Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Cardiac
Failure
Newly added section:
CABOMETYX
can cause severe and fatal cardiac failure [see
Adverse Reactions (6.1)]. Cardiac failure occurred in 0.5% of patients
treated with CABOMETYX as a single agent, including fatal cardiac failure in
0.1% of patients. Median time to onset of cardiac failure was 73 days (range:
44 days to 159 days).
Consider
baseline and periodic evaluations of left ventricular ejection fraction.
Monitor for signs and symptoms of cardiovascular events. Withhold and resume at
a reduced dose upon recovery or permanently discontinue CABOMETYX depending on
the severity [see Dosage and
Administration (2.3)].
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
- Cardiac
Failure [see Warnings and Precautions
(5.5)]
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
…
Other clinically relevant adverse reactions (all
grades) that were reported in <10% of patients treated with CABOMETYX
included: wound complications (2%), cardiac failure (<1%), convulsion
(<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and
hepatitis cholestatic (<1%).
…
Clinically relevant adverse reactions in <15% of
patients who received CABOMETYX included cardiac arrhythmia, hemorrhage,
thromboembolic events, kidney injury, proteinuria, hypotension, peripheral
neuropathy, reversible posterior leukoencephalopathy syndrome, alopecia, hair
color changes, and cardiac failure.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Newly added information:
…
Cardiac Failure: Advise patients that CABOMETYX can cause cardiac failure. Advise
patients to immediately contact their healthcare provider for signs or symptoms
of cardiac failure [see Warnings and
Precautions (5.5)].
…
PATIENT
INFORMATION
Additions and/or revisions underlined:
Before
you take CABOMETYX, tell your healthcare provider about all of your
medical conditions, including if you:
…
…
What are the
possible side effects of CABOMETYX?
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hemorrhage
Additions and/or
revisions underlined:
. . .
Withhold CABOMETYX for 3 weeks prior to scheduled
surgery, including dental surgery to reduce the risk of hemorrhage. Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery
as recommended [see Dosage and
Administration (2.5), Warnings and Precautions (5.10, 5.11)].
.
. .
5.4
Hypertension and Hypertensive Crisis
Additions and/or
revisions underlined:
CABOMETYX
can cause hypertension, including hypertensive crisis [see Adverse Reactions (6.1)]. Hypertension was reported in 37%
(16% Grade 3 and less than 1% Grade 4) of CABOMETYX- treated patients. In
CABINET (n=195) [see Clinical Studies
(14.4)], hypertension was reported in 65% (26% Grade 3) of
CABOMETYX-treated patients.
.
. .
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive changes;
please refer to label for complete information
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or
revisions underlined:
The
safety and effectiveness of CABOMETYX for the treatment of differentiated
thyroid cancer (DTC) and neuroendocrine tumors (NETs) have been
established in pediatric patients aged 12 years and older.
Use
of CABOMETYX in pediatric patients aged 12 years and older with DTC and NETs
is supported by evidence from adequate and well-controlled studies of CABOMETYX
in adults with additional population pharmacokinetic data demonstrating that
cabozantinib exposure is within the same range between adults and pediatric
patients aged 12 years and older at the recommended dosages [see Dosage and Administration (2.4, 2.5),
Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies
(14.3, 14.4)].
.
. .
8.5 Geriatric Use
Additions and/or
revisions underlined:
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. In COSMIC-311, 50% of 125 patients treated with CABOMETYX were
age 65 years and older, and 12%
were 75 years and older. In CABINET, 38% of 63 patients treated with CABOMETYX
were age 65 years and older, and 5% were 75 years and older in the pNET cohort,
and 55% of 132 patients treated with CABOMETYX were age 65 years and older, and
13% were 75 years and older in the epNET cohort [see Clinical Studies (14)].
No overall differences in safety or effectiveness
were observed between these patients and younger patients.
Of the 320 patients with RCC treated with CABOMETYX
in combination with nivolumab in CHECKMATE-9ER, 41% were 65 years or
older and 9% were 75 years or older [see Clinical Studies (14.1)].
No overall difference in safety was reported
between older and younger patients receiving both CABOMETYX and
nivolumab.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions and/or
revisions underlined:
.
. .
PATIENT
INFORMATION
Additions and/or
revisions underlined:
.
. .
What is CABOMETYX?
CABOMETYX
is a prescription medicine used to treat:
people
with liver cancer (hepatocellular carcinoma) who have been previously treated
with the medicine sorafenib.
adults
and children 12 years of age and older who have a type of thyroid cancer called
differentiated thyroid cancer (DTC) that has spread (locally advanced or
metastatic), and,
has progressed
after treatment with a VEGFR-targeted treatment, and
your DTC can no
longer be treated with radioactive iodine, or you are not able to receive
radioactive iodine treatment.
adults and children 12 years of age and older who have
a type of cancer called pancreatic neuroendocrine tumors (pNET) or
extra-pancreatic neuroendocrine tumors (epNET) that has been previously
treated, cannot be treated by surgery, and has spread (locally advanced or
metastatic).
It
is not known if CABOMETYX is safe and effective in children younger than 12
years of age.
.
. .
How should I take
CABOMETYX?
Take
CABOMETYX exactly as your healthcare provider tells you to take it.
Do not take CABOMETYX
with food. Take CABOMETYX at least 1 hour before or at least 2 hours after
eating.
Swallow
CABOMETYX tablets whole.
Do not crush, chew or
split CABOMETYX tablets
. . .
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hemorrhage
(Additions and/or revisions underlined)
Severe and fatal hemorrhages occurred with CABOMETYX [see Adverse Reactions
(6.1)]. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies.
Discontinue CABOMETYX for Grade 3 or
4 hemorrhage and
prior to surgery as recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.10, 5.11)].
Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
5.10 Osteonecrosis of the Jaw
(Additions and/or revisions underlined)
Withhold
CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose
[see Dosage and Administration (2.5)].
5.13 Thyroid Dysfunction
(Newly
added section)
Thyroid dysfunction, primarily hypothyroidism, has
been observed with CABOMETYX. Based on the safety population [see Adverse Reactions (6.1)], thyroid dysfunction occurred in 19% of
patients treated with CABOMETYX, including
Grade 3 in 0.4% of patients.
Patients
should be assessed
for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored
for signs and symptoms
of thyroid dysfunction during CABOMETYX treatment.
Thyroid function
testing and management
of dysfunction should be performed as clinically indicated [see Dosage and Administration (2.5)].
(Newly
added section)
Thyroid dysfunction, primarily hypothyroidism, has
been observed with CABOMETYX. Based on the safety population [see Adverse Reactions (6.1)], thyroid dysfunction occurred in 19% of
patients treated with CABOMETYX, including
Grade 3 in 0.4% of patients.
Patients
should be assessed
for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored
for signs and symptoms
of thyroid dysfunction during CABOMETYX treatment.
Thyroid function
testing and management
of dysfunction should be performed as clinically indicated [see Dosage and Administration (2.5)].
5.14 Hypocalcemia
(Newly
added section)
CABOMETYX can cause hypocalcemia. Based on the safety population
[see Adverse Reactions
(6.1)], hypocalcemia occurred in 13% of
patients treated with CABOMETYX, including
Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected
in CABOSUN.
In COSMIC-311 [see Clinical Studies (14.3)], hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade
3 in 6% and
Grade 4 in 3% of patients.
Monitor blood calcium
levels and replace
calcium as necessary
during treatment. Withhold and resume at reduced dose upon recovery or permanently
discontinue CABOMETYX depending
on severity [see Dosage and Administration (2.5)].
5.4 Hypertension and Hypertensive Crisis
(Additions and/or revisions underlined)
CABOMETYX can cause
hypertension, including hypertensive crisis [see Adverse Reactions (6.1)]. Hypertension was reported
in 37% (16% 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 [see Dosage and Administration (2.5)]. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled
with anti- hypertensive therapy or for hypertensive crisis [see Dosage and Administration (2.5)].
5.5 Diarrhea
(Additions and/or revisions underlined)
Diarrhea occurred
in 62% of patients
treated with CABOMETYX. Grade 3 diarrhea
occurred in 10% of patients treated with CABOMETYX [see Adverse Reactions
(6.1)].
Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to <
or equal to Grade 1, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.5)].
5.7 Hepatotoxicity
5.8 Adrenal Insufficiency
(Additions and/or revisions underlined)
CABOMETYX in combination
with nivolumab can cause primary or secondary
adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically
indicated. Withhold CABOMETYX and/or nivolumab
and resume CABOMETYX at a reduced dose
depending on severity [see Dosage and
Administration
(2.5)].
5.9 Proteinuria
(Additions and/or revisions underlined)
Proteinuria was observed in 8% of patients receiving CABOMETYX [see Adverse Reactions (6.1)].
Monitor
urine protein regularly during CABOMETYX treatment.
For Grade 2 or
3 proteinuria, withhold CABOMETYX until improvement to < or equal to Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients
who develop nephrotic syndrome [see Dosage and Administration (2.5)].
6
Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse
reactions are discussed elsewhere in the labeling:
6.1 Clinical Trial Experience
(Additions and/or revisions underlined)
The data described
in the WARNINGS AND PRECAUTIONS
section and below reflect exposure to CABOMETYX: as a single agent in 409 patients
with RCC enrolled in randomized, active-controlled trials (CABOSUN, METEOR), 467 patients with HCC enrolled in a randomized, placebo-controlled trial (CELESTIAL), and 125 patients with DTC
enrolled in a randomized, placebo-controlled trial (COSMIC-311), and in combination with nivolumab
240 mg/m2 every 2 weeks in 320 patients
with RCC enrolled
in a randomized, active-controlled trial (CHECKMATE-9ER).
(Newly
added information)
Differentiated Thyroid Cancer
The safety of CABOMETYX was evaluated in COSMIC-311, a randomized, double-blind, placebo-controlled trial in which 187 patients with advanced
differentiated thyroid cancer
were randomized to receive CABOMETYX 60 mg orally once daily (n=125)
or placebo (n=62)
with supportive care until disease progression or unacceptable toxicity [see Clinical Studies (14.3)]. At
the
time of the primary efficacy analysis, the median duration of treatment
was 4.4 months (range 0.0 – 15.7) for patients receiving CABOMETYX and 2.3 months (range 0.3 – 11.6) for patients receiving placebo. The median age was 66 years (range 32 to 85 years),
55% were female, 70% were White, 18% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib.
Adverse reactions occurring in = 25% of CABOMETYX-treated patients, in order of decreasing
frequency were: diarrhea,
PPE, fatigue, and hypertension, and stomatitis.
Grade 3-4 adverse reactions which occurred in = 5% of patients were PPE, hypertension, fatigue, diarrhea, and stomatitis. Serious adverse reactions occurred in 34% of patients who received CABOMETYX. Serious
adverse reactions in =2% included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal adverse reactions occurred in 1.6% of
patients in the CABOMETYX arm, including
arterial hemorrhage (0.8%) and pulmonary
embolism (0.8%).
The median average
daily dose was 42.0 mg for CABOMETYX. The dose was reduced in 56% of patients receiving CABOMETYX; 22% of
patients required a second dose reduction.
The most frequent
adverse reactions (=5%) leading
to dose reduction
of CABOMETYX were PPE, diarrhea,
fatigue, proteinuria, and decreased
appetite. Dose interruptions occurred in 72% patients
receiving CABOMETYX. Adverse reactions requiring dosage
interruption in =5% of patients
were PPE, diarrhea, dyspnea,
hypertension, decreased appetite and proteinuria. Adverse reactions
leading to permanent discontinuation of CABOMETYX occurred in 5% of patients.
(Newly added Table 12 and 13: Adverse Reactions and Laboratory Abnormalities in COSMIC-311)
8
Use in Specific Populations
8.4 Pediatric Use
(Newly
added information)
The safety and effectiveness of CABOMETYX for
the
treatment of differentiated thyroid cancer
(DTC) have been established
in pediatric patients aged 12 years and older.
Use
of CABOMETYX in pediatric patients aged 12 years and older with DTC is supported
by evidence from adequate
and well-controlled studies
of CABOMETYX in adults with additional
population pharmacokinetic data demonstrating that cabozantinib exposure is within the same range between adults and pediatric
patients aged 12 years and older at the recommended dosages
[see Dosage and Administration (2.5), Adverse Reactions
(6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)].
The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.
8.5 Geriatric Use
(Newly
added information)
In COSMIC-311, 50% of 125 patients
treated with CABOMETYX were age
65 years and older, and 12% were 75 years and older [see Clinical Studies (14)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Newly
added information)
Proteinuria: Advise patients
to contact their healthcare provider for signs or symptoms
of proteinuria [see Warnings and
Precautions (5.9)].
Thyroid dysfunction: Advise patients that CABOMETYX can cause
thyroid dysfunction and that their thyroid function
should be monitored
regularly during treatment. Advise
patients to immediately contact their healthcare provider for signs or symptoms of thyroid
dysfunction [see Warnings and Precautions (5.13)].
Hypocalcemia: Advise patients that CABOMETYX can cause low calcium
levels and that their serum calcium levels should be monitored regularly during treatment. Advise
patients to immediately contact their healthcare provider for signs or symptoms
of hypocalcemia [see Warnings and Precautions (5.14)].
Patient Information
(Additions and/or revisions underlined)
CABOMETYX
is a prescription medicine used to treat:
• adults and children 12 years of age and older who have
a type of thyroid cancer called differentiated thyroid cancer (DTC) that has spread (locally advanced or
metastatic), and,
o has progressed after treatment with a VEGFR-targeted
treatment, and
o your DTC can no longer be treated with radioactive
iodine, or you are not able to receive radioactive iodine treatment.
It is not known if CABOMETYX is safe and effective in
children younger than 12 years of age.
Before you take CABOMETYX, tell your healthcare provider
about all of your medical conditions,
including if you:
• have a low calcium level in your blood (hypocalcemia)
• change in thyroid function. CABOMETYX can cause changes
in your thyroid function, including changes to thyroid hormone levels in your blood. Your
healthcare provider will do blood tests to check your thyroid function before and during treatment with
CABOMETYX.
• decreased calcium level in your blood (hypocalcemia).
CABOMETYX can cause you to have a decreased amount of calcium in your blood. Your
healthcare provider will do blood tests to check you for this problem and give you calcium if needed. Tell
your healthcare provider right away if you get any of the following signs or symptoms:
o muscle stiffness or muscle spasms o sudden weight gain
o numbness or tingling in your fingers, toes, or around your mouth
o swelling of your arms, hands, legs, and ankles
o seizures
Your healthcare provider may change your dose,
temporarily stop, or permanently stop treatment with
CABOMETYX if you have certain side effects.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Hepatoxicity
(Newly added
subsection)
CABOMETYX in combination with nivolumab can
cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST
elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of
and periodically throughout treatment. Consider more frequent monitoring of
liver enzymes as compared to when the drugs are administered as single agents.
For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider
administering corticosteroids [see Dosage and Administration (2.4)].
With the combination of CABOMETYX and
nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST > 3 times ULN (Grade greater than or equal to 2) was reported in 83 patients, of whom 23
(28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in
74 (89%). Among the 44 patients with Grade greater than or equal to 2 increased ALT or AST who were
rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent
or with both (n=24), recurrence of Grade greater than or equal to 2 increased ALT or AST was observed
in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7
patients receiving both CABOMETYX and nivolumab.
5.8 Adrenal Insufficiency
(Newly added
subsection)
CABOMETYX
in combination with nivolumab can cause primary or secondary adrenal
insufficiency. For Grade 2 or higher adrenal insufficiency, initiate
symptomatic treatment, including hormone replacement as clinically indicated.
Withhold CABOMETYX and/or nivolumab depending on severity.
Adrenal
insufficiency occurred in 4.7% (15/320) of patients with RCC who received
CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse
reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX
and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of
patients with RCC.
Approximately
80% (12/15) of patients with adrenal insufficiency received hormone replacement
therapy, including systemic corticosteroids. Adrenal insufficiency resolved in
27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with
nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after
symptom improvement; of these, all (n=6) received hormone replacement therapy
and 2 had recurrence of adrenal insufficiency.
6
Adverse Reactions
(Additions and/or
revisions underlined)
The
following clinically significant adverse reactions are discussed elsewhere in
the labeling:
6.1 Clinical Trials Experience
(Extensive
changes; please refer to label)
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or
revisions underlined)
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.
Of
the 320 patients randomized to CABOMETYX administered with nivolumab in
CHECKMATE-9ER, 41% were 65 years or older and 9% were 75 years or older. No
overall difference in safety was reported between elderly patients and younger
patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
…
- Adrenal insufficiency:
Advise patients receiving with nivolumab to contact their healthcare provider
immediately for signs or symptoms of adrenal insufficiency [see Warnings and Precautions (5.8)].
…
PATIENT INFORMATION
(Extensive
changes; please refer to label)
Approved Drug Label (PDF)
5
Warnings and Precautions
Hemorrhage
(Additions and/or revisions underlined)
Severe
and fatal hemorrhages occurred with
CABOMETYX [see Adverse
Reactions (6.1)]. The incidence
of Grade 3 to 5 hemorrhagic events was
5% in CABOMETYX-treated patients in RCC and HCC studies.
Impaired Wound Healing
(Additions and/or revisions
underlined)
Wound
complications occurred with CABOMETYX [see Adverse Reactions (6.1)]. Withhold CABOMETYX for at
least 3 weeks prior
to elective surgery [see Dosage and Administration (2.1)]. Do not administer
CABOMETYX for at least 2 weeks
after major surgery and until
adequate wound healing. The
safety of resumption of CABOMETYX after resolution of wound healing
complications has not been established.
Perforations and Fistulas
(Additions and/or revisions
underlined)
Monitor patients for signs and symptoms of fistulas
and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who
experience a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.4)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or revisions
underlined)
·
Hypertension and hypertensive crisis:
Inform patients of the signs and symptoms of
hypertension.
• Osteonecrosis of the jaw: Advise patients regarding
good oral hygiene practices.
Advise patients to immediately contact their
healthcare provider for signs or
symptoms associated with osteonecrosis of the jaw [see
Warnings and Precautions
(5.8)].
• Impaired wound healing: Advise patients that CABOMETYX
may impair wound
healing. Advise patients to inform their healthcare
provider of any planned surgical
procedure [see Dosage and Administration (2.1),
Warnings and Precautions (5.9)].
Advise females of reproductive potential of the potential
risk to a fetus. Advise
females to inform their healthcare provider of a
known or suspected pregnancy
[see Warnings and Precautions (5.11), Use in Specific
Populations (8.1)].
PATIENT INFORMATION
Before you take CABOMETYX, tell your healthcare provider
about all of your medical conditions,
including if you:
• plan to have any surgery, dental procedure, or have had
a recent surgery. You should stop taking
CABOMETYX at least 3 weeks before planned
surgery. See “What are the possible side effects of
CABOMETYX?”
·
Wound healing problems have happened in some
people who take CABOMETYX. Tell your healthcare provider if you plan to have any
surgery before or during treatment with CABOMETYX.
o You should stop taking CABOMETYX at least 3 weeks
before planned surgery.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hemorrhage
(additions underlined)
Severe and fatal hemorrhages have occurred with
CABOMETYX. In two RCC studies, the incidence of Grade greater than or
equal to 3 hemorrhagic events was 3% in CABOMETYX-treated patients.
5.2 GI Perforations and Fistulas
(additions underlined)
![]()
In RCC studies, fistulas were reported in 1%
of CABOMETYX-treated patients. Fatal perforations occurred in patients treated
with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations
were reported in 1% of CABOMETYX-treated patients.
Monitor patients for 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
(additions underlined)
![]()
CABOMETYX
treatment results in an increased incidence of thrombotic events. In RCC
studies, venous thromboembolism occurred in 9% (including 5%
pulmonary embolism) and arterial thromboembolism occurred in 1%
of CABOMETYX-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.
5.4 Hypertension and Hypertensive Crisis
(additions underlined)
![]()
CABOMETYX
treatment results in an increased incidence of treatment-emergent hypertension,
including hypertensive crisis. In RCC studies, hypertension was reported in 44%
(18% Grade greater than or equal to 3) of CABOMETYX-treated patients.
…
5.5 Diarrhea
![]()
(additions
underlined)
In RCC studies, diarrhea occurred in 74% of
patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients
treated with CABOMETYX. 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.
5.6 Palmar-Plantar Erythrodysesthesia
(additions underlined)
In RCC studies, palmar-plantar
erythrodysesthesia (PPE) occurred in 42% of patients treated with
CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX.
Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3
PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
6
Adverse Reactions
6.1 Clinical Trial Experience
(additions underlined)
…
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 60 mg CABOMETYX daily and 72 patients received 50 mg
sunitinib taken 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, two patients died due to
gastrointestinal perforation, one patient had acute renal failure, and one
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 (greater than or equal to 5%) in patients treated with
CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE,
fatigue, ALT increased, 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 greater than or equal to 1% Patients Who
Received CABOMETYX in CABOSUN
(please refer to label
to view Table 3)
8
Use in Specific Populations
8.5 Geriatric Use
(additions underlined)
In RCC studies, 41% of patients treated with
CABOMETYX were age 65 years and older, and 8% of patients were75 years and
older.
Grade 3-4 adverse reactions occurred in 73% of
patients age 65 years and older, and in 76% of patients 75 years and older. No
overall differences in safety or efficacy were observed between older and
younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions underlined)
…
Gastrointestinal disorders: 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.
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