Included as part of the PRECAUTIONS section.
Severe hemorrhage occurred with CABOMETYX. The incidence
of Grade ≥ 3 hemorrhagic events was 2.1% in CABOMETYX-treated patients
and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the
cabozantinib clinical program.
Do not administer CABOMETYX to patients that have or are
at risk for severe hemorrhage.
GI Perforations And Fistulas
In a randomized study in renal cell carcinoma, fistulas
were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated
patients and 0% of everolimus-treated patients. Gastrointestinal (GI)
perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of
everolimus-treated patients. Fatal perforations occurred in the cabozantinib
Monitor patients for symptoms of fistulas and
perforations. Discontinue CABOMETYX in patients who experience a fistula which
cannot be appropriately managed or a GI perforation.
CABOMETYX treatment results in an increased incidence of
thrombotic events. Venous thromboembolism was reported in 7.3% of
CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary
embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of
everolimus-treated patients. Events of arterial thromboembolism were reported
in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients.
Fatal thrombotic events occurred in the cabozantinib clinical program.
Discontinue CABOMETYX in patients who develop an acute
myocardial infarction or any other arterial thromboembolic complication.
Hypertension And Hypertensive Crisis
CABOMETYX treatment results in an increased incidence of
treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade
≥ 3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥ 3) of
everolimus-treated patients. Monitor blood pressure prior to initiation and
regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that
is not adequately controlled with medical management; when controlled, resume
CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that
cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if
there is evidence of hypertensive crisis or severe hypertension despite optimal
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. Withhold CABOMETYX in patients who develop intolerable Grade 2
diarrhea or Grade 3-4 diarrhea that cannot be managed with standard
antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a
reduced dose. Dose modification due to diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia syndrome (PPES)
occurred in 42% of patients treated with CABOMETYX and in 6% of patients
treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated
patients and in < 1% of everolimus-treated patients. Withhold CABOMETYX in
patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement
to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES
occurred in 16% of patients.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS),
a syndrome of subcortical vasogenic edema diagnosed by characteristic finding
on MRI, occurred in the cabozantinib clinical program. Perform an evaluation
for RPLS in any patient presenting with seizures, headache, visual
disturbances, confusion or altered mental function. Discontinue CABOMETYX in
patients who develop RPLS.
Based on data from animal studies and its mechanism of
action, CABOMETYX can cause fetal harm when administered to a pregnant woman.
Cabozantinib administration to pregnant animals during organogenesis resulted
in embryolethality at exposures below those occurring clinically at the
recommended dose, and in increased incidences of skeletal variations in rats
and visceral variations and malformations in rabbits. Advise pregnant women of
the potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with CABOMETYX and for 4 months after
the last dose [See Use in Specific Populations and CLINICAL
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Inform patients of the following:
Hemorrhage: Instruct patients to contact their
healthcare provider to seek immediate medical attention for signs or symptoms
of unusual severe bleeding or hemorrhage [see WARNINGS AND PRECAUTIONS].
Diarrhea: Advise patients to notify their
healthcare provider at the first signs of poorly formed or loose stool or an
increased frequency of bowel movements [see WARNINGS AND PRECAUTIONS].
Palmar-plantar erythrodysesthesia syndrome: Advise
patients to contact their healthcare provider for progressive or intolerable
rash [see WARNINGS AND PRECAUTIONS].
Wound healing: Patients should be advised to
contact their healthcare provider before any planned surgeries, including
dental surgery [see DOSAGE AND ADMINISTRATION].
Drug interactions: Advise patients to inform their
healthcare provider of all prescription or nonprescription medication or herbal
products that they are taking.
Weight loss: Advise patients to report significant
Embryo-fetal toxicity: Advise females of
reproductive potential of the potential risk to a fetus. Advise females to
contact their healthcare provider if they become pregnant, or if pregnancy is
suspected, during treatment with CABOMETYX [see WARNINGS AND PRECAUTIONS,
Use In Specific Populations].
Females of reproductive potential: Advise patients
of reproductive potential to use effective contraception during treatment with
CABOMETYX and for at least four months after the final dose of CABOMETYX [see Use
in Specific Populations].
Lactation: Advise women not to breastfeed during
treatment with CABOMETYX and for 4 months following the last dose [see Use
in Specific Populations].
Important Administration Information
- Instruct patients not to eat for at least 2 hours before
and at least 1 hour after taking CABOMETYX. Instruct patients to not crush
CABOMETYX tablets and to take CABOMETYX tablets with a full glass (at least 8
ounces) of water.
- Advise patients not to consume grapefruits or grapefruit
juice while taking CABOMETYX. [see DOSAGE AND ADMINISTRATION]
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Cabozantinib was not carcinogenic in a 26-week
carcinogenicity study in rasH2 transgenic mice.
Cabozantinib was not mutagenic in vitro in the bacterial
reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic
assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Based on nonclinical findings, male and female fertility
may be impaired by treatment with CABOMETYX. In a fertility study in which
cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5
mg/kg/day, male fertility was significantly compromised at doses equal to or
greater than 2.5 mg/kg/day (approximately 13-fold of human AUC at the
recommended dose), with a decrease in sperm counts and reproductive organ
weights. In females, fertility was significantly reduced at doses equal to or
greater than 1 mg/kg/day (5-fold of human AUC at the recommended dose) with a
significant decrease in the number of live embryos and a significant increase
in pre- and post-implantation losses.
Observations of effects on reproductive tract tissues in
general toxicology studies were supportive of effects noted in the dedicated
fertility study and included hypospermia and absence of corpora lutea in male
and female dogs in a 6-month repeat dose study at plasma exposures (AUC)
approximately 0.5-fold (males) and < 0.1-fold (females) of those expected in
humans at the recommended dose. In addition, female rats administered 5
mg/kg/day for 14 days (approximately 9-fold of human AUC at the recommended
dose) exhibited ovarian necrosis.
Use In Specific Populations
Based on findings from animal studies and its mechanism
of action, CABOMETYX can cause fetal harm when administered to a pregnant woman
[see CLINICAL PHARMACOLOGY]. There are no available data in pregnant
women to inform the drug-associated risk. In animal developmental and
reproductive toxicology studies administration of cabozantinib to pregnant rats
and rabbits during organogenesis resulted in embryofetal lethality and
structural anomalies at exposures that were below those occurring clinically at
the recommended dose [see Nonclinical Toxicology]. Advise pregnant women
or women of childbearing potential of the potential hazard to a fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
In an embryo-fetal development study in pregnant rats,
daily oral administration of cabozantinib throughout organogenesis caused
increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg
(approximately 0.12-fold of human AUC at the recommended dose). Findings included
delayed ossification and skeletal variations at a dose of 0.1 mg/kg/day
(approximately 0.04-fold of human AUC at the recommended dose).
In pregnant rabbits, daily oral administration of
cabozantinib throughout organogenesis resulted in findings of visceral
malformations and variations including reduced spleen size and missing lung
lobe at 3 mg/kg (approximately 1.1-fold of the human AUC at the recommended
In a pre- and postnatal study in rats, cabozantinib was
administered orally from gestation day 10 through postnatal day 20.
Cabozantinib did not produce adverse maternal toxicity or affect pregnancy,
parturition or lactation of female rats, and did not affect the survival,
growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day
(0.05-fold of the maximum recommended clinical dose).
There is no information regarding the presence of
cabozantinib or its metabolites in human milk, or their effects on the
breastfed infant, or milk production. Because of the potential for serious
adverse reactions in a breastfed infant from CABOMETYX, advise a lactating
woman not to breastfeed during treatment with CABOMETYX and for 4 months after
the final dose.
Females And Males Of Reproductive Potential
CABOMETYX can cause fetal harm when administered to a
pregnant woman [see Use in Specific Populations ]. Advise females of
reproductive potential to use effective contraception during treatment with
CABOMETYX and for 4 months after the final dose.
Females and Males
Based on findings in animals, CABOMETYX may impair
fertility in females and males of reproductive potential [see Nonclinical
The safety and effectiveness of CABOMETYX in pediatric
patients have not been studied.
Juvenile Animal Data
Juvenile rats were administered cabozantinib daily at
doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2
years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses
equal and greater than 1 mg/kg/day (approximately 0.16 times the clinical dose
of 60 mg/day based on body surface area). Hypoactivity was observed at both
doses tested on Postnatal Day 22. Targets were generally similar to those seen
in adult animals, occurred at both doses, and included the kidney (nephropathy,
glomerulonephritis), reproductive organs, gastrointestinal tract (cystic
dilatation and hyperplasia in Brunner's gland and inflammation of duodenum; and
epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and
lymphoid depletion), and liver. Tooth abnormalities and whitening as well as
effects on bones including reduced bone mineral content and density, physeal
hypertrophy, and decreased cortical bone also occurred at all dose levels.
Recovery was not assessed at the 2 mg/kg dose level (approximately 0.32 times
the clinical dose of 60 mg based on body surface area) due to high levels of
mortality. At the low dose level, effects on bone parameters were partially
resolved but effects on the kidney and epididymis/testis persisted after
In the Phase 3 study, 41% of RCC patients treated with
CABOMETYX were age 65 years and older, and 8% were age 75 and older. No
differences in safety or efficacy were observed between older and younger
Increased exposure to cabozantinib has been observed in
patients with mild to moderate hepatic impairment. Reduce the CABOMETYX dose in
patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic
impairment. CABOMETYX is not recommended for use in patients with severe
hepatic impairment [see DOSAGE AND ADMINISTRATION, and CLINICAL
Dosage adjustment is not required in patients with mild
or moderate renal impairment. There is no experience with CABOMETYX in patients
with severe renal impairment [see CLINICAL PHARMACOLOGY].