Quizartinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rithish Nimmagadda,MBBS.[2]
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Black Box Warning
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QT Prolongation, Torsades De Pointes, and Cardiac Arrest
See full prescribing information for complete Boxed Warning.
Quizartinib prolongs the QT interval. Prior to drug administration and periodically, perform electrocardiograms (ECGs), monitor for hypokalemia or hypomagnesemia, and correct deficiencies.
Torsades de pointes and cardiac arrest have occurred in patients receiving quizartinib. Do not administer the drug to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome. Do not initiate treatment with quizartinib or escalate the dose if the QT interval corrected by Fridericia's formula (QTcF) is greater than 450 ms. Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. Reduce the quizartinib dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Quizartinib is available only through a restricted program called the Vanflyta Risk Evaluation and Mitigation Strategy (REMS). |
Overview
Quizartinib is a a kinase inhibitor that is FDA approved 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.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include The most common (>20%) adverse reactions, including laboratory abnormalities, are 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, and upper respiratory tract infection..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Take quizartinib tablets orally once daily with or without food at approximately the same time each day. Swallow tablets whole. Do not cut, crush, or chew the tablets.
A treatment course consists of up to 2 cycles of quizartinib in combination with induction cytarabine and anthracycline, up to 4 cycles of quizartinib in combination with high-dose cytarabine consolidation, and up to 36 cycles of quizartinib as maintenance therapy or until disease progression or unacceptable toxicity occurs. Quizartinib maintenance therapy should be initiated following consolidation chemotherapy upon blood count recovery of absolute neutrophil count >500/mm3 and platelet count >50,000/mm3.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of quizartinib have not been established in pediatric patients
Off-Label Use and Dosage (Pediatric)
Contraindications
Patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or a history of ventricular arrhythmias or torsades de pointes
Warnings
|
QT Prolongation, Torsades De Pointes, and Cardiac Arrest
See full prescribing information for complete Boxed Warning.
Quizartinib prolongs the QT interval. Prior to drug administration and periodically, perform electrocardiograms (ECGs), monitor for hypokalemia or hypomagnesemia, and correct deficiencies.
Torsades de pointes and cardiac arrest have occurred in patients receiving quizartinib. Do not administer the drug to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome. Do not initiate treatment with quizartinib or escalate the dose if the QT interval corrected by Fridericia's formula (QTcF) is greater than 450 ms. Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. Reduce the quizartinib dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Quizartinib is available only through a restricted program called the Vanflyta Risk Evaluation and Mitigation Strategy (REMS). |
-QT Prolongation, Torsades De Pointes, and Cardiac Arrest
Quizartinib 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 quizartinib that predicts the risk of cardiac arrhythmias is unclear. Inhibition of IKsand 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 quizartinib.
Of the 1,081 patients with AML treated with quizartinib in clinical trials, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6%, 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 quizartinib 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 (e.g., 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 quizartinib if the QTcF interval is greater than 450 ms. Do not use the drug 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 quizartinib. During induction and consolidation, perform an ECG prior to initiation and then once weekly during therapy 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 quizartinib. 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 quizartinib with drugs known to prolong the QT interval is required.
Reduce the quizartinib dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure.
Reduce quizartinib dose if QTc increases to greater than 480 ms and less than 500 ms. Interrupt therapy and resume at a reduced dose if QTc increases to greater than 500 ms. Permanently discontinue the drug in patients who develop recurrent QTc greater than 500 ms or QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Quizartinib is available only through a restricted program under a REMS.
Quizartinib REMS
Quizartinib 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 REMS include the following:
Prescribers must be certified in the Vanflyta REMS by enrolling and completing training.
Prescribers must counsel patients receiving quizartinib about the risk of QT prolongation, torsades de pointes, and cardiac arrest, and provide patients with a Patient Wallet Card.
Pharmacies that dispense quizartinib must be certified with the Vanflyta REMS and must verify prescribers are certified through the REMS.
Further information about the Vanflyta REMS is available at www.VANFLYTAREMS.com or by telephone at 1-855-212-6670.
Embryo-fetal Toxicity
Based on findings in animals and its mechanism of action, quizartinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of quizartinib to pregnant rats during organogenesis at exposures 3 times the maximum recommended human dose (MRHD) of 53 mg/day caused structural abnormalities and alterations to growth.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with quizartinib and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with quizartinib and for 4 months after the last dose.
Adverse Reactions
Clinical Trials Experience
The most common (>20%) adverse reactions, including laboratory abnormalities, are 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, and upper respiratory tract infection
Postmarketing Experience
There is limited information regarding Quizartinib Postmarketing Experience in the drug label.
Drug Interactions
Strong CYP3A Inhibitors: Reduce the quizartinib dose.
Strong or Moderate CYP3A Inducers: Avoid concomitant use.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Quizartinib in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Quizartinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Quizartinib during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Quizartinib in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Quizartinib in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Quizartinib in geriatric settings.
Gender
There is no FDA guidance on the use of Quizartinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Quizartinib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Quizartinib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Quizartinib in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Quizartinib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Quizartinib in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Quizartinib Administration in the drug label.
Monitoring
There is limited information regarding Quizartinib Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Quizartinib and IV administrations.
Overdosage
There is limited information regarding Quizartinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Quizartinib Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Quizartinib Mechanism of Action in the drug label.
Structure
There is limited information regarding Quizartinib Structure in the drug label.
Pharmacodynamics
There is limited information regarding Quizartinib Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Quizartinib Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Quizartinib Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Quizartinib Clinical Studies in the drug label.
How Supplied
There is limited information regarding Quizartinib How Supplied in the drug label.
Storage
There is limited information regarding Quizartinib Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Quizartinib Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Quizartinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
Vanflyta®
Look-Alike Drug Names
There is limited information regarding Quizartinib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.