CABOMETYX® (cabozantinib) TABLETS
BRIEF SUMMARY OF PRESCRIBING INFORMATION.
PLEASE SEE THE CABOMETYX PACKAGE INSERT FOR
FULL PRESCRIBING INFORMATION.
INITIAL U.S. APPROVAL: 2012
1 INDICATIONS AND USAGE
1.1 Renal Cell Carcinoma
CABOMETYX is indicated for the treatment of patients with advanced renal cell
carcinoma (RCC).
1.2 Hepatocellular Carcinoma
CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma
(HCC) who have been previously treated with sorafenib.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hemorrhage
Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3
to 5 hemorrhagic events was 5% in CABOMETYX-treated patients.
Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer
CABOMETYX to patients who have a recent history of hemorrhage, including
hemoptysis, hematemesis, or melena.
5.2 Perforations and Fistulas
Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients.
Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of
CABOMETYX-treated patients.
Monitor patients for signs and symptoms of fistulas and perforations, including
abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula
which cannot be appropriately managed or a GI perforation.
5.3 Thrombotic Events
CABOMETYX increased the risk of thrombotic events. Venous thromboembolism
occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism
occurred in 2% of CABOMETYX-treated patients. Fatal thrombotic events occurred
in CABOMETYX-treated patients.
Discontinue CABOMETYX in patients who develop an acute myocardial infarction or
serious arterial or venous thromboembolic events that require medical intervention.
5.4 Hypertension and Hypertensive Crisis
CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension
was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX-treated
patients.
Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor
blood pressure 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 or
for hypertensive crisis.
5.5 Diarrhea
Diarrhea occurred in 63% of patients treated with CABOMETYX. Grade 3 diarrhea
occurred in 11% of patients treated with CABOMETYX.
Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at
a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be
managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
5.6 Palmar-Plantar Erythrodysesthesia
Palmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with
CABOMETYX. Grade 3 PPE occurred in 13% of patients treated with CABOMETYX.
Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a
reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
5.7 Proteinuria
Proteinuria was observed in 7% of patients receiving CABOMETYX. Monitor urine
protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients
who develop nephrotic syndrome.
5.8 Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with
CABOMETYX. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion,
tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent
jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral
examination prior to initiation of CABOMETYX and periodically during CABOMETYX.
Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at
least 28 days prior to scheduled dental surgery or invasive dental procedures, if
possible. Withhold CABOMETYX for development of ONJ until complete resolution.
5.9 Wound Complications
Wound complications have been reported with CABOMETYX. Stop CABOMETYX at
least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based
on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients
with dehiscence or wound healing complications requiring medical intervention.
5.10 Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of
subcortical vasogenic edema diagnosed by characteristic finding on MRI, can
occur with CABOMETYX. 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.
5.11 Embryo-Fetal Toxicity
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.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed above and in
the Warnings and Precautions section of the prescribing information: Hemorrhage,
Perforations and Fistulas, Thrombotic Events, Hypertension and Hypertensive Crisis,
Diarrhea, Palmar-plantar Erythrodysesthesia, Proteinuria, Osteonecrosis of the Jaw,
Wound Complications, Reversible Posterior Leukoencephalopathy Syndrome
6.1 Clinical Trial Experience
The data described in the WARNINGS AND PRECAUTIONS section below reflect
exposure to CABOMETYX as a single agent in 409 patients with RCC enrolled in
randomized, active-controlled trials (CABOSUN, METEOR) and 467 patients with HCC
enrolled in a randomized, placebo-controlled trial (CELESTIAL).
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reflect the rates observed
in practice.
Renal Cell Carcinoma
METEOR
The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial
in which 331 patients with advanced renal cell carcinoma received CABOMETYX
60 mg once daily and 322 patients received everolimus 10 mg once daily until
disease progression or unacceptable toxicity. Patients on both arms who had
disease progression could continue treatment at the discretion of the investigator.
The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients
receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving
everolimus.
Adverse reactions which occurred in ≥ 25% of CABOMETYX-treated patients, in
order of decreasing frequency, were: diarrhea, fatigue, nausea, decreased appetite,
palmar-plantar erythrodysesthesia (PPE), hypertension, vomiting, weight decreased,
and constipation. Grade 3-4 adverse reactions and laboratory abnormalities
which occurred in ≥ 5% of patients were hypertension, diarrhea, fatigue, PPE,
hyponatremia, hypophosphatemia, hypomagnesemia, lymphopenia, anemia,
hypokalemia, and increased GGT.
The dose was reduced in 60% of patients receiving CABOMETYX and in 24%
of patients receiving everolimus. Twenty percent (20%) of patients received
CABOMETYX 20 mg once daily as their lowest dose. The most frequent adverse
reactions leading to dose reduction in patients treated with CABOMETYX were:
diarrhea, PPE, fatigue, and hypertension. Adverse reactions leading to dose
interruption occurred in 70% patients receiving CABOMETYX and in 59% patients
receiving everolimus. Adverse reactions led to study treatment discontinuation in
10% of patients receiving CABOMETYX and in 10% of patients receiving everolimus.
The most frequent adverse reactions leading to permanent discontinuation in
patients treated with CABOMETYX were decreased appetite (2%) and fatigue (1%).
Table 1. Adverse Reactions Occurring in ≥ 10% Patients Who
Received CABOMETYX in METEOR
Adverse Reaction
CABOMETYX
(n=331) 1
Everolimus
(n=322)
All
Grades2
Grade
3-4
All
Grades2
Grade
3-4
Percentage (%) of Patients
Gastrointestinal
Diarrhea 74 11 28 2
Nausea 50 4 28 <1
Vomiting 32 2 14 <1
Stomatitis 22 2 24 2
Constipation 25 <1 19 <1
Abdominal pain 3 23 4 13 2
Dyspepsia 12 <1 5 0
General
Fatigue 56 9 47 7
Mucosal inflammation 19 <1 23 3
Asthenia 19 4 16 2
Metabolism and Nutrition
Decreased appetite 46 3 34 <1
Skin and Subcutaneous Tissue
Palmar-plantar
erythrodysesthesia 42 8 6 <1
Rash 4 23 <1 43 <1
Dry skin 11 0 10 0
Vascular
Hypertension 5 39 16 8 3
Investigations
Weight decreased 31 2 12 0
Nervous System
Dysgeusia 24 0 9 0
Headache 11 <1 12 <1
Dizziness 11 0 7 0
Endocrine
Hypothyroidism 21 0 <1 <1
Respiratory, Thoracic, and
Mediastinal
Dysphonia 20 <1 4 0
Dyspnea 19 3 29 4
Cough 18 <1 33 <1
Blood and Lymphatic
Anemia 17 5 38 16
Musculoskeletal and Connective
Tissue
Pain in extremity 14 1 8 <1
Muscle spasms 13 0 5 0
Arthralgia 11 <1 14 1
Renal and Urinary
Proteinuria 12 2 9 <1
1 One subject randomized to everolimus received cabozantinib.
2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) Version 4.0
3 Includes the following terms: abdominal pain, abdominal pain upper, and
abdominal pain lower
4 Includes the following terms: rash, rash erythematous, rash follicular,
rash macular, rash papular, rash pustular, rash vesicular, genital rash,
intermittent leg rash, rash on scrotum and penis, rash maculo-papular,
rash pruritic, contact dermatitis, dermatitis acneiform
5 Includes the following terms hypertension, blood pressure increased,
hypertensive crisis, blood pressure fluctuation
Other clinically important adverse reactions (all grades) that were reported in
<10% of patients treated with CABOMETYX included: wound complications (2%),
convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis
cholestatic (<1%).
Table 2. Laboratory Abnormalities Occurring in ≥ 25% Patients
Who Received CABOMETYX in METEOR
Laboratory Abnormality
CABOMETYX
(n=331)
Everolimus
(n=322)
All
Grades
Grade
3-4
All
Grades
Grade
3-4
Percentage (%) of Patients
Chemistry
Increased AST 74 3 40 <1
Increased ALT 68 3 32 <1
Increased creatinine 58 <1 71 0
Increased triglycerides 53 4 73 13
Hypophosphatemia 48 8 36 5
Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1
Increased ALP 35 2 29 1
Hypomagnesemia 31 7 4 <1
Hyponatremia 30 8 26 6
Increased GGT 27 5 43 9
Hematology
Leukopenia 35 <1 31 <1
Neutropenia 31 2 17 <1
Anemia1 31 4 71 17
Lymphopenia 25 7 39 12
Thrombocytopenia 25 <1 27 <1
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; GGT, gamma glutamyl transferase.
NCI CTCAE, Version 4.0
1 Based on laboratory abnormalities
CABOSUN
The safety of CABOMETYX was evaluated in CABOSUN, a randomized, open-label
trial in patients with advanced renal cell carcinoma, in which 78 patients received
CABOMETYX 60 mg once daily and 72 patients received sunitinib 50 mg once
daily (4 weeks on treatment followed by 2 weeks off), until disease progression
or unacceptable toxicity. The median duration of treatment was 6.5 months (range
0.2 – 28.7) for patients receiving CABOMETYX and 3.1 months (range 0.2 – 25.5)
for patients receiving sunitinib.
Within 30 days of treatment, there were 4 deaths in patients treated with
CABOMETYX and 6 deaths in patients treated with sunitinib. Of the 4 patients treated
with CABOMETYX, 2 patients died due to gastrointestinal perforation, 1 patient had
acute renal failure, and 1 patient died due to clinical deterioration. All Grade 3-4
adverse reactions were collected in the entire safety population. The most frequent
Grade 3-4 adverse reactions (≥5%) in patients treated with CABOMETYX were
hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, increased
ALT, decreased appetite, stomatitis, pain, hypotension, and syncope.
The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for
sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced
in 46% of patients receiving CABOMETYX and in 35% of patients receiving
sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in
71% of patients receiving sunitinib. Based on patient disposition, 21% of patients
receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to
an adverse reaction.
Table 3. Grade 3-4 Adverse Reactions Occurring in ≥ 1% Patients
Who Received CABOMETYX in CABOSUN
Adverse Reaction
CABOMETYX
(n = 78)
Sunitinib
(n = 72)
Grade 3-41 Grade 3-41
Percentage (%) of Patients
Patients with any Grade 3-4 Adverse
Reaction 68 65
Gastrointestinal
Diarrhea 10 11
Stomatitis 5 6
Nausea 3 4
Vomiting 1 3
Constipation 1 0
General
Fatigue 6 17
Pain 5 0
Metabolism and Nutrition
Hyponatremia2 9 8
Hypophosphatemia2 9 7
Decreased appetite 5 1
Dehydration 4 1
Hypocalcemia2 3 0
Hypomagnesemia2 3 0
Hyperkalemia2 1 3
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia 8 4
Skin ulcer 3 0
Vascular
Hypertension3 28 21
Hypotension 5 1
Angiopathy 1 1
Investigations
Increased ALT2 5 0
Weight decreased 4 0
Increased AST 2 3 3
Increased blood creatinine 2 3 3
Lymphopenia 2 1 6
Thrombocytopenia 2 1 11
Nervous System
Syncope 5 0
Respiratory, Thoracic, and Mediastinal
Dyspnea 1 6