BRIEF SUMMARY

QUIZARTINIB (July 2023)

Indication- As a part of a treatment for newly  diagnonised active myeloid leukemia

Dosage-   VANFLYTA tablets once daily with or without food at approximately the same time each day.

ADR-  The most common (>20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, potassium decreased, albumin decreased, phosphorus decreased,

CI- Contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias.

Pat Inform- Inform patients of symptoms that may be associated with significant QTc interval prolongation including dizziness, lightheadedness, and fainting.

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U.S. FDA APPROVED DRUGS SURING 2023                                     

Serial No 28.

Name of the Drug-    VANFLYTA

Active Ingredient -   Quizartinib

Pharmacological Classification- To use as a part of a treatment for newly                                                                              diagnonised active myeloid leukemia

                                                                                                                                                Date of Approval-          7/20/23   

  HIGHLIGHTS OF PRESCRIBING NFORMATION-

These highlights do not include all the information needed to use                             VANFLYTA safely and effectively.

See full prescribing information for VANFLYTA. VANFLYTA® (quizartinib) tablets, for oral use

Initial U.S. Approval: 2023

WARNING: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST

See full prescribing information for complete boxed warning.

 VANFLYTA prolongs the QT interval.

 Prior to VANFLYTA 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 VANFLYTA. Do not administer VANFLYTA to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome.

Do not initiate treatment with VANFLYTA or escalate the VANFLYTA 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 VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure.

VANFLYTA is available only through a restricted program called the VANFLYTA Risk Evaluation and Mitigation Strategy (REMS).

INDICATIONS AND USAGE-

VANFLYTA is a kinase inhibitor 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. 

ADVERSE REACTIONS-

 The most common (>20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, potassium decreased, albumin decreased, phosphorus decreased, alkaline phosphatase increased, magnesium decreased, febrile neutropenia, diarrhea, mucositis, nausea, calcium decreased, abdominal pain, sepsis, neutropenia, headache, creatine phosphokinase increased, vomiting, and upper respiratory tract infection.

CONTRA-INDICATIONS

 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:                                   Monitor electrocardiograms and levels of serum electrolytes. Reduce, interrupt, or permanently discontinue VANFLYTA as appropriate.

Embryo-Fetal Toxicity:                                                                                         

 VANFLYTA can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. 

 DOSAGE AND ADMINISTRATION-.
 

 Take VANFLYTA tablets orally once daily with or without food at approximately the same time each day.

See Full Prescribing Information for recommended VANFLYTA dosage regimen and dosage modifications.

DOSAGE FORMS AND STRENGTHS-

 Tablets: 17.7 mg or 26.5 mg.

PATIENT COUNSELING INFORMATION-

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

QT Prolongation, Torsades de Pointes, and Cardiac Arrest-

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

 VANFLYTA REMS VANFLYTA is available only through a restricted program called the VANFLYTA REMS. Inform patients that they will be given a VANFLYTA 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

Drug Interactions-

Advise patients to inform their healthcare providers of all concomitant medications, including over-thecounter medications, vitamins, and herbal products.

Advise patients to avoid concomitant use of St. John’s wort as it is a strong CYP3A inducer

Embryo-Fetal Toxicity and Use of Contraceptives-

 Advise pregnant women of the potential risk to the fetus.

Advise female patients of reproductive potential to use effective contraception during treatment with VANFLYTA 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 VANFLYTA treatment.

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-

Advise females and males of reproductive potential that VANFLYTA may impair fertility

Lactation-

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

Dosing and Storage Instructions-

 Advise patients that VANFLYTA 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 VANFLYTA 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 of VANFLYTA 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. ? Store VANFLYTA at room temperature from 20°C to 25°C (68°F to 77°F). 

Manufactured for: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 VANFLYTA® is a registered trademark of Daiichi Sankyo Company, Ltd. Copyright © 2023, Daiichi Sankyo, Inc. USPI-VAN-C1-0723-r001

CLINICAL PHARMACOLOGY

1 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.

2. Pharmacodynamics- The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of quizartinib have not been fully characterized.

Cardiac Electrophysiology-                                                                                            In vitro studies have shown that quizartinib is a predominant inhibitor of the slow delayed rectifier potassium current, IKs.

The exposure-response analysis predicted a concentration-dependent QTcF interval median prolongation of 18 and 24 ms [upper bound of 2-sided 90% confidence interval (CI): 21 and 27 ms] at the median steady-state Cmax of quizartinib at the 26.5 mg and 53 mg dose level during maintenance therapy

3 Pharmacokinetics-                                                                                                           The pharmacokinetics of quizartinib and its major circulating active metabolite (AC886) were characterized in healthy subjects and in patients with cancer and are presented as geometric mean (percent coefficient of variation [%CV]) unless otherwise specified.

Steady state exposure following 35.4 mg VANFLYTA once daily during consolidation therapy in patients with newly diagnosed AML Cmax 204 ng/mL (64%) 172 ng/mL (47%) AUC0-24h 3,930 ng•h/mL (78%) 3,800 ng•h/mL (46%)

Steady state exposure following 53 mg VANFLYTA once daily during maintenance therapy in patients with newly diagnosed AML Cmax 529 ng/mL (60%) 262 ng/mL (48%) AUC0-24h 10,200 ng•h/mL (75%) 5,790 ng•h/mL (46%) Accumulation ratio* (AUC0-24h) 5.4 (4.4) 8.7 (6.8) *Mean (±SD)

Absorption-                                                                                                                   The mean (SD) absolute bioavailability of quizartinib from the tablet formulation was 71% (±7%) in healthy subjects.

After oral administration under fasted conditions, time to peak concentration (median Tmax) of Reference ID: 5212288 14 quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively, in healthy subjects.

No clinically significant differences in the pharmacokinetics of quizartinib were observed when administered with a high-fat, high-calorie meal.

Distribution-                                                                                                                      Volume of distribution at steady state in healthy subjects was estimated to be 275 L (17%). In vitro plasma protein binding of quizartinib and AC886 is 99% or greater. In vitro blood-to-plasma ratio for quizartinib and AC886 ranges from 0.79-1.30 and 1.36-3.19, respectivel

Elimination-                                                                                                                  Total body clearance of quizartinib in healthy subjects was estimated to be 2.23 L/hour (29%). The mean (SD) effective half-lives (t1/2) in patients with newly diagnosed AML for quizartinib and AC886 during maintenance therapy are 81 hours (±73) and 136 hours (±113), respectively.

Metabolism-                                                                                                                     In vitro quizartinib is primarily metabolized via oxidation by CYP3A4/5 and AC886 is formed and metabolized by CYP3A4/5.

Specific Populations-                                                                                                There were no clinically significant differences in the exposure of quizartinib and AC886 based on age (range 18 to 91 years), sex, race (White 65%, Asian 18%, Black or African American 9%), or body weight (range 37 to 153 kg).

Patients with Renal Impairment-                                                                                   Mild or moderate renal impairment (i.e., estimated creatinine clearance [CLcr] by Cockcroft-Gault equation: 30 to 89 mL/min) were not associated with clinically significant differences in the exposure of quizartinib and AC886.

The impact of severe renal impairment (CLcr <30 mL/min) on the pharmacokinetics of quizartinib and AC886 is unknown

Patients with Hepatic Impairment-                                                                                  Mild (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 (total bilirubin >1.5 to 3 times ULN and any value for AST) hepatic impairment were not associated with clinically significant differences in the exposure of quizartinib and AC886.

The impact of severe hepatic impairment (Child-Pugh Class C or total bilirubin >3 times ULN and any value for AST) on the pharmacokinetics of quizartinib and AC886 is unknown

 Drug Interaction Studies and Model-Informed Approaches Reference ID: 5212288 15 Clinical Studies Strong CYP3A Inhibitors

The AUC of quizartinib increased by 94% and the Cmax by 17% following coadministration of a single 53 mg quizartinib dose with ketoconazole (a strong CYP3A inhibitor). The AUCinf of AC886 decreased by 94% and Cmax by 60%.

Moderate CYP3A Inhibitors A clinically significant change in quizartinib and AC886 exposure (Cmax and AUCinf) was not observed following coadministration of a single quizartinib dose with fluconazole (a moderate CYP3A inhibitor).

Strong or Moderate CYP3A Inducers-                                                                               The AUCinf of quizartinib decreased by 90% and Cmax by 45% following concomitant use of a single 53 mg dose of quizartinib with efavirenz (a moderate CYP3A inducer). The AUC of AC886 decreased by 96% and the Cmax by 68%.

The effect of concomitant use with a strong CYP3A inducer may result in even greater effect on quizartinib pharmacokinetics based on mechanistic understanding of the drugs involved.

Gastric Acid Reducing Agents-                                                                                    No clinically significant differences in quizartinib pharmacokinetics were observed when used concomitantly with lansoprazole (a proton pump inhibitor that reduces gastric acid).

Other Drugs-                                                                                                              There were no clinically significant differences in the pharmacokinetics of P-gp substrates (dabigatran etexilate) or UGT1A1 substrates (raltegravir) when used concomitantly with quizartinib. In Vitro Studies Cytochrome P450 (CYP)

 USE IN SPECIFIC P0OPULATIONS

1. Pregnancy Risk Summary -

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

There are no available data on VANFLYTA use in pregnant women to evaluate for a drug-associated risk.

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.

2 Lactation Risk Summary 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 VANFLYTA and for one month after the last dose.

3. Females and Males of Reproductive Potential-

VANFLYTA can cause embryo-fetal harm when administered to pregnant women

Pregnancy Testing-                                                                                                          Verify pregnancy status in females of reproductive potential within seven 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-                                                                                                                        Based on genotoxicity findings, 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

4. Pediatric Use-

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

5. Geriatric Use-

There were 533 patients with newly diagnosed AML in the clinical study; of the total number of VANFLYTA-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.

6. Renal impairment- 

No dosage adjustment is recommended in patients with mild to moderate renal impairment (i.e., estimated creatinine clearance [CLcr] by Cockcroft-Gault equation: CLcr 30 to 89 mL/min). VANFLYTA has not been studied in patients with severe renal impairment (CLcr <30 mL/min)

7. 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).

VANFLYTA 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