Dosing and uses of Cometriq, Cabometyx (cabozantinib)
Adult dosage forms and strengths
capsule (Cometriq)
- 20mg
- 80mg
tablet (Cabometyx)
- 20mg
- 40mg
- 60mg
Medullary Thyroid Cancer
Cometriq: Indicated for treatment of progressive, metastatic medullary thyroid cancer
140 mg PO qDay on empty stomach (see Administration)
Renal Cell Carcinoma
Cabometyx: Indicated for advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy
60 mg PO qDay
Dosage modifications
CYP3A4 inhibitors
- Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
- Cometriq
- If strong CYP3A4 inhibitor required, decrease cabozantinib dose by 40 mg/day
- Resume previous dose 2-3 days after strong CYP3A4 inhibitor discontinued
- Cabometyx
- If strong CYP3A4 inhibitor required, decrease cabozantinib dose by 20 mg/day
- Resume previous dose 2-3 days after strong CYP3A4 inhibitor discontinued
CYP3A4 inducers
- Avoid coadministration of strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort)
- Cometriq
- If strong CYP3A4 inducer required, increase dose by 40 mg/day
- Resume previous dose 2-3 days after strong CYP3A4 inducer discontinued
- Do not exceed 180 mg/day
- Cabometyx
- If strong CYP3A4 inducer required, increase dose by 20 mg/day
- Resume previous dose 2-3 days after strong CYP3A4 inducer discontinued
- Do not exceed 80 mg/day
Hepatic impairment
- Moderate-to-severe (Cometriq): Not recommended
- Cabometyx
- Mild-to-moderate: Reduce starting dose to 40 mg/day
- Severe: Not recommended
Withhold dose
- Withhold dose for Grade 4 hematologic adverse reactions, ≥Grade 3 nonhematologic adverse reactions, or intolerable Grade 2 adverse reactions
- Upon resolution (ie, reutrn 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)
Permanently discontinue
- Development of visceral perforation or fistula formation
- Severe hemorrhage
- Serious arterial 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
Pediatric dosage forms and strengths
Safety and efficacy not established
Cometriq, Cabometyx (cabozantinib) adverse (side) effects
>10% (Cometriq)
All grades
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%; ≥Grade 3, 13%)
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%)
Dysphagia (13%)
Muscle spasms (12%)
Dyspepsia (11%)
Erythema (11%)
>10% (Cabometyx)
Diarrhea, all grades (74%)
AST increased, all grades (74%)
ALT increased, all grades (68%)
Creatinine increased, all grades (58%)
Fatigue, all grades (56%)
Triglycerides increased, all grades (53%)
Nausea, all grades (50%)
Hypophosphatemia, all grades (48%)
Decreased appetite, all grades (46%)
Palmar-plantar erythrodysesthesia syndrome, all grades (42%)
Hypertension, all grades (39%)
Hyperglycemia, all grades (37%)
Hypoalbuminemia, all grades (36%)
ALP increased, all grades (35%)
WBCs decreased, all grades (35%)
Vomiting, all grades (32%)
Hypomagnesemia, all grades (31%)
Weight decreased, all grades (31%)
ANC decreased, all grades (31%)
Hgb decreased, all grades (31%)
Hyponatremia, all grades (30%)
GGT increased, all grades (27%)
Constipation, all grades (25%)
Lymphocytes decreased, all grades (25%)
Platelets decreased, all grades (25%)
Dysgeusia, all grades (24%)
Abdominal pain, all grades (23%)
Rash, all grades (23%)
Stomatitis, all grades (22%)
Hypothyroidism, all grades (21%)
Dysphonia, all grades (20%)
Dyspnea, all grades (19%)
Mucosal inflammation, all grades (19%)
Asthenia, all grades (19%)
Cough, all grades (18%)
Anemia, all grades (17%)
Hypertension, grades 3-4 (16%)
Muscle spasms, all grades (13%)
Dyspepsia, all grades (12%)
Proteinuria, all grades (12%)
Diarrhea, grades 3-4 (11%)
Dry skin, grades 3-4 (11%)
Headache, all grades (11%)
Dizziness, all grades (11%)
Arthralgia, all grades (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%)
eripheral 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, grades 3-4 (9%)
Palmar-plantar erythrodysesthesia syndrome, grades 3-4 (8%)
Hyponatremia, grades 3-4 (8%)
Hypophosphatemia, grades 3-4 (8%)
Hypomagnesemia, grades 3-4 (7%)
Lymphocytes decreased, grades 3-4 (7%)
Anemia, grades 3-4 (5%)
GGT decreased, grades 3-4 (5%)
Nausea, grades 3-4 (4%)
Asthenia, grades 3-4 (4%)
Abdominal pain, grades 3-4 (4%)
Hgb decreased, grades 3-4 (4%)
Triglycerides increased, grades 3-4 (4%)
ALT increased, grades 3-4 (3%)
AST increased, grades 3-4 (3%)
Dyspnea, grades 3-4 (3%)
Decreased appetite, grades 3-4 (3%)
Proteinuria, grades 3-4 (2%)
Vomiting, grades 3-4 (2%)
Stomatitis, grades 3-4 (2%)
ANC decreased, grades 3-4 (2%)
ALP decreased, grades 3-4 (2%)
Hypoalbuminemia, grades 3-4 (2%)
Hyperglycemia, grades 3-4 (2%)
<1%
Reversible posterior leukoencephalopathy syndrome (RPLS)
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 for symptoms and discontinue Cabometyx in patients who experience a fistula which cannot be appropriately managed or a GI perforation
Serious and sometimes 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
Diarrhea commonly reported (see Adverse effects)
Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare)
Avoid coadministration with strong CYP3A4 inhibitors or inducers; if unable to avoid, dose adjustment required (see Dosage modifications)
Hepatic impairment
- Cometriq: Not recommended with moderate-to-severe hepatic impairment
- Cabometyx: Not recommended with severe hepatic impairment; dosage adjustment required with mild-to-moderate impairment (see Dosage modifications)
Pregnancy and lactation
Pregnancy
Based on its mechanism of action, can cause fetal harm when administered to pregnant women
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 of Cometriq, Cabometyx (cabozantinib)
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); 2-3 hr (Cabometyx)
A 19% increase in the peak plasma concentration of the tablet formulation (Cabometyx) compared with the capsule formulation (Cometriq)
High fat meal increases Cmax and AUC by 41% and 57% respectively compared to fasted conditions
Steady-state achieved: Day 15
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)
Total body clearance: 4.4 L/hr (Cometriq); 2.2 L/hr (Cabometyx)
Excretion: 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)
