Quizartinib (Monograph)

Brand name: Vanflyta
Drug class: Antineoplastic Agents

Introduction

Quizartinib dihydrochloride, a kinase inhibitor, is an antineoplastic agent.

Uses for Quizartinib

Quizartinib dihydrochloride has the following uses:

Quizartinib 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.

Quizartinib is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with quizartinib in this setting has not been demonstrated.

Quizartinib Dosage and Administration

General

Quizartinib dihydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 17.7 mg (of quizartinib) or 26.5 mg (of quizartinib).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Select patients for treatment based on the presence of FLT3-ITD mutation positivity.

• 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.

• See Full Prescribing Information for recommended quizartinib dosage regimen and dosage modifications.

Cautions for Quizartinib

Contraindications

Patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or a history of ventricular arrhythmias or torsades de pointes.

Warnings/Precautions

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, I_Ks, as compared to all other medications that prolong the QTc interval, which is via the rapid delayed rectifier potassium current, I_Kr. Therefore, the level of QTc prolongation with quizartinib that predicts the risk of cardiac arrhythmias is unclear. Inhibition of I_Ksand I_Kr 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.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, quizartinib can cause embryo-fetal harm when administered to a pregnant woman.

There are no available data on quizartinib use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day). Advise pregnant women of the potential risk to a fetus.

The background risk in the U.S. general population of major birth defects is 2-4%, and of miscarriage is 15-20% of clinically recognized pregnancies.

Lactation

There are no data on the presence of quizartinib or its metabolites in human milk, or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with quizartinib and for one month after the last dose.

Females and Males of Reproductive Potential

Quizartinib can cause embryo-fetal harm when administered to pregnant women.

Verify pregnancy status in females of reproductive potential within seven days before starting treatment with quizartinib.

Advise female patients of reproductive potential to use effective contraception during treatment with quizartinib and for 7 months after the last dose.

Based on genotoxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment with quizartinib and for 4 months after the last dose.

Based on findings from animal studies, quizartinib may impair female fertility. These effects on fertility were reversible.

Based on findings from animal studies, quizartinib may impair male fertility. These effects on fertility were reversible.

Pediatric Use

Safety and effectiveness of quizartinib have not been established in pediatric patients.

Geriatric Use

There were 533 patients with newly diagnosed AML in the clinical study; of the total number of quizartinib-treated patients, 69 (26%) were 65 years of age and older, while 1 (0.4%) was 75 years of age. 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 (i.e., estimated creatinine clearance [CL_cr] by Cockcroft-Gault equation: CL_cr 30 to 89 mL/minute). Quizartinib has not been studied in patients with severe renal impairment (CL_cr <30 mL/minute).

Hepatic Impairment

No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A or total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1 to 1.5 times ULN and any value for AST) or moderate hepatic impairment (Child-Pugh Class B or total bilirubin >1.5 to 3 times ULN and any value for AST). Quizartinib has not been studied in patients with severe (Child-Pugh Class C or total bilirubin >3 times ULN and any value for AST) hepatic impairment.

Common Adverse Effects

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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A Inhibitors: Reduce the quizartinib dose.

• Strong or Moderate CYP3A Inducers: Avoid concomitant use.

Actions

Mechanism of Action

Quizartinib is a small molecule inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major active metabolite AC886 bind to the adenosine triphosphate (ATP) binding domain of FLT3 with comparable affinity, and both had 10-fold lower affinity towards FLT3-ITD mutation compared to FLT3 in a binding assay. Quizartinib and AC886 inhibited FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting downstream FLT3 receptor signaling and blocking FLT3-ITD-dependent cell proliferation. Quizartinib showed antitumor activity in a mouse model of FLT3-ITD-dependent leukemia.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Inform patients of symptoms that may be associated with significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider.

• Advise patients that quizartinib is available only through a restricted program called the Vanflyta REMS. Inform patients that they will be given a quizartinib Patient Wallet Card that they should carry with them at all times and show to all of their healthcare providers. This card describes signs and symptoms related to QT prolongation/cardiac arrhythmia which, if experienced, should prompt the patient to immediately seek medical attention.

• Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products. Advise patients to avoid concomitant use of St. John's wort as it is a strong CYP3A inducer.

• Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with quizartinib and for 7 months after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during quizartinib treatment. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with quizartinib and for 4 months after the last dose.

• Advise females and males of reproductive potential that quizartinib may impair fertility.

• Advise women not to breastfeed during treatment with quizartinib and for one month after the last dose.

• Advise patients that quizartinib should be taken once daily at approximately the same time each day and may be taken with or without food.

• Advise patients to swallow tablets whole. Advise patients not to cut, crush, or chew the tablets.

• Instruct patients that if a dose of quizartinib is vomited, not to take an additional dose that day, and to wait until the next scheduled dose on the following day. If a dose is missed or not taken at the usual time, instruct patients to take the dose as soon as possible on the same day and return to the usual dosing schedule the following day.

• Instruct patients to store quizartinib at room temperature from 20°C to 25°C (68°F to 77°F).

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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