Adverse Reaction
CABOMETYX
(n = 78)
Sunitinib
(n = 72)
Grade 3-41 Grade 3-41
Percentage (%) of Patients
Dysphonia 1 0
Blood and Lymphatic
Anemia 1 3
Psychiatric
Depression 4 0
Confusional state 1 1
Infections
Lung infection 4 0
Musculoskeletal and Connective Tissue
Back pain 4 0
Bone pain 3 1
Pain in extremity 3 0
Arthralgia 1 0
Renal and Urinary
Renal failure acute 4 1
Proteinuria 3 1
ALT, alanine aminotransferase; AST, aspartate aminotransferase
1 NCI CTCAE Version 4.0
2 Laboratory abnormalities are reported as adverse reactions and not
based on shifts in laboratory values
3 Includes the following term: hypertension
Hepatocellular Carcinoma
The safety of CABOMETYX was evaluated in CELESTIAL, a randomized, doubleblind,
placebo-controlled trial in which 704 patients with advanced hepatocellular
carcinoma were randomized to receive CABOMETYX 60 mg orally once daily (n=467)
or placebo (n=237) until disease progression or unacceptable toxicity. The median
duration of treatment was 3.8 months (range 0.1 – 37.3) for patients receiving
CABOMETYX and 2.0 months (range 0.0 – 27.2) for patients receiving placebo. The
population exposed to CABOMETYX was 81% male, 56% White, and had a median
age of 64 years.
Adverse reactions occurring in ≥ 25% of CABOMETYX-treated patients, in order
of decreasing frequency were: diarrhea, decreased appetite, PPE, fatigue, nausea,
hypertension, and vomiting. Grade 3-4 adverse reactions which occurred in ≥ 5% of
patients were PPE, hypertension, fatigue, diarrhea, asthenia, and decreased appetite.
There were 6 adverse reactions leading to death in patients receiving CABOMETYX
(hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein
thrombosis, pulmonary embolism, upper gastrointestinal hemorrhage).
The median average daily dose was 35.8 mg for CABOMETYX. The dose was reduced
in 62% of patients receiving CABOMETYX; 33% of patients required a reduction
to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities
leading to dose reduction of CABOMETYX were: PPE, diarrhea, fatigue, hypertension,
and increased AST. Adverse reactions leading to dose interruption occurred in
84% patients receiving CABOMETYX. Adverse reactions leading to permanent
discontinuation of CABOMETYX occurred in 16% of patients. The most frequent
adverse reactions leading to permanent discontinuation of CABOMETYX were PPE
(2%), fatigue (2%), decreased appetite (1%), diarrhea (1%), and nausea (1%).
Table 4. Adverse Reactions Occurring in ≥ 5% of CABOMETYXTreated
Patients in CELESTIAL1
Adverse Reaction
CABOMETYX
(n = 467)
Placebo
(n = 237)
All
Grades2
Grade
3-4
All
Grades2
Grade
3-4
Percentage (%) of Patients
Gastrointestinal
Diarrhea 54 10 19 2
Nausea 31 2 18 2
Vomiting 26 <1 12 3
Stomatitis 13 2 2 0
Dyspepsia 10 0 3 0
General
Fatigue 45 10 30 4
Asthenia 22 7 8 2
Mucosal inflammation 14 2 2 <1
Metabolism and Nutrition
Decreased appetite 48 6 18 <1
Skin and Subcutaneous Tissue
Palmar-plantar
erythrodysesthesia 46 17 5 0
Rash3 21 2 9 <1
Vascular
Hypertension4 30 16 6 2
Investigations
Weight decreased 17 1 6 0
Nervous System
Dysgeusia 12 0 2 0
Endocrine
Hypothyroidism 8 <1 <1 0
Respiratory, Thoracic, and
Mediastinal
Dysphonia 19 1 2 0
Dyspnea 12 3 10 <1
Musculoskeletal and Connective
Tissue
Pain in extremity 9 <1 4 1
Muscle spasms 8 <1 2 0
1 Includes terms with a between-arm difference of ≥ 5% (all grades) or
≥ 2% (Grade 3-4)
2 NCI CTCAE Version 4.0
3 Includes the following terms: rash, rash erythematous, rash generalized,
rash macular, rash maculo-papular, rash papular, rash pruritic, rash
pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis
contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected
4 Includes the following terms: hypertension, blood pressure diastolic
increased, blood pressure increased
Table 5. Laboratory Abnormalities Occurring in ≥ 5% of
CABOMETYX-Treated Patients in CELESTIAL1
Laboratory Abnormality
CABOMETYX
N=467
Placebo
N=237
All
Grades
Grade
3-4
All
Grades
Grade
3-4
Percentage of Patients
Chemistry
Increased LDH 84 9 29 2
Increased ALT 73 12 37 6
Increased AST 73 24 46 19
Hypoalbuminemia 51 1 32 1
Increased ALP 43 8 38 6
Hypophosphatemia 25 9 8 4
Hypokalemia 23 6 6 1
Hypomagnesemia 22 3 3 0
Increased amylase 16 2 9 2
Hypocalcemia 8 2 0 0
Hematology
Decreased platelets 54 10 16 1
Neutropenia 43 7 8 1
Increased hemoglobin 8 0 1 0
1 Includes laboratory abnormalities with a between-arm difference of ≥ 5%
(all grades) or ≥ 2% (Grade 3 4)
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; LDH, blood lactate dehydrogenase
7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on CABOMETYX
Strong CYP3A4 Inhibitors
Coadministration of a cabozantinib capsule formulation with a strong CYP3A4
inhibitor increased the exposure of cabozantinib, which may increase the risk of
exposure-related adverse reactions. Avoid coadministration of CABOMETYX with
strong CYP3A4 inhibitors. Reduce the dosage of CABOMETYX if coadministration
with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice
which may also increase exposure of cabozantinib.
Strong CYP3A Inducers
Coadministration of a cabozantinib capsule formulation with a strong CYP3A4
inducer decreased the exposure of cabozantinib, which may reduce efficacy. Avoid
coadministration of CABOMETYX with strong CYP3A4 inducers. Increase the dosage
of CABOMETYX if coadministration with strong CYP3A4 inducers cannot be avoided.
Avoid St. John’s wort which may also decrease exposure of cabozantinib.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, CABOMETYX
can cause fetal harm when administered to a pregnant woman. 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 Data). Advise pregnant women of the potential
risk to a fetus.
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.
Data
Animal Data
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
area under the curve AUC at the recommended dose). Findings included delayed
ossification and skeletal variations at a dose of 0.01 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 dose).
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).
8.2 Lactation
Risk Summary
There is no information regarding the presence of cabozantinib or its metabolites in
human milk, or their effects on the breastfed child or milk production. Because of the
potential for serious adverse reactions in breastfed children, advise women not to
breastfeed during treatment with CABOMETYX and for 4 months after the final dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating
CABOMETYX.
Contraception
CABOMETYX can cause fetal harm when administered to a pregnant woman.
Females
Advise females of reproductive potential to use effective contraception during
treatment with CABOMETYX and for 4 months after the final dose.
Infertility
Females and Males
Based on findings in animals, CABOMETYX may impair fertility in females and males
of reproductive potential.
8.4 Pediatric Use
The safety and effectiveness of CABOMETYX in pediatric patients have not been
established.
Juvenile Animal Toxicity Data
Juvenile rats were administered cabozantinib 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 ≥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 a dose of 2 mg/kg (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 treatment ceased.
8.5 Geriatric Use
In CABOSUN and METEOR, 41% of 409 patients treated with CABOMETYX were
age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of
467 patients treated with CABOMETYX were age 65 years and older, and 15% were
75 years and older.
No overall differences in safety or effectiveness were observed between these
patients and younger patients.
8.6 Hepatic Impairment
Increased exposure to cabozantinib has been observed in patients with moderate
(Child-Pugh B) hepatic impairment. Reduce the CABOMETYX dose in patients with
moderate hepatic impairment. Avoid CABOMETYX in patients with severe hepatic
impairment (Child-Pugh C), since it has not been studied in this population.
8.7 Renal Impairment
No dosage adjustment is recommended in patients with mild or moderate renal
impairment. There is no experience with CABOMETYX in patients with severe
renal impairment.
10 OVERDOSAGE
One case of overdosage was reported following administration of another
formulation of cabozantinib; a patient inadvertently took twice the intended dose
for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status
changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase
in BUN. The extent of recovery was not documented.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate
medical attention for signs or symptoms of unusual severe bleeding or hemorrhage.
Perforations and fistulas: Advise patients that gastrointestinal disorders such as
diarrhea, nausea, vomiting, and constipation may develop during CABOMETYX
treatment and to seek immediate medical attention if they experience persistent or
severe abdominal pain because cases of gastrointestinal perforation and fistula have
been reported in patients taking CABOMETYX.
Thrombotic events: Venous and arterial thrombotic events have been reported.
Advise patients to report signs or symptoms of an arterial thrombosis. Venous
thromboembolic events including pulmonary embolus have been reported. Advise
patients to contact their health care provider if new onset of dyspnea, chest pain, or
localized limb edema occurs.
Hypertension: Inform patients of the signs and symptoms of hypertension. Advise
patients to undergo routine blood pressure monitoring and to contact their health
care provider if blood pressure is elevated or if they experience signs or symptoms
of hypertension.
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.
Palmar-plantar erythrodysesthesia: Advise patients to contact their healthcare
provider for progressive or intolerable rash.
Wound healing: Advise patients to contact their healthcare provider before any
planned surgeries, including dental surgery.
Reversible posterior leukoencephalopathy syndrome: Advise patients to immediately
contact their health care provider for new onset or worsening neurological function.
Drug interactions: Advise patients to inform their healthcare provider of all
prescription or nonprescription medications, vitamins or herbal products. Inform
patients to avoid grapefruit, grapefruit juice, and St. John’s wort.
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.
Females of reproductive potential: Advise females of reproductive potential to use
effective contraception during treatment with CABOMETYX and for 4 months after
the final dose of CABOMETYX.
Lactation: Advise women not to breastfeed during treatment with CABOMETYX and
for 4 months following the last dose.
Important administration information
Instruct patients not to take CABOMETYX at least 1 hour before or at
least 2 hours after eating.
This brief summary is based on the CABOMETYX Prescribing Information
Revision 01/2019
Distributed by Exelixis, Inc. Alameda, CA 94502
CABOMETYX is a registered trademark of Exelixis, Inc.
© 2019 Exelixis, Inc.
Printed in USA 01/19 CA-1121