Indication
VANFLYTA is indicated in combination with standard
cytarabine and anthracycline induction and cytarabine
consolidation, and as maintenance monotherapy following
consolidation chemotherapy, for the treatment of adult
patients with newly diagnosed acute myeloid leukemia (AML)
that is FLT3 internal tandem duplication (ITD)–positive as
detected by an FDA-approved test.
Limitations of Use:
VANFLYTA is not indicated as maintenance
monotherapy following allogeneic hematopoietic stem cell
transplantation (HSCT); improvement in overall survival with
VANFLYTA in this setting has not been demonstrated.
Contraindications
VANFLYTA is contraindicated in patients
with severe hypokalemia, severe hypomagnesemia, long QT
syndrome, or in patients with a history of ventricular
arrhythmias or torsades de pointes.
Warnings and Precautions
QT Prolongation, Torsades de Pointes, and
Cardiac Arrest (See BOXED WARNING)
VANFLYTA prolongs
the QT interval in a dose- and concentration-dependent manner.
The mechanism of QTc interval prolongation is via inhibition of
the slow delayed rectifier potassium current, IKs, as
compared to all other medications that prolong the QTc interval,
which is via the rapid delayed rectifier potassium current,
IKr.
Therefore, the level of QTc prolongation with
VANFLYTA that predicts the risk of cardiac arrhythmias is
unclear. Inhibition of IKs and IKr may
leave patients with limited reserve, leading to a higher risk of
QT prolongation and serious cardiac arrhythmias, including fatal
outcomes. Torsades de pointes, ventricular fibrillation, cardiac
arrest, and sudden death have occurred in patients treated with
VANFLYTA.
Of the 1,081 patients with AML treated with
VANFLYTA in clinical trials, torsades de pointes occurred in
approximately 0.2% of patients, cardiac arrest occurred in 0.6%
of patients, including 0.4% with a fatal outcome, and 0.1% of
patients experienced ventricular fibrillation. These severe
cardiac arrhythmias occurred predominantly during the induction
phase.
Of the 265 patients with newly diagnosed
FLT3-ITD–positive AML treated with VANFLYTA in combination with
chemotherapy in the clinical trial, 2.3% were found to have a
QTcF greater than 500 ms and 10% of patients had an increase
from baseline QTcF greater than 60 ms. The clinical trial
excluded patients with a QTcF ≥450 ms or other factors that
increased the risk of QT prolongation or arrhythmic events (eg,
NYHA Class III or IV congestive heart failure, hypokalemia,
family history of long QT interval syndrome).
Therefore, avoid use in patients who are at
significant risk of developing torsades de pointes, including
uncontrolled or significant cardiac disease, recent myocardial
infarction, heart failure, unstable angina, bradyarrhythmias,
tachyarrhythmias, uncontrolled hypertension, high-degree
atrioventricular block, severe aortic stenosis, or uncontrolled
hypothyroidism.
Do not initiate treatment with VANFLYTA if the
QTcF interval is greater than 450 ms. Do not use VANFLYTA in
patients with severe hypokalemia, severe hypomagnesemia, long QT
syndrome, or in patients with a history of ventricular
arrhythmias or torsades de pointes. Perform an ECG and correct
electrolyte abnormalities prior to initiation of treatment with
VANFLYTA.
During induction and consolidation, perform an
ECG prior to initiation and then once weekly during VANFLYTA
treatment or more frequently as clinically indicated. During
maintenance, perform ECGs prior to initiation, once weekly for
at least the first month following dose initiation and
escalation, and as clinically indicated thereafter.
Do not escalate the dose if QTcF is greater than
450 ms. Perform ECG monitoring of the QT interval more
frequently in patients who are at significant risk of developing
QT interval prolongation and torsades de pointes, or following
dose escalation.
Monitor and correct hypokalemia and
hypomagnesemia prior to and during treatment with VANFLYTA.
Maintain electrolytes in the normal range. Monitor electrolytes
and ECGs more frequently in patients who experience diarrhea or
vomiting. Monitor patients more frequently with ECGs if
coadministration of VANFLYTA with drugs known to prolong the QT
interval is required.
Reduce the VANFLYTA dose when used concomitantly
with strong CYP3A inhibitors, as they may increase quizartinib
exposure. Reduce VANFLYTA if QTc increases to greater than 480
ms and less than 500 ms. Interrupt and reduce VANFLYTA if QTc
increases to greater than 500 ms. Permanently discontinue
VANFLYTA in patients who develop recurrent QTc greater than 500
ms or QTc interval prolongation with signs or symptoms of
life-threatening arrhythmia. VANFLYTA is available only through
a restricted program under a REMS.
VANFLYTA REMS
VANFLYTA is available only through a restricted
distribution program under a REMS called the VANFLYTA REMS
because of the serious risk of QT prolongation, torsades de
pointes, and cardiac arrest.
Notable requirements of the VANFLYTA REMS
include the following:
- Prescribers must be certified in the VANFLYTA REMS by
enrolling and completing training.
- Prescribers must counsel patients receiving VANFLYTA about
the risk of QT prolongation, torsades de pointes, and
cardiac arrest, and provide patients with a Patient Wallet
Card.
- Pharmacies that dispense VANFLYTA must be certified with the
VANFLYTA REMS and must verify prescribers are certified
through the VANFLYTA REMS.
Further information about the VANFLYTA REMS is
available at www.VANFLYTAREMS.com
or by telephone at 1-855-212-6670.
Embryo-Fetal Toxicity
Advise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment with VANFLYTA and for 7 months
after the last dose. Advise males with female partners of
reproductive potential to use effective contraception during
treatment with VANFLYTA and for 4 months after the last dose.
Adverse
Reactions
The safety of VANFLYTA (35.4 mg orally once
daily with chemotherapy, 26.5 mg to 53 mg orally once daily as
maintenance) in adult patients with newly diagnosed FLT3-ITD
positive AML is based on QuANTUM-First.
Serious adverse reactions in ≥5% of patients who
received VANFLYTA plus chemotherapy were: febrile neutropenia
(11%). Fatal adverse reactions occurred in 10% of patients who
received VANFLYTA plus chemotherapy, including sepsis (5%),
fungal infections (0.8%), brain edema (0.8%), and one case each
of febrile neutropenia, pneumonia, cerebral infarction, acute
respiratory distress syndrome, pulmonary embolism, ventricular
dysfunction, and cardiac arrest.
Permanent discontinuation due to an adverse
reaction in patients in the VANFLYTA plus chemotherapy arm
occurred in 20% of patients. The most frequent (≥2%) adverse
reaction which resulted in permanent discontinuation in the
VANFLYTA arm was sepsis (5%).
Dosage interruptions of VANFLYTA due to an
adverse reaction occurred in 34% of patients. Adverse reactions
which required dosage interruption in ≥2% of patients in the
VANFLYTA arm included neutropenia (11%), thrombocytopenia (5%),
and myelosuppression (3%).
Dose reductions of VANFLYTA due to an adverse
reaction occurred in 19% of patients. Adverse reactions which
required dosage reductions in ≥2% of patients in the VANFLYTA
arm were neutropenia (9%), thrombocytopenia (5%), and
electrocardiogram QT prolonged (4%).
The most common adverse reactions (≥10% with a
difference between arms of ≥2% compared to placebo), including
laboratory abnormalities, were decreased lymphocytes, decreased
potassium, decreased albumin, decreased phosphorus, increased
alkaline phosphatase, decreased magnesium, febrile neutropenia,
diarrhea, mucositis, nausea, decreased calcium, abdominal pain,
sepsis, neutropenia, headache, increased creatine phosphokinase,
vomiting, upper respiratory tract infections,
hypertransaminasemia, thrombocytopenia, decreased appetite,
fungal infections, epistaxis, increased potassium, herpesvirus
infections, insomnia, QT prolongation, increased magnesium,
increased sodium, dyspepsia, anemia, and eye irritation.
Drug
Interactions
Strong CYP3A Inhibitors
VANFLYTA is a CYP3A substrate. Concomitant use
of VANFLYTA with a strong CYP3A inhibitor increases quizartinib
systemic exposure, which may increase the risk of VANFLYTA
adverse reactions. Reduce the dosage of VANFLYTA.
Strong or Moderate CYP3A Inducers
Concomitant use of VANFLYTA with strong or
moderate CYP3A inducers decreases quizartinib systemic exposure,
which may reduce VANFLYTA efficacy. Avoid concomitant use of
VANFLYTA with strong or moderate CYP3A inducers.
QT Interval–Prolonging Drugs
VANFLYTA prolongs the QT/QTc interval.
Coadministration of VANFLYTA with other drugs that prolong the
QT interval may further increase the incidence of QT
prolongation. Monitor patients more frequently with ECG if
coadministration of VANFLYTA with drugs known to prolong the QT
interval is required.
Use in
Specific Populations
Pregnancy
VANFLYTA can cause embryo-fetal harm when
administered to a pregnant woman. Advise pregnant women of the
potential risk to the fetus.
Lactation
Advise women not to breastfeed during treatment
with VANFLYTA and for one month after the last dose.
Females and Males of Reproductive
Potential
Pregnancy
Testing
Verify pregnancy status in females of
reproductive potential within 7 days before starting treatment
with VANFLYTA.
Contraception
Females
Advise female patients of reproductive potential to use
effective contraception during treatment with VANFLYTA and for 7
months after the last dose.
Males
Advise
male patients with female partners of reproductive potential to
use effective contraception during treatment with VANFLYTA and
for 4 months after the last dose.
Infertility
Females
Based on findings from animal studies, VANFLYTA may impair
female fertility. These effects on fertility were reversible.
Males
Based
on findings from animal studies, VANFLYTA may impair male
fertility. These effects on fertility were reversible.
Pediatric
Use
Safety and effectiveness of VANFLYTA have not
been established in pediatric patients.
Geriatric Use
No overall differences in safety or efficacy were
observed between patients 65 years of age and older and younger
adult patients.
Renal Impairment
No dosage adjustment is recommended in patients with
mild to moderate renal impairment (CLcr 30 to 89 mL/min).
VANFLYTA has not been studied in patients with severe renal
impairment (CLcr <30 mL/min).
Hepatic Impairment
No dosage adjustment is recommended in patients with
mild hepatic impairment or moderate hepatic impairment. VANFLYTA
has not been studied in patients with severe hepatic impairment.
To report SUSPECTED ADVERSE
REACTIONS, contact Daiichi Sankyo, Inc, at 1-877-437-7763 or the
FDA at 1-800-FDA-1088 or fda.gov/medwatch.
Please see Full Prescribing Information,
including Boxed WARNINGS, and Medication Guide.
