use of antidiarrheal agents (Ref).

Mechanism: Not clearly established; multiple mechanisms have been proposed, including direct local irritation by excreted metabolites (Ref), transient lactose intolerance (Ref), inhibition of microcirculation in GI tract secondary to VEGF inhibition (Ref), KIT inhibition (Ref), and immunomodulatory effects (Ref).

Onset: Varied; median time to first occurrence of diarrhea: ~4 to 4.9 weeks (Ref).

Risk factors:

• Higher cabozantinib exposure (Ref)

Endocrinopathy

Treatment with cabozantinib may result in endocrinopathy, including hypothyroidism, hyperthyroidism, and adrenocortical insufficiency (Ref). Cases of thyrotoxicosis have been reported; subsequent hypothyroidism occurred secondary to transient thyrotoxicosis cases (Ref). Hypothyroidism may be irreversible (Ref). Primary or secondary adrenal insufficiency may occur when cabozantinib is used in combination with nivolumab. Postmarketing pharmacovigilance data has also linked adrenal insufficiency with cabozantinib when used as a single agent (Ref).

Mechanism: Not clearly established; multiple mechanisms of thyroid dysfunction with tyrosine kinase inhibitors have been proposed, including inhibition of iodide uptake, decreased synthesis of thyroid hormone, effects on deiodinase activity, destructive thyroiditis secondary to apoptosis of thyroid follicular cells; and prevention of vascular endothelial growth factor (VEGF) binding to normal thyroid cells, inhibition of thyroid blood flow, and tissue ischemia (Ref). Adrenal insufficiency may be related to inhibition of VEGF, which is highly expressed in the fenestrated capillaries of endocrine organs (Ref).

Onset: Varied; thyrotoxicosis occurred as early as 2 weeks following initiation of cabozantinib (Ref). Median time to onset of immune-related thyroid effects (in combination with nivolumab): 9.5 to 18.1 weeks (Ref). Median time to onset of adrenal insufficiency with VEGF tyrosine kinase inhibitors: 72 days (range: 14 to 201 days) (Ref).

Risk factors:

• Adrenal insufficiency: Combination with immune checkpoint inhibitor therapy (Ref)

Fistula formation and gastrointestinal perforation

Gastrointestinal fistula and gastrointestinal perforation, including fatal cases, have occurred with inhibitors of the vascular endothelial growth factor (VEGF) pathway, including cabozantinib. Nongastrointestinal fistulas have also occurred, including tracheal/esophageal fistula (Ref), with cases of bronchial perforation reported (in combination with nivolumab) (Ref).

Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (ie, VEGF inhibition) resulting in regression of capillaries of intestinal villi and impaired wound healing (Ref).

Onset: Delayed; median time to first occurrence of fistula formation: 14 to 30.3 weeks (Ref); median time to first occurrence of GI perforation: ~6 to 10 weeks (Ref).

Risk factors:

• Bowel tumor necrosis (Ref)

• Comorbid bowel conditions (eg, abdominal carcinomatosis, ulcer) (Ref)

• History of aerodigestive, pelvic, or abdominal irradiation (Ref)

• Tumor invasion at fistula/perforation site (Ref)

Hemorrhage

Severe and fatal hemorrhage may occur with cabozantinib. Patients on therapeutic doses of anticoagulation, including warfarin, direct thrombin inhibitors, and factor X inhibitors, were excluded from clinical trials (Ref). However, limited real-world data support cautious use of therapeutic anticoagulation, particularly with direct oral anticoagulants, with cabozantinib in patients with an indication for anticoagulation (Ref). Cases of intracranial hemorrhage in patients with brain metastases attributed to renal cell carcinoma treated with cabozantinib (in combination with nivolumab following stereotactic brain irradiation) (Ref) and single agent cabozantinib following initiation of rivaroxaban (Ref) have been reported.

Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (ie, vascular endothelial growth factor [VEGF] inhibition). Possible mechanisms include direct vascular damage through tumor necrosis, loss of vascular integrity through impacts on endothelial cell function (eg, exposure of procoagulant phospholipids within the luminal membrane), inhibition of the coagulation cascade through VEGF effects on tissue factor, and thrombocytopenia with concurrent chemotherapy (Ref).

Onset: Delayed; median time to first occurrence of grade ≥3 hemorrhage: 20.9 weeks (Ref); median time to hemorrhagic events: 9.1 weeks (Ref).

Risk factors:

• Concomitant therapeutic anticoagulation (data are conflicting) (Ref)

• Tumor invasion or infiltration of major blood vessels

• Preexisting high-risk esophagogastric varices, portal hypertension, or thrombocytopenia secondary to underlying liver cirrhosis in hepatocellular carcinoma patients

Hepatotoxicity

Cabozantinib treatment is associated with a two- to threefold risk of increased serum aspartate aminotransferase (AST) and/or increased serum alanine aminotransferase (ALT); grade 3 and 4 events have been reported (Ref). A higher frequency is noted when cabozantinib is used in combination with nivolumab. In a meta-analysis of patients treated with cabozantinib in a variety of tumors, cabozantinib is associated with a higher relative risk of all-grade and high-grade ALT elevation, and all-grade AST elevation when compared to other anticancer therapies, including other vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (Ref). In clinical trials, hepatoxicity resolved in a majority of patients following treatment with systemic corticosteroids; however, recurrence of transaminitis occurred in some patients following resumption of cabozantinib, nivolumab, or the combination. Isolated grade 1 or 2 hyperbilirubinemia is associated with the UGT1A1*28 TA7/TA7 phenotype (Ref).

Mechanism: Not clearly established; dose-related; may be related to pharmacologic action and mitochondrial toxicity (Ref). Isolated hyperbilirubinemia may be attributed to reduced glucuronidation and excretion of unconjugated of bilirubin (Ref).

Onset: Delayed; median time to onset of hepatic adverse effects (in combination with nivolumab): 8.1 to 10.1 weeks (Ref).

Risk factors:

• Combination with immune checkpoint inhibitor therapy

• UGT1A1*28 TA7/TA7 phenotype (isolated hyperbilirubinemia) (Ref).

Hypertension

Hypertension is frequently associated with inhibitors of the vascular endothelial growth factor (VEGF) pathway (eg, cabozantinib), including grade ≥3 events and hypertensive crisis. In a meta-analysis evaluating vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, cabozantinib was associated with an ~7-fold increase in the risk of all-grade hypertension; the relative risk high-grade hypertensive events were highest in cabozantinib-treated patients (Ref). Among second-line treatments for advanced hepatocellular carcinoma, cabozantinib is associated with the highest risk of hypertension (Ref). Hypertension associated with inhibition of the VEGF pathway appears to be reversible and usually resolves upon discontinuation of therapy (Ref).

Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (ie, VEGF inhibition). Multiple mechanisms have been proposed, including endothelial vasoconstriction and vascular resistance through reduction in nitric oxide and prostacyclin synthesis and increases in circulating endothelin-1 (Ref), interruption of survival signaling in endothelial cells and decreased angiogenesis, leading to cellular apoptosis, reduced microvascular density (rarefaction), and ultimately an increase in vascular resistance (Ref), and regulation of endothelial cell function in the renal glomeruli (Ref).

Onset: Intermediate; median time to first occurrence of hypertension: ~2 to 3 weeks(Ref).

Risk factors:

• Advanced age (Ref)

• eGFR <60 mL/minute/1.73 m² (Ref)

• Higher cabozantinib exposure (Ref)

• History of smoking (Ref)

• Hyperlipidemia (Ref)

• Obesity (Ref)

• Preexisting hypertension or cardiovascular disease (Ref)

• Previous treatment with anthracycline (Ref)

Hypocalcemia

Treatment with cabozantinib is associated with the development of hypocalcemia, including grade 3 to 4 events. In a meta-analysis of treated patients, cabozantinib was associated with a significantly increased risk of all-grade and high-grade hypocalcemia when compared with placebo or sunitinib (Ref); however results are conflicting (Ref).

Mechanism: Not clearly established; multiple mechanisms have been proposed including vitamin D and/or magnesium malabsorption secondary to adverse effects (eg, nausea, vomiting, diarrhea, anorexia), tumor lysis syndrome, and direct effect on bone metabolism via vascular endothelial growth factor inhibitory effects on osteoblasts and osteoclasts (Ref).

Onset: Delayed; median time to onset of electrolyte disorders: 56 days (Ref).

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw, has been reported in patients receiving cabozantinib and is characterized in oncology patients by nonhealing (persistence >8 weeks) exposed or necrotic bone in the maxillofacial region in patients with current or previous treatment with bone modifying agents or angiogenic inhibitors and no history of radiation or metastatic disease to the jaw (Ref). ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, or gingival ulceration/erosion.

Mechanism: Dose-related; related to pharmacologic action (ie, vascular endothelial growth factor inhibition) resulting in wound healing impairment, and effects on bone remodeling and local host defense mechanisms (Ref).

Onset: Delayed; median time to first occurrence of osteonecrosis: 10 weeks (Ref); a published case in a patient with medullary thyroid cancer occurred ~3 months following initiation of cabozantinib (Ref).

Risk factors:

• Concomitant exposure to antiresorptive therapy (eg, bisphosphonates, denosumab) (Ref)

• Ill-fitting dentures (Ref)

• Invasive dental procedures (Ref)

• Poor oral health (Ref)

• Tobacco use (Ref)

• Uncontrolled diabetes (Ref)

Proteinuria

Proteinuria, including grade 3 and 4 events, has occurred with cabozantinib; nephrotic syndrome has also occurred. Kidney biopsy of patients with proteinuria have demonstrated findings consistent with thrombotic microangiopathy (Ref). In studies with other vascular endothelial growth factor (VEGF) inhibitor therapy, proteinuria is typically asymptomatic and reversible following discontinuation (Ref).

Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (ie, VEGF inhibition) resulting in renal podocyte dysfunction (Ref). Additional mechanisms have been proposed, including potential adaptive hyperfiltration response following nephrectomy in renal cell cancer (Ref).

Onset: Varied; median time to first occurrence of proteinuria: 4.1 weeks (Ref); a delayed onset (median: 35.5 months) has also been reported (Ref).

Risk factors:

• Concurrent use of nephrotoxic agents (Ref)

• Diabetes mellitus (Ref)

• Hypertension (Ref)

• Japanese ethnicity (Ref)

• Preexisting grade 1 proteinuria (Ref)

• Prolonged cabozantinib use (Ref)

Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported with cabozantinib; signs and symptoms include seizure, headache, visual disturbances, confusion, and/or altered mental status. RPLS is characterized by subcortical vasogenic edema on MRI.

Mechanism: Dose-related; exact mechanism is unknown, likely secondary to pharmacologic action (ie, vascular endothelial growth factor [VEGF] inhibition) and related hypertension and endothelial dysfunction (Ref).

Onset: Varied; in a study of patients treated with alternative VEGF inhibitor therapy, RPLS occurred after a median duration of 9.5 weeks (range: 0.1 to 34 weeks) (Ref). A case of RPLS in a patient treated with cabozantinib occurred 3 weeks following initiation of therapy (Ref).

Risk factors:

• Females (Ref)

• Hypomagnesemia (Ref)

Thromboembolic events

Cabozantinib is associated with an increased risk of thrombosis, including fatal events (Ref). Venous thromboembolism (VTE) (including pulmonary embolism) and arterial thromboembolism have been observed in cabozantinib-treated patients. Meta-analyses evaluating the risk of major adverse cardiovascular events with angiogenesis inhibitors identified cabozantinib associated with a higher risk of VTE (Ref).

Mechanism: Not clearly established; likely dose-related and related to pharmacologic action (ie, vascular endothelial growth factor inhibition). Proposed mechanisms include endothelial cell apoptosis creating a prothrombotic state; lack of endothelial cell renewal resulting in exposure of the extracellular matrix to circulating blood and platelet activation through exposure to collagen and von Willebrand factor; increased tissue factor expression; reduced nitric oxide and thrombomodulin expression; and direct platelet activation (Ref).

Onset: Delayed; median time to first occurrence of arterial thromboembolism: 9 to 11.4 weeks (Ref). Median time to first occurrence of VTE: 9 to 16.1 weeks (Ref).

Wound healing impairment

Vascular endothelial growth factor (VEGF) receptor inhibitors, including cabozantinib, are associated with wound healing impairment. Grade 3 to 5 wound complications in approximately one-fourth of patients necessitated premature closure of a phase 2 study evaluating cabozantinib for recurrent/metastatic salivary gland carcinoma (off-label use); two-thirds of the wound complications occurred at sites of prior high-dose radiation (Ref). The safety of resuming cabozantinib following resolution of wound healing complications has not been established.

Mechanism: Not clearly established; likely dose-related and related to pharmacologic action (ie, VEGF inhibition). Proposed mechanisms include platelet dysfunction and decreased expression of endothelial tissue factor (Ref).

Onset: Delayed; median time to first occurrence of wound complications: ~7 to 11 weeks (Ref). Grade 3 to 5 cases have occurred at a median of 7.1 months (range: 2.1 to 12.6 months) in patients receiving cabozantinib for the treatment of salivary gland carcinoma (off-label use) (Ref).

Risk factors:

• Prior exposure to high-dose radiotherapy at complication site (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Cardiovascular: Cardiac arrhythmia (<15%), edema (16%), hypertension (30% to 67%; including hypertensive crisis) (table 1)Hypertension, thromboembolic complications (19%; including arterial thromboembolism [2%] (table 2)Arterial Thromboembolism, deep vein thrombosis, embolism, pulmonary embolism [4% to 5%] (table 3)Pulmonary Embolism, venous thromboembolism [6% to 7%] (table 4)Venous Thromboembolism)

**Cabozantinib: Adverse Reaction: Hypertension**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
30%	N/A	5%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
64%	N/A	37%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
30%	N/A	6%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
67%	N/A	55%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
Overt hypertension: 61%	N/A	30%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	211	N/A	107
33%	N/A	4%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
39%	8%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

**Cabozantinib: Adverse Reaction: Arterial Thromboembolism**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
2%	0%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109
2%	N/A	60 mg once daily	Oral tablets	N/A	N/A	N/A

**Cabozantinib: Adverse Reaction: Pulmonary Embolism**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
5%	0%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	62
4%	N/A	60 mg once daily	Oral tablets	N/A	N/A	N/A

**Cabozantinib: Adverse Reaction: Venous Thromboembolism**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
6%	3%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109
7%	N/A	60 mg once daily	Oral tablets	N/A	N/A	N/A

Dermatologic: Alopecia (16%), erythema of skin (11%), hair discoloration (34%) (table 5)Hair Discoloration, palmar-plantar erythrodysesthesia (42% to 50%) (table 6)Palmar-Plantar Erythrodysesthesia, skin rash (19% to 57%), xeroderma (11% to 19%)

**Cabozantinib: Adverse Reaction: Hair Discoloration**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
34%	1%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109

**Cabozantinib: Adverse Reaction: Palmar-Plantar Erythrodysesthesia**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
46%	N/A	0%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
46%	N/A	5%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
50%	N/A	2%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
42%	6%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

Endocrine & metabolic: Hyperglycemia (37%), hyperkalemia (14%), hypoalbuminemia (14% to 51%), hypocalcemia (8% to 52%) (table 7)Hypocalcemia, hypoglycemia (11%), hypokalemia (10% to 23%), hypomagnesemia (11% to 31%), hyponatremia (10% to 30%), hypophosphatemia (19% to 48%), hypothyroidism (8% to 34%) (table 8)Hypothyroidism, increased lactate dehydrogenase (84% to 90%), increased serum triglycerides (53%), weight loss (17% to 48%)

**Cabozantinib: Adverse Reaction: Hypocalcemia**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
36%	10%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	62
20%	5%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	67
8%	0%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	237
17%	3%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	31
52%	27%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109

**Cabozantinib: Adverse Reaction: Hypothyroidism**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
34%	N/A	5%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
8%	N/A	<1%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
25%	N/A	3%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
21%	<1%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

Gastrointestinal: Abdominal pain (23% to 27%), constipation (25% to 27%), decreased appetite (23% to 48%), diarrhea (51% to 74%; grades 3/4: 6% to 16%) (table 9)Diarrhea, dysgeusia (10% to 35%), dyspepsia (10% to 16%), dysphagia (13%), increased serum amylase (16%), mouth pain (36%), mucosal swelling (14% to 19%), nausea (24% to 50%; grades 3/4: 1% to 8%), stomatitis (13% to 51%; grades 3/4: 2% to 6%), vomiting (14% to 32%; grades 3/4: ≤6%)

**Cabozantinib: Adverse Reaction: Diarrhea**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
All grades: 51%	N/A	All grades: 3%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
Grades 3/4: 7%	N/A	Grades 3/4: 0%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
All grades: 65%	N/A	All grades: 42%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
Grades 3/4: 11%	N/A	Grades 3/4: 5%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
All grades: 54%	N/A	All grades: 19%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
Grades 3/4: 10%	N/A	Grades 3/4: 2%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
All grades: 63%	N/A	All grades: 23%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
Grades 3/4: 6%	N/A	Grades 3/4: 0%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
All grades: 63%	N/A	All grades: 33%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
Grades 3/4: 16%	N/A	Grades 3/4: 2%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
All grades: 74%	All grades: 28%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A
Grades 3/4: 11%	Grades 3/4: 2%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

Genitourinary: Proteinuria (2% to 15%) (table 10)Proteinuria

**Cabozantinib: Adverse Reaction: Proteinuria**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
15%	N/A	3%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
2%	N/A	N/A	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	N/A
12%	9%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

Hematologic & oncologic: Anemia (17% to 31%; grades 3/4: 4% to 5%), hemorrhage (<15%; grades ≥3: 3% to 5%) (table 11)Hemorrhage, leukopenia (35%; grades 3/4: <1%), lymphocytopenia (22% to 53%; grades 3/4: 7% to 16%), neutropenia (31% to 43%; grades 3/4: 2% to 7%), thrombocytopenia (25% to 35%; grades 3/4: <1%)

**Cabozantinib: Adverse Reaction: Hemorrhage**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
All grades: <15%	N/A	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A
All grades: <15%	N/A	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A
Grades ≥3: 3%	Grades ≥3: 1%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109
Grades ≥3: 5%	N/A	60 mg once daily	Oral tablets	N/A	N/A	N/A

Hepatic: Hyperbilirubinemia (12% to 25%) (table 12)Hyperbilirubinemia, increased gamma-glutamyl transferase (26% to 27%), increased serum alanine aminotransferase (63% to 86%) (table 13), increased serum alkaline phosphatase (34% to 52%), increased serum aspartate aminotransferase (70% to 86%) (table 14)

**Cabozantinib: Adverse Reaction: Hyperbilirubinemia**
Drug (Cabozantinib)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Placebo)
12%	5%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	62
25%	14%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	109

**Cabozantinib: Adverse Reaction: Increased Serum Alanine Aminotransferase**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
66%	N/A	11%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
63%	N/A	18%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
73%	N/A	37%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
75%	N/A	39%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
86%	N/A	41%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
68%	32%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

**Cabozantinib: Adverse Reaction: Increased Serum Aspartate Aminotransferase**
Drug (Cabozantinib)	Comparator (Everolimus)	Placebo	Dose	Dosage Form	Indication	Number of Patients (Cabozantinib)	Number of Patients (Everolimus)	Number of Patients (Placebo)
77%	N/A	18%	60 mg once daily	Oral tablets	Differentiated thyroid cancer	125	N/A	62
70%	N/A	21%	60 mg once daily	Oral tablets	Extra-pancreatic neuroendocrine tumors	132	N/A	67
73%	N/A	46%	60 mg once daily	Oral tablets	Hepatocellular carcinoma	467	N/A	237
76%	N/A	48%	60 mg once daily	Oral tablets	Pancreatic neuroendocrine tumors	63	N/A	31
86%	N/A	35%	140 mg once daily	Oral capsules	Progressive metastatic medullary thyroid cancer	214	N/A	109
74%	40%	N/A	60 mg once daily	Oral tablets	Renal cell carcinoma	331	322	N/A

Nervous system: Asthenia (19% to 22%), dizziness (11% to 25%), fatigue (41% to 79%), headache (10% to 18%), voice disorder (10% to 20%)

Neuromuscular & skeletal: Arthralgia (11% to 14%), limb pain (9% to 14%), muscle spasm (8% to 13%), musculoskeletal pain (36% to 41%)

Renal: Acute kidney injury (<15%), increased serum creatinine (23% to 58%)

Respiratory: Cough (17% to 18%), dyspnea (12% to 19%)

1% to 10%:

Cardiovascular: Hypotension (7%)

Dermatologic: Hyperkeratosis (7%)

Endocrine & metabolic: Dehydration (7%)

Gastrointestinal: Gastrointestinal fistula (1%), gastrointestinal perforation (1% to 3%), hemorrhoids (9%), xerostomia (10%)

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

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

Respiratory: Pleural effusion (≥2%)

Miscellaneous: Fistula (nongastrointestinal: 1% to 4%, including transesophageal fistula), postoperative wound complication (2%)

<1%:

Gastrointestinal: Pancreatitis

Hepatic: Cholestatic hepatitis

Nervous system: Posterior reversible encephalopathy syndrome, seizure

Frequency not defined:

Cardiovascular: Acute myocardial infarction, syncope

Endocrine & metabolic: Cushing syndrome

Infection: Sepsis

Nervous system: Myasthenia

Renal: Nephrotic syndrome

Respiratory: Hypoxia, pneumonia

Postmarketing:

Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, coronary artery dissection, heart failure (Ref), myocardial rupture (arterial rupture, aortic rupture)

Dermatologic: Bullous rash (Ref), dermatologic disorder (acquired perforating dermatosis) (Ref)

Endocrine & metabolic: Adrenocortical insufficiency (Ref), hyperthyroidism (Ref), thyrotoxicosis (Ref)

Hematologic & oncologic: Thrombotic microangiopathy (Ref)

Ophthalmic: Chorioretinitis (Ref), retinal detachment (Ref)

Miscellaneous: Radiation recall phenomenon (Ref), wound healing impairment

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to cabozantinib or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Primary and secondary adrenal insufficiency have occurred with the combination of cabozantinib and nivolumab, including cases of grade 2 to 3 adrenal insufficiency. The majority of patients received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in approximately one-fourth of patients. In cases where cabozantinib and nivolumab were withheld for adrenal insufficiency, most reinitiated treatment after symptom improvement with recurrence of adrenal insufficiency in some patients.

• Dermatologic toxicity: Palmar-plantar erythrodysesthesia syndrome occurred in nearly half of patients; grade 3 events were reported.

• GI toxicity: Diarrhea has been commonly observed in cabozantinib-treated patients; grade 3 and 4 diarrhea has occurred. GI perforations and fistulas (including fatal cases) have been reported in a small percentage of patients who received cabozantinib. Tracheal/esophageal fistulas were also noted; some cases were fatal.

• Hemorrhage: Severe and fatal hemorrhages have occurred with cabozantinib, including grade 3 or higher events.

• Hepatotoxicity: Increased frequencies of grade 3 and 4 ALT and AST elevations may occur when cabozantinib is administered in combination with nivolumab (compared to cabozantinib alone). ALT or AST elevations may recur when rechallenged with cabozantinib and/or nivolumab.

• Hypertension: Cabozantinib may cause hypertension, including hypertensive crisis. Stage 1 and 2 hypertension were commonly seen in cabozantinib-treated patients; grade 3 and 4 hypertension has been reported.

• Hypocalcemia: Cabozantinib may cause hypocalcemia, including grade 3 and 4 events.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw has occurred rarely with cabozantinib; manifestations may include jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

• Proteinuria: Proteinuria occurred in some patients receiving cabozantinib; nephrotic syndrome was also reported (rare).

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema (based on MRI findings), may occur with cabozantinib. Signs of RPLS include seizures, headache, visual disturbances, confusion, or altered mental function.

• Thromboembolic events: Cabozantinib may cause arterial or venous thromboembolic events. Venous thromboembolism (including pulmonary embolism) and arterial thromboembolism have been observed in cabozantinib-treated patients. Fatal thromboembolic events have occurred.

• Thyroid dysfunction: Thyroid dysfunction (primarily hypothyroidism) has occurred with cabozantinib, including grade 3 thyroid dysfunction.

• Wound healing impairment: Cabozantinib inhibits vascular endothelial growth factor receptors 1, 2, and 3; wound healing complications have been reported with cabozantinib.

Dosage form specific issues:

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

Dosage Forms: US

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

Kit, Oral, as s-malate:

Cometriq (100 MG Daily Dose): 80 mg (28s) and 20 mg (28s)

Cometriq (140 MG Daily Dose): 80 mg (28s) and 20 mg (84s)

Cometriq (60 MG Daily Dose): 20 mg (84s)

Tablet, Oral, as s-malate:

Cabometyx: 20 mg, 40 mg, 60 mg

Generic Equivalent Available: US

Pricing: US

Kit (Cometriq (100 MG Daily Dose) Oral)

80 & 20 mg (per each): $415.27

Kit (Cometriq (140 MG Daily Dose) Oral)

3 x 20 MG &80 MG (per each): $207.64

Kit (Cometriq (60 MG Daily Dose) Oral)

20 mg (per each): $276.85

Tablets (Cabometyx Oral)

20 mg (per each): $1,052.05

40 mg (per each): $1,052.05

60 mg (per each): $1,052.05

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

Tablet, Oral, as s-malate:

Cabometyx: 20 mg, 40 mg, 60 mg

Prescribing and Access Restrictions

Contact Exelixis Access Services (EASE) for information on obtaining cabozantinib (1-844-900-3273 or https://www.ease.us).

Administration: Adult

Oral: Administer on an empty stomach (at least 1 hour before or 2 hours after eating); do not administer with food. Swallow whole; do not open capsules or crush, chew, or split tablets. Do not substitute cabozantinib tablets and capsules.

Note: The prescribing information (for Cometriq) describes when to give food with respect to cabozantinib; no food should be consumed for at least 2 hours before or for at least 1 hour after the cabozantinib dose.

Cabozantinib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea/vomiting (Ref).

Administration: Pediatric

Oral: Tablets: Administer on an empty stomach (at least 1 hour before or 2 hours after eating). Swallow whole; do not crush tablets. Do not substitute cabozantinib tablets and capsules. Antiemetics are recommended as clinically appropriate for the prophylaxis and treatment of nausea and vomiting (Ref).

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

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2024 [table 2]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Use: Labeled Indications

Hepatocellular carcinoma, advanced (Cabometyx): Treatment (as a single agent) of hepatocellular carcinoma (HCC) in patients who have previously been treated with sorafenib.

According to guidelines from the American Society of Clinical Oncology for systemic therapy for advanced HCC, cabozantinib is a second-line therapy option in patients who received first-line immune check point inhibitor combination therapy or following first-line therapy with sorafenib or lenvatinib (ASCO [Gordan 2024]).

Neuroendocrine tumors, locally advanced or metastatic, unresectable (Cabometyx):

Treatment (as a single agent) of unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNETs) in adults and pediatric patients ≥12 years of age who have been previously treated.

Treatment (as a single agent) of unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNETs) in adults and pediatric patients ≥12 years of age who have been previously treated.

Renal cell carcinoma, advanced (Cabometyx):

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

Treatment (as a single agent) of advanced RCC.

Thyroid cancer, differentiated, locally advanced or metastatic (Cabometyx): Treatment (as a single agent) of locally advanced or metastatic differentiated thyroid cancer that has progressed following VEGFR-targeted therapy in adults and pediatric patients ≥12 years of age who are radioactive iodine-refractory or ineligible.

Thyroid cancer, medullary (Cometriq): Treatment (as a single agent) of progressive, metastatic medullary thyroid cancer.

Medication Safety Issues

Sound-alike/look-alike issues:

Cabozantinib may be confused with axitinib, bosutinib, cabazitaxel, capecitabine, capivasertib, capmatinib, ceritinib, cobimetinib, crizotinib, dasatinib, imatinib, lenvatinib, nilotinib, ponatinib, regorafenib, ruxolitinib, tivozanib, vandetanib, vemurafenib.

Cabometyx may be confused with Cometriq, Copiktra.

Cometriq may be confused with Cabometyx, CoQ10 (abbreviation often used for coenzyme Q10).

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Administration issues:

Cabozantinib tablets (Cabometyx) and capsules (Cometriq) are NOT interchangeable; do NOT substitute.

Metabolism/Transport Effects

Substrate of CYP2C9 (Minor), CYP3A4 (Major), MRP2; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Androgens: Hypertension-Associated Agents may increase hypertensive effects of Androgens. Risk C: Monitor

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may increase adverse/toxic effects of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor

Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor

CYP3A4 Inducers (Moderate): May decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification

CYP3A4 Inducers (Strong): May decrease serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily Risk D: Consider Therapy Modification

CYP3A4 Inhibitors (Moderate): May increase serum concentration of Cabozantinib. Risk C: Monitor

CYP3A4 Inhibitors (Strong): May increase serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, decrease cabozantinib capsules (Cometriq) by 40 mg from previous dose or decrease cabozantinib tablets (Cabometyx) by 20 mg from previous dose. Risk D: Consider Therapy Modification

Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor

Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification

Grapefruit Juice: May increase serum concentration of Cabozantinib. Risk X: Avoid

MRP2 Inhibitors: May increase serum concentration of Cabozantinib. Risk C: Monitor

Phenobarbital-Primidone: May decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification

Rifabutin: May decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification

Rifapentine: May decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification

Solriamfetol: May increase hypertensive effects of Hypertension-Associated Agents. Risk C: Monitor

St John's Wort: May decrease serum concentration of Cabozantinib. Risk X: Avoid

Food Interactions

A high-fat meal increased C_max and AUC by 41% and 57%, respectively compared to the fasted state. Cabozantinib serum concentrations may be increased when taken with grapefruit or grapefruit juice. Management: Must be taken on an empty stomach, at least 1 hour before and 2 hours after food. Avoid concurrent use with grapefruit or grapefruit juice.

Reproductive Considerations

Evaluate pregnancy status prior to initiating therapy in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 4 months after the last cabozantinib dose.

Adverse effects to fertility were observed in animal toxicology studies; data are lacking on possible fertility effects in humans.

Pregnancy Considerations

Based on its mechanism of action and findings from animal reproduction studies, in utero exposure to cabozantinib may cause fetal harm.

Breastfeeding Considerations

It is not known if cabozantinib is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during treatment and for 4 months after the last cabozantinib dose.

Dietary Considerations

Avoid grapefruit and grapefruit juice throughout therapy.

Monitoring Parameters

Monitor kidney function, liver function (at baseline and periodically; consider monitoring more frequently when cabozantinib is administered in combination with nivolumab), CBC with differential, serum electrolytes, including calcium (regularly during treatment), thyroid function testing (at baseline and as clinically indicated). Monitor urine protein (regularly during treatment). Consider monitoring urine protein/creatinine ratio (at baseline and as clinically indicated) (Brose 2021). Evaluate pregnancy status (prior to treatment in patients who could become pregnant). Monitor BP (regularly during therapy). Monitor for signs/symptoms of GI perforations or fistulas (including abscess and sepsis), bleeding/hemorrhage, palmar-plantar erythrodysesthesia syndrome, reversible posterior leukoencephalopathy syndrome (evaluate patients who present with seizures, headache, visual disturbances, confusion, or altered mental function), osteonecrosis of the jaw (perform oral examination prior to initiation and periodically during therapy), thyroid dysfunction (assess for signs of thyroid dysfunction at baseline; monitor for signs/symptoms during treatment), wound healing complications, diarrhea, stomatitis, thromboembolic events, and for signs/symptoms of adrenal insufficiency (when used in combination with nivolumab). Assess patients for proper oral hygiene practices. Monitor adherence.

Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017], ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); ECG and QTc assessment in patients at moderate- or high-risk of QTc prolongation (assess QTc monthly during the first 3 months and every 3 to 6 months thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months during the first year for moderate-risk patients and every 6 to 12 months thereafter) (ESC [Lyon 2022]).

The American Society of Clinical Oncology hepatitis B screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends hepatitis B virus (HBV) screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

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).

Pharmacokinetics (Adult Data Unless Noted)

Distribution: V_d: ~349 L (Cometriq); ~319 L (Cabometyx).

Bioavailability: Following a single 140 mg dose, a 19% increase in the C_max was observed with the tablet (compared to the capsule), although the difference in AUC was <10%.

Protein binding: ≥99.7% to plasma proteins.

Metabolism: Hepatic via CYP3A4.

Half-life elimination: ~55 hours (Cometriq); ~99 hours (Cabometyx).

Time to peak: 2 to 5 hours (Cometriq); 3 to 4 hours (Cabometyx).

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

Clearance (at steady state): 4.4 L/hour (Cometriq); 2.2 L/hour (Cabometyx).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered liver function: Cabozantinib exposure was increased by 81% (Cometriq only; there was no clinically significant difference for Cabometyx) in subjects with mild impairment (Child-Turcotte-Pugh class A) and by 63% in subjects with moderate impairment (Child-Turcotte-Pugh class B), compared to subjects with normal liver function.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Cabometyx;
(AR) Argentina: Arkus | Dabatrox | Exobozan | Zanterib;
(AT) Austria: Cabometyx | Cometriq;
(AU) Australia: Cabometyx;
(BD) Bangladesh: Cabanib | Caboxen | Cabozanix;
(BE) Belgium: Cabometyx;
(BR) Brazil: Cabometyx;
(CH) Switzerland: Cabometyx;
(CL) Chile: Cabometyx | Dabatrox;
(CO) Colombia: Cabometyx;
(CZ) Czech Republic: Cabometyx | Cometriq;
(DE) Germany: Cabometyx | Cometriq;
(EC) Ecuador: Dabatrox;
(EE) Estonia: Cabometyx | Cometriq;
(ES) Spain: Cabometyx;
(FI) Finland: Cabometyx | Cometriq;
(FR) France: Cabometyx;
(GB) United Kingdom: Cabometyx | Cometriq;
(GR) Greece: Cabometyx;
(HK) Hong Kong: Cabometyx;
(HR) Croatia: Cabometyx;
(HU) Hungary: Cabometyx | Cometriq;
(IE) Ireland: Cabometyx;
(IN) India: Cabotib | Cabozanib | Cazanat;
(IT) Italy: Cabometyx | Cometriq;
(JP) Japan: Cabometyx;
(KR) Korea, Republic of: Cabometyx;
(KW) Kuwait: Cabometyx;
(LB) Lebanon: Cabometyx;
(LT) Lithuania: Cabometyx | Cometriq;
(LU) Luxembourg: Cabometyx;
(LV) Latvia: Cabometyx;
(MX) Mexico: Aptimetyx;
(MY) Malaysia: Cabometyx;
(NL) Netherlands: Cabometyx | Cometriq;
(NO) Norway: Cabometyx | Cometriq;
(NZ) New Zealand: Cabometyx;
(PE) Peru: Dabatrox;
(PL) Poland: Cabometyx | Cometriq;
(PR) Puerto Rico: Cabometyx | Cometriq;
(PT) Portugal: Cabometyx | Cometriq;
(QA) Qatar: Cabometyx;
(RO) Romania: Cabometyx;
(RU) Russian Federation: Cabometix | Cabometyx;
(SA) Saudi Arabia: Cabometyx;
(SE) Sweden: Cabometyx | Cometriq;
(SG) Singapore: Cabometyx;
(SI) Slovenia: Cabometyx;
(SK) Slovakia: Cabometyx | Cometriq;
(TR) Turkey: Cabometyx;
(TW) Taiwan: Cabometyx;
(UA) Ukraine: Cabometyx;
(ZA) South Africa: Cabometyx

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Cabozantinib: Drug information