Dosing & Uses
Dosage Forms & Strengths
capsule (Cometriq)
- 20mg
- 80mg
tablet (Cabometyx)
- 20mg
- 40mg
- 60mg
Medullary Thyroid Cancer
Cometriq only
Indicated for treatment of progressive, metastatic medullary thyroid cancer (MTC)
140 mg PO qDay
Continue until disease progression or unacceptable toxicity occurs
Renal Cell Carcinoma
Cabometyx only
Indicated for advanced renal cell carcinoma (RCC)
60 mg PO qDay
Continue until disease progression or unacceptable toxicity occurs
Hepatocellular Carcinoma
Cabometyx only
Indicated for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib
60 mg PO qDay
Continue until disease progression or unacceptable toxicity occurs
Dosage Modifications
CYP3A4 inhibitors
- Avoid coadministration with strong CYP3A4 inhibitors
- Cometriq: If strong CYP3A4 inhibitor required, decrease cabozantinib dose by 40 mg/day (eg, from 140 mg to 100 mg qDay)
- Cabometyx: If strong CYP3A4 inhibitor required, decrease cabozantinib dose by 20 mg/day (eg, from 60 mg to 40 mg qDay)
- Resume previous dose 2-3 days after strong CYP3A4 inhibitor discontinued
CYP3A4 inducers
- Avoid coadministration of strong CYP3A4 inducers
- Cometriq: If strong CYP3A4 inducer required, increase dose by 40 mg/day (eg, from 140 mg to 180 mg qDay); do not exceed 180 mg/day
- Cabometyx: If strong CYP3A4 inducer required, increase dose by 20 mg/day (eg, from 60 mg to 80 mg qDay); do not exceed 80 mg/day
- Resume previous dose 2-3 days after strong CYP3A4 inducer discontinued
Withhold dose
- Withhold dose for Grade 4 hematologic adverse reactions, ≥Grade 3 nonhematologic adverse reactions, or intolerable Grade 2 adverse reactions
- Upon resolution (ie, return to baseline or Grade 1), reduce dose as follows:
- Cometriq
- If previous daily dose 140 mg, resume at 100 mg/day
- If previous daily dose 100 mg, resume at 60 mg/day
- If previous daily dose 60 mg, resume at 60 mg if tolerated, otherwise, discontinue
- Cabometyx
- If previous daily dose 60 mg, resume at 40 mg/day
- If previous daily dose 40 mg, resume at 20 mg/day
- If previous daily dose 20 mg, resume at 20 mg if tolerated, otherwise, discontinue
Patients undergoing surgery
- Stop drug at least 28 days prior to scheduled surgery, including dental surgery (see Cautions)
For Grade ≤3 adverse reactions
- Dosage modifications and/or supportive care may be required
- If dose reduction is required, a 20 mg decrease from the previously administered dose is recommended
Permanently discontinue
- Development of visceral or gastrointestinal perforation or fistula formation
- Severe hemorrhage
- Serious thromboembolic event (eg, myocardial infarction, cerebral infarction)
- Nephrotic syndrome
- Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
- Osteonecrosis of the jaw
- Reversible posterior leukoencephalopathy syndrome
Hepatic impairment
- Cometriq
- Mild-to-moderate (Child-Pugh A or B): Reduce starting dose to 80 mg/day
- Moderate (Child-Pugh C): Not recommended
- Cabometyx
- Mild (Child-Pugh A): No dosage adjustment necessary
- Moderate (Child-Pugh B): Reduce starting dose to 40 mg/day
- Severe (Child-Pugh C): Avoid use
Renal impairment
- Mild-to-moderate (CrCl ≥30 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): No experience
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
Adverse effects are for all grades unless otherwise specified
>10% (Cometriq)
AST, ALT increased (86%)
Diarrhea (63%)
Hypertension, treatment-emergent (61%)
Increased TSH (57%)
Lymphopenia (53%)
ALP increased (52%)
Hypocalcemia (52%)
Stomatitis (51%)
Palmar-plantar erythrodysesthesia syndrome (50%)
Weight decreased (48%)
Appetite decreased (46%)
Nausea (43%)
Fatigue (41%)
Oral pain (36%)
Neutropenia (35%)
Thrombocytopenia (35%)
Dysgeusia (34%)
Hair color changes, depigmentation, graying (34%)
Hypertension (33%)
Hypophosphatemia (28%)
Constipation (27%)
Abdominal pain (27%)
Hypobilirubinemia (25%)
Vomiting (24%)
Asthenia (21%)
Dysphonia (20%)
Rash (19%)
Dry skin (19%)
Hypomagnesemia (19%)
Hypokalemia (18%)
Headache (18%)
Alopecia (16%)
Dizziness (14%)
Arthralgia (14%)
Palmar-plantar erythrodysesthesia syndrome, Grade 3 or 4 (13%)
Dysphagia (13%)
Muscle spasms (12%)
Dyspepsia (11%)
Erythema (11%)
>10% (Cabometyx)
Diarrhea (74%)
AST increased (74%)
ALT increased (68%)
Creatinine increased (58%)
Fatigue (56%)
Triglycerides increased (53%)
Nauseas (50%)
Hypophosphatemia (48%)
Decreased appetite (46%)
Palmar-plantar erythrodysesthesia syndrome (42%)
Hypertension (39%)
Hyperglycemia (37%)
Hypoalbuminemia (36%)
ALP increased (35%)
WBCs decreased (35%)
Vomiting (32%)
Hypomagnesemia (31%)
Weight decreased (31%)
ANC decreased (31%)
Hgb decreased (31%)
Hyponatremia (30%)
GGT increased (27%)
Constipation (25%)
Lymphocytes decreased (25%)
Platelets decreased (25%)
Dysgeusia (24%)
Abdominal pain (23%)
Rash (23%)
Stomatitis (22%)
Hypothyroidism (21%)
Dysphonia (20%)
Dyspnea (19%)
Mucosal inflammation (19%)
Asthenia (19%)
Cough (18%)
Anemia (17%)
Hypertension, Grade 3-4 (16%)
Muscle spasms (13%)
Dyspepsia (12%)
Proteinuria (12%)
Diarrhea (11%)
Dry skin, Grade 3-4 (11%)
Headache (11%)
Dizziness (11%)
Arthralgia (11%)
1-10% (Cometriq)
Hyponatremia (10%)
Hemorrhoids (9%)
Musculoskeletal chest pain (9%)
Anxiety (9%)
Paresthesia (7%)
Peripheral sensory neuropathy (7%)
Dehydration (7%)
Hyperkeratosis (7%)
Hypotension (7%)
Venous thromboembolism (6%)
Peripheral neuropathy (5%)
Non-GI fistula (4%)
GI perforation (3%)
Arterial thromboembolism (2%)
Proteinuria (2%)
GI fistula (1%)
Osteonecrosis of the jaw (1%)
1-10% (Cabometyx)
Fatigue, Grade 3-4 (9%)
Palmar-plantar erythrodysesthesia syndrome, Grade 3-4 (8%)
Hyponatremia, Grade 3-4 (8%)
Hypophosphatemia, Grade 3-4 (8%)
Hypomagnesemia, Grade 3-4 (7%)
Lymphocytes decreased, Grade 3-4 (7%)
Anemia, Grade 3-4 (5%)
GGT decreased, Grade 3-4 (5%)
Nausea, Grade 3-4 (4%)
Asthenia, Grade 3-4 (4%)
Abdominal pain, Grade 3-4 (4%)
Hgb decreased, Grade 3-4 (4%)
Triglycerides increased, Grade 3-4 (4%)
ALT increased, Grade 3-4 (3%)
AST increased, Grade 3-4 (3%)
Dyspnea, Grade 3-4 (3%)
Decreased appetite, Grade 3-4 (3%)
Proteinuria, Grade 3-4 (2%)
Vomiting, Grade 3-4 (2%)
Stomatitis, Grade 3-4 (2%)
ANC decreased, Grade 3-4 (2%)
ALP decreased, Grade 3-4 (2%)
Hypoalbuminemia, Grade 3-4 (2%)
Hyperglycemia, Grade 3-4 (2%)
<1%
Reversible posterior leukoencephalopathy syndrome (RPLS)
Postmarketing Effects
Suprahepatic international normalized ratio and epistaxis (during concomitant use of warfarin)
Warnings
Black Box Warnings
Perforations and fistulas (Cometriq)
- GI perforations occurred in 3% and fistula formation in 1%
- Non-GI fistulas (eg, tracheal, esophageal) reported in 4%
- Discontinue if perforation or fistula formation occurs
Hemorrhage (Cometriq)
- Severe, sometimes fatal, hemorrhage including hemoptysis and GI hemorrhage occurred in 3%
- Monitor for signs and symptoms of bleeding
- Do not administer with severe hemorrhage
Contraindications
None
Cautions
GI perforations and fistulas reported (see Black Box Warnings for Cometriq); monitor patients for symptoms of perforations and fistulas, including abscess and discontinue therapy in patients who experience a fistula which cannot be appropriately managed or have a GI perforation
Serious and fatal hemorrhage reported (see Black Box Warnings for Cometriq); do not administer Cabometyx to patients with risk for severe hemorrhage
Thromboembolic events reported; discontinue if acute MI or any other arterial thromboembolic event develops
May impair wound healing; stop treatment at least 28 days prior to schedules surgery; withhold with dehiscence or wound healing complications requiring medical intervention
Osteonecrosis of the jaw reported (rare); discontinue at least 28 days prior to invasive dental procedures
Increases risk of treatment-emergent hypertension; discontinue for severe hypertension that cannot be controlled with antihypertensive therapy
Palmar-plantar erythrodysesthesia syndrome reported; withhold treatment if needed (see Dosage Modifications)
Proteinuria may occur
Fetal harm may occur when administered to a pregnant woman (see Pregnancy)
Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare)
Diarrhea
- Cabometyx only
- Diarrhea occurred in 74% of patients treated with Cabometyx and in 28% of patients treated with everolimus
- Grade 3 diarrhea occurred in 11% of Cabometyx-treated patients and in 2% of everolimus-treated patients (see Dosage Modifications)
Drug interactions overview
- CYP3A4 inhibitors
- Cometriq: Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%
- Cabometyx: Coadministration with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions
- CYP3A4 inducers
- Cometriq: Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%
- Cabometyx: Coadministration with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, can cause fetal harm when administered to pregnant women
Verify pregnancy status of females of reproductive potential before initiation
Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the final dose
May impair male and female fertility
Lactation
Unknown whether distributed in breast milk
Because of potential for serious adverse reactions in a breastfed infant from cabozantinib, advise females of reproductive potential to not breastfeed during treatment and for 4 months after the final dose
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment)
Absorption
Peak plasma time: 2-5 hr; (Cometriq); 3-4 hr (Cabometyx)
Steady-state achieved: Day 15
A 19% increase in the peak plasma concentration of the tablet formulation (Cabometyx) compared with the capsule formulation (Cometriq)
Effects of food
- High fat meal increases Cmax and AUC by 41% and 57% respectively compared to fasted conditions
Distribution
Protein Bound: ≥99.7%
Vd: 349 L (Cometriq); 319 L (Cabometyx)
Metabolism
Metabolized via hepatic CYP3A4
Metabolites: XL184 N-oxide
CYP3A4 substrate; CYP2C8 inhibitor (noncompetitive), CYP2C9 and CYP2C19 inhibitor (mixed), CYP3A4 (weak competitive); CYP1A1 inducer
P-gp transport inhibitor
Elimination
Half-life: 55 hr (Cometriq); 99 hr (Cabometyx)
Clearance: 4.4 L/hr (Cometriq); 2.2 L/hr (Cabometyx)
Excretion (Cabometyx): 54% feces, 27% urine
Administration
Oral Administration
Do not substitute Cabometyx tablets and Cometriq capsules for one another
Take on empty stomach, do not eat for at least 2 hr before or 1 hr after administration
Swallow capsule or tablet whole; do not chew or empty contents of capsule; do not crush tablet
Do not take a missed dose within 12 hr of the next dose
Do not ingest foods (eg, grapefruit, grapefruit juice) or nutritional supplements known to affect CYP3A4 substrates (eg, St. John’s wort)
Storage
Tablets or capsules: Store at room temperature (20-25°C [68-77°F])
Images
Patient Handout
Formulary
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