Pronunciation
(ka boe ZAN ti
nib)
Index Terms
BMS-907351Cabozantinib
(S)-malateCabozantinib
s-MalateCabozantinib-s-malateXL184
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.
CabometyxCometriq
Pharmacologic
Category
Antineoplastic
Agent, Tyrosine Kinase InhibitorAntineoplastic
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). Note: The
prescribing information describe 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. Swallow whole; do not open capsules or crush
tablets.
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 (High risk with
Inhibitors).Monitor therapy
Bisphosphonate
Derivatives: Angiogenesis Inhibitors (Systemic) 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 (High risk with
Inducers).Monitor therapy
Conivaptan: May
increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Avoid combination
CYP3A4 Inducers
(Moderate): May decrease the serum concentration of CYP3A4 Substrates (High
risk with Inducers). 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 (High
risk with Inhibitors). 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 (High risk with
Inducers). 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 (High risk with
Inhibitors).Monitor therapy
Deferasirox: May
decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Enzalutamide:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers). 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 (High risk with
Inhibitors).Monitor therapy
Fusidic Acid
(Systemic): May increase the serum concentration of CYP3A4 Substrates (High
risk with Inhibitors). Avoid combination
Grapefruit
Juice: May increase the serum concentration of Cabozantinib. Avoid
combination
Idelalisib: May
increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors). Avoid combination
MiFEPRIStone:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors). 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 (High risk with
Inducers). 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 (High risk with
Inhibitors).Monitor therapy
Palbociclib: May
increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Monitor therapy
Pitolisant: May
decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that
has a narrow therapeutic index should be avoided. Other CYP3A4 substrates
should be monitored more closely when used with pitolisant. Consider
therapy modification
Sarilumab: May
decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Siltuximab: May
decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Simeprevir: May
increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Monitor therapy
St John's Wort:
May decrease the serum concentration of Cabozantinib. Avoid combination
Stiripentol: May
increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors). 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 (High risk with
Inducers).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.
Dosage form
specific issues:
• Formulations:
Cabozantinib is available in tablets (Cabometyx) and capsules (Cometriq) which
are NOT interchangeable; do NOT substitute.
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; hematuria; 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.
