Quizartinib Dihydrochloride (Monograph)

Brand name: Vanflyta
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for quizartinib to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of quizartinib and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Warning

Quizartinib prolongs the QT interval in a dose- and concentration-related manner. Prior to administration and periodically, monitor for hypokalemia or hypomagnesemia, and correct deficiencies. Perform ECGs to monitor the QTc at baseline, weekly during induction and consolidation therapy, weekly for at least the first month of maintenance, and periodically thereafter.
Torsades de pointes and cardiac arrest have occurred in patients receiving quizartinib. Do not administer to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome.
Do not initiate or escalate dosage if the QT interval corrected by the Fridericia's formula (QTcF) is greater than 450 ms.
Monitor ECGs more frequently if concominant use of drugs known to prolong the QT interval is required.
Reduce the quizartinib dosage when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure.
Because of the risk of QT prolongation, quizaritinib is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vanflyta REMS.

Introduction

Antineoplastic; receptor tyrosine kinase FLT3 inhibitor.

Uses for Quizartinib Dihydrochloride

Acute Myeloid Leukemia

Used in combination with standard cytarabine and anthracycline induction and cytarabine consolidation therapies, 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 (designated an orphan drug by FDA for this use).

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

Quizartinib Dihydrochloride Dosage and Administration

General

Pretreatment Screening

Obtain baseline ECG; do not initiate treatment if the QT interval corrected by Fridericia's formula (QTcF) is >450 ms.
Evaluate for and correct hypokalemia and hypomagnesemia prior to treatment.
Select patients for treatment of AML with quizartinib based on the presence of FLT3-ITD mutation positivity, as detected by an FDA-approved test.
Verify pregnancy status in females of reproductive potential within 7 days prior to starting treatment.

Patient Monitoring

Monitor ECG weekly (or more frequently if indicated) during induction and consolidation. During maintenance, monitor ECG weekly during the first month following dosage initiation and escalation, then periodically as clinically indicated. Do not escalate quizartinib dosage if QTcF is >450 ms.
Monitor for hypokalemia and hypomagnesemia periodically during therapy and correct deficiencies if present.

REMS Program

Available only through the Vanflyta Risk Evaluation and Mitigation Strategy (REMS) program due to serious risks of QT prolongation, torsades de pointes, and cardiac arrest.
Prescribers must be certified in the Vanflyta REMS by enrolling and completing training.
Prescribers must counsel patients 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 by the Vanflyta REMS and must verify that prescribers are certified through the Vanflyta REMS.
Further information about the Vanflyta REMS is available at [Web] or by phone at 1-855-212-6670.

Other General Considerations

For patients who proceed to hematopoietic stem cell transplantation (HSCT), stop quizartinib 7 days before starting a conditioning regimen.

Administration

Administer orally with or without food at approximately the same time each day. Swallow tablets whole. Do not cut, crush, or chew.

If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose is missed or not taken at the usual time, administer as soon as possible on the same day and return to the usual schedule the following day. Do not administer two doses on the same day.

Dosage

Dosage of quizartinib dihydrochloride expressed in terms of quizartinib.

Adults

Acute Myeloid Leukemia

Oral

For induction: up to 2 cycles in combination with cytarabine and anthracycline.

For consolidation: up to 4 cycles in combination with high dose cytarabine.

For maintenance: initiate following consolidation chemotherapy upon blood count recovery of ANC >500/mm³ and platelet count >50,000/mm³. Administer up to 36 cycles or until disease progression or unacceptable toxicity occurs.

See Table 1 for dosage recommendations.

Patients can receive up to 2 cycles of induction. If a 5+2 regimen is used for the second induction cycle, quizartinib is given on days 6–19.

Patient can receive up to 4 cycles of consolidation.

Table 1. Quizartinib Dosage Regimen.1
	Induction	Consolidation	Maintenance
Dose	35.4 mg once daily starting on day 8 (for 7+3 regimen)	35.4 mg once daily starting on day 6	Administer 26.5 mg once daily on days 1–14 of the first cycle if QTcF is ≤450 ms. Increase dosage to 53 mg once daily on day 15 of the first cycle if QTcF is ≤450 ms. Maintain the 26.5 mg once daily dosage if QTcF >500 ms was observed during induction or consolidation.
Duration (28-day cycles)	Two weeks in each cycle (days 8–21 for 7+3 regimen)	Two weeks in each cycle (days 6–19)	Once daily with no break between cycles for up to 36 cycles

<C> Dosage Modification for Toxicity

Dosage modifications are recommended for adverse reactions (see Tables 2 and 3).

Recommend bone marrow evaluation.

Table 2. Recommended Dosage Modifications for Adverse Reactions.1
Adverse reaction	Recommended Action
QTcF 450–480 ms (Grade 1)	Continue current dose.
QTcF 481–500 ms (Grade 2)	Reduce the dosage without interruption (see Table 3). Resume at the previous dosage in the next cycle if QTcF has decreased to <450 ms. Monitor closely for QT prolongation during the first cycle at the increased dosage.
QTcF >500 ms (Grade 3)	Interrupt quizartinib treatment. Resume at a reduced dose (see Table 3) when QTcF returns to <450 ms. Maintain the 26.5 mg once daily dosage during maintenance if QTcF >500 ms was observed during induction or consolidation.
Recurrent QTcF >500 ms (Grade 3)	Permanently discontinue quizartinib if QTcF >500 ms recurs despite appropriate dosage reduction and correction/elimination of other risk factors (e.g., serum electrolyte abnormalities, concomitant QT prolonging medications).
Torsades de pointes, polymorphic ventricular tachycardia, signs/symptoms of life-threatening arrhythmia (Grade 4)	Permanently discontinue quizartinib.
Grade 3 or 4 hypokalemia (<3 mmol/L) or hypomagnesemia (<0.4 mmol/L or <0.9 mg/dL)	Interrupt quizartinib treatment Correct hypokalemia and hypomagnesemia according to institutional guidelines. Restart quizartinib at previous dosage when the adverse reaction improves to Grade 2 or less without symptoms.
Grade 4 neutropenia or thrombocytopenia after achieving remission	Reduce quizartinib dosage (see Table 3).
Grade 3 or 4 non-hematologic adverse reactions	Interrupt quizartinib treatment. Resume treatment at the previous dosage if adverse reaction improves to Grade 1 or less. Resume treatment at a reduced dosage (see Table 3) if adverse reaction improves to Grade 2. Discontinue quizartinib if Grade 3 or 4 adverse reaction persists beyond 28 days.

Table 3. Recommended Dosage Adjustments for Adverse Reactions.1
Current Dosage	Modified Dosage
53 mg once daily	35.4 mg once daily
35.4 mg once daily	26.5 mg once daily
26.5 mg once daily	Interrupt
17.7 mg once daily	Interrupt

<C> Dosage Modifications for Concomitant Strong CYP3A Inhibitors

Reduce dosage of quizartinib when used concomitantly with strong CYP3A inhibitors (see Table 4). If current dosage is 17.7 mg once daily, interrupt quizartinib treatment for the duration of strong CYP3A inhibitor use. After discontinuation of a strong CYP3A inhibitor for 5 half-lives, resume the quizartinib dosage that was taken before initiating the strong inhibitor.

Table 4. Dosage Adjustments for Concomitant Use with Strong CYP3A Inhibitors.1
Current Dosage	Modified Dosage
53 mg once daily	26.5 mg once daily
35.4 mg once daily	17.7 mg once daily
26.5 mg once daily	17.7 mg once daily

Special Populations

Hepatic Impairment

No dosage adjustment recommended in mild hepatic impairment (Child-Pugh Class A; total bilirubin less than or equal to ULN and AST greater than ULN; or total bilirubin >1 to 1.5 times ULN with any AST) or moderate hepatic impairment (Child-Pugh Class B or total bilirubin >1.5 to 3 times ULN with any AST). Not studied in severe hepatic impairment.

Renal Impairment

No dosage adjustment recommended in mild or moderate renal impairment (Cl_cr 30–89 mL/min). Not studied in severe renal impairment.

Geriatric Patients

No recommendations at this time.

Cautions for Quizartinib Dihydrochloride

Contraindications

Severe hypokalemia.
Severe hypomagnesemia.
Long QT syndrome.
History of ventricular arrhythmias.
History of torsades de pointes.

Warnings/Precautions

Warnings

QT Prolongation, Torsades de Pointes, and Cardiac Arrest

Risk of QT prolongation, torsades de pointes, and cardiac arrest (see Boxed Warning).

Quizartinib prolongs the QT interval in a dose- and concentration-dependent manner via inhibition of the slow delayed rectifier potassium current. Level of QTc prolongation with quizartinib that predicts the risk of cardiac arrhythmias unclear. Torsades de pointes, ventricular fibrillation, cardiac arrest, and sudden death reported.

Do not initiate treatment if QT interval corrected by Fridericia's formula (QTcF) interval >450 ms. Do not use in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. 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.

Perform ECG and correct electrolyte abnormalities prior to initiating treatment. During induction and consolidation, perform ECG prior to initiation and then once weekly during treatment or more frequently as clinicially indicated. During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dosage initiation and escalation, and as clinically indicated thereafter. Do not escalate dosage if QTcF >450 ms.

Monitor QT interval more frequently in patients who are at significant risk of developing QT interval prolongation and torsades de pointes, or following dosage escalation.

Monitor and correct hypokalemia and hypomagnesemia prior to and during treatment. Maintain electrolytes in the normal range. Monitor electrolytes and ECG more frequently in patients with diarrhea or vomiting.

Monitor ECG more frequently if concomitant use of quizartinib with drugs known to prolong the QT interval required. Reduce dosage of quizartinib when using with strong CYP3A inhibitors, as they may increase quizartinib exposure.

Adjust dosage of quizartinib if QTc increases to >480 ms; interrupt quizartinib treatment and reduce dosage if QTc increases to >500 ms. Permanently discontinue quizartinib in patients who develop recurrent QTc >500 ms and patients who develop QTc prolongation with signs or symptoms of life-threatening arrhythmia.

Quizartinib is only available through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vanflyta REMS. For further information, visit the REMS website ([Web]) or call 1-855-212-6670.

Other Warnings and Precautions

Fetal/Neonatal Morbidity and Mortality

Quizartinib can cause fetal harm.

Advise pregnant women of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential within 7 days before starting quizartinib treatment. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Specific Populations

Pregnancy

Based on animal studies and its mechanism of action, quizartinib can cause embryo-fetal harm when administered to a pregant woman. Advise pregnant women of potential risk. Verify pregnancy status in females of reproductive potential within 7 days before starting quizartinib treatment.

Lactation

No data on the presence of quizartinib and its metabolites in human milk, or the effects on the breast-fed child or milk production. Advise women not to breast-feed during treatment and for 1 month after the last dose to avoid potential serious adverse reactions in the breast-fed child.

Females and Males of Reproductive Potential

Can cause embyro-fetal harm. Verify pregnancy status in females of reproductive potential within 7 days before starting treatment.

Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

May cause reversible female and male infertility.

Pediatric Use

Safety and effectiveness not established in pediatric patients.

Geriatric Use

No overall differences in safety or efficacy observed between patients ≥65 years of age and younger adult patients.

Hepatic Impairment

Mild or moderate hepatic impairment had no clinically significant impact on exposure to quizartinib or its active metabolite AC886; no dosage adjustment required. Not studied in severe hepatic impairment (Child-Pugh Class C or total bilirubin >3 times ULN with any AST).

Renal Impairment

Mild or moderate renal impairment had no clinically significant impact on exposure to quizartinib or its active metabolite AC886; no dosage adjustment required. Not studied in severe renal impairment (Cl_cr <30 mL/min).

Common Adverse Effects

The most common adverse reactions, occuring in >20% of patients receiving quizartinib, included decreased lymphocytes, decreased potassium, decreased albumin, decreased phosphorus, decreased magnesium, increased alkaline phosphatase, febrile neutropenia, diarrhea, mucositis, nausea, decreased calcium, abdominal pain, sepsis, neutropenia, headache, increased creatine phosphokinase, vomiting, and upper respiratory tract infection.

Drug Interactions

Quizartinib is a CYP3A4/5 and P-glycoprotein (P-gp) substrate; its active metabolite, AC886, is a substrate for breast cancer resistance protein (BCRP).

Quizartinib is not a substrate of BCRP, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, organic anion transporter (OAT) 2, multidrug and toxin extrusion (MATE) 1, or multidrug resistance protein (MRP) 2. It does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. It does inhibit UDP-glucuronosyltransferase (UGT) 1A1. Quizartinib does not induce CYP3A4, CYP1A2, or CYP2B6.

AC886 is not a substrate for OATP1B1, OATP1B3, MATE1, or MRP2. It does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. It does not induce CYP3A4, CYP1A2, or CYP2B6.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increases quizartinib systemic exposure, which may increase risk of quizartinib adverse reactions. Reduce quizartinib dosage when using concomitantly with a strong CYP3A inhibitor.

Strong or Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreases quizartinib systemic exposure which may reduce quizartinib efficacy. Avoid concomitant use with strong or moderate CYP3A inducers.

Drugs Associated with QT Prolongation

Coadministration with other drugs that prolong the QT interval may further increase incidence of QT prolongation. Monitor patients more frequently with ECG if coadministration of quizartinib with drugs known to prolong the QT interval required (e.g., antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine, tacrolimus).

Specific Drugs

Drug	Interaction	Comments
Dabigatran	No clinically significant differences in pharmacokinetics of dabigatran observed.
Efavirenz	AUC of quizartinib decreased by 90% and maximum concentration decreased by 45%. AUC of AC886 decreased by 96% and maximum concentration decreased by 68%.	Avoid concomitant use.
Fluconazole	Clinically significant change in quizartinib and AC886 exposure not observed.
Ketoconazole	AUC of quizartinib increased by 94% and maximum concentration increased by 17% following coadministration. AUC of AC886 decreased by 94% and maximum concentration decreased by 60%.	Reduce quizartinib dosage when used concomitantly.
Lansoprazole	No clinically significant differences in quizartinib pharmacokinetics observed.
Raltegravir	No clinically significant differences in pharmacokinetics of raltegravir observed.

Quizartinib Dihydrochloride Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability (oral tablet): 71%.

Time to maximum concentration: 4 hours (range: 2–8 hours) for quizartinib; 5–6 hours (range: 4–120 hours) for AC886 (active metabolite).

Steady state quizartinib concentrations achieved at day 15.

Distribution

Extent

Unknown if distributed in human milk.

Plasma Protein Binding

Quizartinib and AC886: ≥99%.

Elimination

Metabolism

Quizartinib: oxidation by CYP3A4/5.

AC886 (active metabolite): formed and metabolized by CYP3A4/5.

Elimination Route

Fecal excretion: 76.3% (4% as unchanged drug).

Urinary excretion: 1.64%.

Half-life

Quizartinib: 81 hours.

AC886: 136 hours.

Special Populations

No clinically significant differences in exposure of quizartinib or AC886 based on age (range: 18–91 years), sex, race, or body weight (range: 37–153 kg).

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Inhibitor of receptor tyrosine kinase FLT3.
Quizartinib and active metabolite AC886 bind to adenosine triphosphate binding domain of FLT3 with comparable affinity, thereby inhibiting FLT3 kinase activity and preventing autophosphorylation of the receptor.
Inhibits downstream FLT3 receptor signaling and blocks FLT3 internal tandem duplication (ITD)-dependent cell proliferation.
Antitumor activity observed in mouse model of FLT3 ITD-dependent leukemia.
Inhibits the slow delayed rectifier potassium current, causing concentration-dependent QT prolongation.

Advice to Patients

Advise patients to report symptoms of significant QTc interval prolongation such as dizziness, lightheadedness, and fainting. Advise patients to report use of all medications to their healthcare provider.
Instruct patients to carry their provided Vanflyta Patient Wallet Card at all times and to show the card to all healthcare providers. The card describes signs and symptoms related to QT prolongation/cardiac arrhythmia which, if experienced, should prompt the patient to seek immediate medical attention.
Advise pregnant women of potential fetal risk. Advise females of reproductive potential to use effective contraception during treatment 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. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.
Advise males and females of reproductive potential of the risk of infertility.
Advise women not to breast-feed during treatment and for 1 month after the last dose.
Advise patients to take quizartinib once daily at approximately the same time each day; tablets should be swallowed whole and not crushed, cut, or chewed. Advise patients that, if a dose if vomited, they should not take an additional dose that day; instead, they should wait until the next scheduled dose on the following day. If a dose of quizartinib is missed or not taken at the usual time, the patient should take the dose as soon as possible on the same day and return to the usual dosing schedule the following day.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Distribution of quizartinib is restricted (see REMS under Dosage and Administration). Quizartinib is available only through the Vanflyta REMS program. Contact the manufacturer or consult the manufacturer website for specific availability information.