Approved Drug Label (PDF)
Boxed Warning
Newly
added section
WARNING: SERIOUS
INFECTIONS, INCLUDING OPPORTUNISTIC INFECTIONS
GAVRETO may increase
the risk for serious infections, including bacterial, fungal, viral and
opportunistic infections, which can lead to hospitalization or death. Withhold,
reduce the dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3),
Warnings and Precautions (5.1)].
5
Warnings and Precautions
Newly
added subsection:
5.1 Serious Infections, Including
Opportunistic Infections
GAVRETO
may increase the risk for serious infections, including fatal and opportunistic
infections. In the AcceleRET-Lung trial [see
Adverse Reactions (6.1)], infections occurred in 72% of patients who
received GAVRETO, including 18% with Grade 3 and 3.7% with Grade 4 and 7% with
fatal outcomes. Among the patients who received chemotherapy/immunotherapy,
infections occurred in 52%, including 10% with Grade 3. Infections in the
GAVRETO arm included pneumonia, urinary tract infection, opportunistic
infections (such as pneumocystis jirovecii pneumonia, and fungal infections)
and others. Monitor patients for signs and symptoms of infection and treat
appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO
based on severity [see Dosage and
Administration (2.3)].
6
Adverse Reactions
Additions
and/or revisions underlined:
The
following clinically significant adverse reactions are described elsewhere in
the labeling:
- Serious
Infections, including Opportunistic Infections [see Warnings and Precautions (5.1)]
.
. .
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
.
. .
In
addition to the 540 patients, certain subsections in the WARNINGS AND
PRECAUTIONS describe adverse reactions observed with exposure to GAVRETO as a single
agent in a randomized, open-label study, AcceleRET-Lung (NCT04222972), which
enrolled 223 patients with RET-fusion positive locally advanced unresectable or
metastatic NSCLC.
.
. .
Other Clinical
Trials Experience
AcceleRET-Lung
trial (NCT04222972)
In
AcceleRET-Lung trial (NCT04222972), single agent GAVRETO (n=108) was compared
to chemotherapy/immunotherapy (n=104) in patients with RET fusion-positive NSCLC. Adverse reactions were infections (72%
vs. 52%), including pneumonia (29% vs. 6%), urinary tract infection
(22% vs. 8%), and opportunistic infections (20% vs. 6%). Opportunistic
infections included
pneumocystis jirovecii pneumonia, fungal infections, legionella pneumonia,
cytomegalovirus infection, and herpes simplex.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION
GUIDE
Newly added Medication Guide;
please refer to label for complete information.
PATIENT
COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
Serious Infections, Including Opportunistic Infections
Advise
patients that GAVRETO may increase the risk of serious infections and to
contact their healthcare provider if they experience symptoms of infections [see Warnings and Precautions (5.1)].
.
. .
Approved Drug Label (PDF)
8
Use in Specific Populations
8.6 Hepatic
Impairment
Additions and/or revisions underlined:
No dose adjustment is required for patients with
mild (total bilirubin less than or equal to ULN and AST > ULN or total
bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin >
1.5 to 3 × ULN and any AST) or severe (total bilirubin > 3
× ULN and any AST) hepatic impairment.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Interstitial Lung Disease/Pneumonitis
Additions and/or
revisions underlined:
Severe, life-threatening, and fatal interstitial
lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO.
Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3%
with Grade 3-4, and 0.2% with fatal reactions.
…
5.2 Hypertension
Additions and/or
revisions underlined:
Hypertension occurred in 35% of patients,
including Grade 3 hypertension in 18% of patients [see Adverse
Reactions (6.1)]. Overall, 8% had their dose interrupted and 4.8%
had their dose reduced for hypertension. Treatment-emergent hypertension was
most commonly managed with anti-hypertension medications.
…
5.3 Hepatoxicity
Additions and/or
revisions underlined:
Serious hepatic adverse reactions occurred in 1.5%
of patients treated with GAVRETO. Increased AST occurred in 49% of
patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37%
of patients, including Grade 3 or 4 in 4.8% [see Adverse
Reactions (6.1)]. The median time to first onset for increased AST was 15
days (range: 5 days to 2.5 years) and for increased ALT was 24 days
(range: 7 days to 3.7 years).
…
5.4 Hemorrhagic Events
Additions and/or
revisions underlined:
Serious, including fatal, hemorrhagic events can
occur with GAVRETO. Grade greater than or equal to 3 hemorrhagic events
occurred in 4.1% of patients treated with GAVRETO including one patient
with a fatal hemorrhagic event.
…
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, 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 GAVRETO have been established in pediatric patients
aged 12 years and older for RET fusion-positive
thyroid cancer. Use of GAVRETO in this age group is supported by evidence
from an adequate and well-controlled study of GAVRETO in adults with additional
population pharmacokinetic data demonstrating that age and body weight had no clinically
meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of
pralsetinib is expected to be similar between adults and pediatric patients age
12 years and older, and that the course of RET
fusion-positive thyroid cancer is sufficiently similar in adults and
pediatric patients to allow extrapolation of data in adults to pediatric
patients [see Adverse Reactions (6.1),
Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
The
safety and effectiveness of GAVRETO have not been established in pediatric
patients with RET fusion-positive
NSCLC or in pediatric patients younger than 12 years old with RET fusion- positive thyroid cancer.
…
8.5 Geriatric Use
Additions
and/or revisions underlined:
Of
the 540 patients in ARROW who received the recommended dose of GAVRETO
at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years
and over.
No
overall differences in pharmacokinetics (PK), safety or effectiveness were
observed between patients aged 65 years or older and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions
and/or revisions underlined:
What is GAVRETO?
…
It
is not known if GAVRETO is safe and effective when used to treat cancers caused
by abnormal RET genes:
swelling of your face, arms, legs, hands, and feet
(edema)
fever
cough
…
The most common severe
abnormal blood test results with GAVRETO include:
decreased
white blood cell, red blood cell, and platelet counts
decreased
levels of phosphate, body salt (sodium), calcium and potassium in the blood
abnormal
liver function blood tests
increased
levels of enzyme called alkaline phosphatase in the blood (test for
liver or bone problems)
increased levels of potassium in the blood
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or
revisions underlined:
…
The
pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to
GAVRETO as a single agent at 400 mg orally
once daily in 438 patients
with RET-altered solid
tumors, including with RET fusion-positive
NSCLC (n = 220), and RET-altered
thyroid cancer ([n=138], including 19 patients with RET fusion-positive thyroid cancer), in ARROW [see Clinical Studies (14)]. Among 438 patients who received
GAVRETO, 47% were exposed for 6 months or longer and 23% were exposed
for greater than one year.
…
RET-altered Thyroid Cancer
The
safety of GAVRETO
was evaluated as a single
agent at 400 mg orally
once daily in 138 patients
with RET-altered thyroid cancer (including
19 patients with RET fusion-positive thyroid
cancer) in ARROW [see Clinical Studies
(14.2)]. Among the 138 patients
who received GAVRETO, 68%
were exposed for 6 months or longer, and 40% were exposed for greater than one
year.
…
Approved Drug Label (PDF)
7
Drug Interactions
7.1 Effects of Other Drugs on GAVRETO
Additions
and/or revisions underlined
Strong
or Moderate CYP3A and/or P-gp Inhibitors
Concomitant
use with a strong or moderate CYP3A inhibitor and/or a P-gp inhibitor
increases pralsetinib exposure [Clinical
Pharmacology (12.3)], which may increase the risk of
adverse reactions related to GAVRETO. Avoid coadministration of GAVRETO
with a strong or moderate CYP3A and/or a P-gp inhibitor. If
coadministration with any of the above inhibitors cannot be avoided,
reduce the GAVRETO dose [see Dosage and
Administration (2.4)].
Strong
or moderate CYP3A Inducers
Concomitant
use with a strong or moderate CYP3A inducer decreases pralsetinib
exposure [see Clinical Pharmacology
(12.3)], which may decrease efficacy of GAVRETO. Avoid
concomitant use of pralsetinib with strong or moderate CYP3A
inducers. If coadministration of GAVRETO with strong or moderate CYP3A
inducers cannot be avoided, increase the GAVRETO dose [see Dosage and Administration (2.5)]
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Tumor Lysis Syndrome
New
subsection added
Cases
of tumor lysis syndrome (TLS) have been reported in patients with medullary
thyroid carcinoma receiving GAVRETO [see
Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have
rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration.
Closely
monitor patients at risk, consider appropriate prophylaxis including hydration,
and treat as clinically indicated.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, please refer to label for complete information
8
Use in Specific Populations
8.1 Pregnancy
…
Additions and/or revisions underlined
Data
Animal Data
In an embryo-fetal development study, once daily
oral administration of pralsetinib to pregnant rats during the period of
organogenesis resulted in 100% post-implantation loss at dose levels
Greater than or equal to 20 mg/kg (approximately 1.8
times the human exposure based on area under the curve [AUC] at the clinical
dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose
level (approximately 0.6 times the human exposure based on AUC at the
clinical dose of 400 mg).
…
8.4 Pediatric Use
Additions
and/or revisions underlined
The
safety and effectiveness of GAVRETO have been established in pediatric patients
aged 12 years and older for RET-mutant
MTC and RET-fusion thyroid cancer.
Use of GAVRETO in this age group is supported by evidence from an adequate and
well-controlled study of GAVRETO in adults with additional population
pharmacokinetic data demonstrating that age and body weight had no clinically
meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of
pralsetinib is expected to be similar between adults and pediatric patients
aged 12 years and older, and that the course of RET-mutant MTC and RET-fusion
thyroid cancer is sufficiently similar in adults and pediatric patients to
allow extrapolation of data in adults to pediatric patients[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
Clinical Studies (14.2)].
The
safety and effectiveness of GAVRETO have not been established in pediatric
patients with RET fusion-positive
NSCLC or in pediatric patients younger than 12 years old with RET-mutant MTC or RET-fusion thyroid cancer.
…
Monitor
growth plates in adolescent patients with open growth plates. Consider
interrupting or discontinuing therapy based on the severity of any growth plate
abnormalities and based on an individual risk-benefit assessment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined
What is GAVRETO?
GAVRETO
is a prescription medicine used to treat certain cancers caused by abnormal rearranged
during transfection (RET) genes in:
adults
with non-small cell lung cancer (NSCLC) that has spread.
adults and children 12 years of age and older
with advanced medullary thyroid cancer (MTC) or MTC that has spread who require
a medicine by mouth or injection (systemic therapy).
adults and children 12 years of age and older with
advanced thyroid cancer or thyroid cancer that has spread who require a
medicine by mouth or injection (systemic therapy) and who have received
radioactive iodine and it did not work or is no longer working.
Your
healthcare provider will perform a test to make sure that GAVRETO is right for
you. It is not known if GAVRETO is safe and effective in children younger
than 12 years of age.
Before taking
GAVRETO, tell your healthcare provider about all of your medical conditions,
including if you:
…
plan
to have surgery. You should stop taking GAVRETO at least 5 days before your
planned surgery. See “What are the
possible side effects of GAVRETO?”
…
What are the
possible side effects of GAVRETO?
GAVRETO may cause
serious side effects, including:
…
Tumor lysis
syndrome (TLS).
TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have
kidney failure and the need for dialysis treatment, an abnormal heartbeat, and
may sometimes lead to hospitalization. Your healthcare provider may do blood
tests to check you for TLS. You should stay well hydrated during treatment with
GAVRETO. Call your healthcare provider or get emergency medical help right away
if you develop any of these symptoms during treatment with GAVRETO:
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined
…
Tumor
Lysis Syndrome
Advise
patients to contact their healthcare provider promptly to report any signs and
symptoms of TLS [see Warnings and
Precautions (5.5)].
…
Administration
Advise
patients to take GAVRETO on an empty stomach (no food intake for at
least 2 hours before and at least 1 hour after taking GAVRETO) [see Dosage and Administration (2.2)].
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