VANFLYTA

1 INDICATIONS AND USAGE 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 [see Dosage and Administration (2.1) and Clinical Studies (14) ] . 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. ( 1 ) 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. ( 1 ) 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 [see Clinical Studies (14) ] .

2 DOSAGE AND ADMINISTRATION Take VANFLYTA tablets orally once daily with or without food at approximately the same time each day. ( 2.2 ) See Full Prescribing Information for recommended VANFLYTA dosage regimen and dosage modifications. ( 2.2 , 2.3 , 2.4 ) 2.1 Patient Selection Select patients for the treatment of AML with VANFLYTA based on the presence of FLT3-ITD mutation positivity [see Clinical Studies (14) ] . Information on FDA-approved tests for the detection of FLT3-ITD mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage A treatment course consists of up to 2 cycles of VANFLYTA in combination with induction cytarabine and anthracycline, up to 4 cycles of VANFLYTA in combination with high-dose cytarabine consolidation, and up to 36 cycles of VANFLYTA as maintenance therapy [see Clinical Studies (14) ] or until disease progression or unacceptable toxicity. VANFLYTA maintenance therapy should be initiated following consolidation chemotherapy upon blood count recovery of absolute neutrophil count >500/mm 3 and platelet count >50,000/mm 3 . See Table 1 for the recommended dosage of VANFLYTA by phase of therapy . Table 1: VANFLYTA Dosage Regimen VANFLYTA Initiation Induction Patients can receive up to 2 cycles of induction. Consolidation Patients can receive up to 4 cycles of consolidation. Maintenance Starting on Day 8 (for 7 + 3 regimen) For 5 + 2 regimen as the second induction cycle, VANFLYTA will be given on Days 6 to 19. Starting on Day 6 Starting on Day 1 Dose 35.4 mg orally once daily 35.4 mg orally once daily Administer 26.5 mg orally once daily Days 1 through 14 of the first cycle if QTcF is less than or equal to 450 ms. Increase the dose to 53 mg once daily on Day 15 of the first cycle if QTcF is less than or equal to 450 ms. Maintain the 26.5 mg once daily dose if QTcF greater than 500 ms was observed during induction or consolidation. Duration (28-day cycles) Two weeks in each cycle (Days 8 to 21) Two weeks in each cycle (Days 6 to 19) Once daily with no break between cycles for up to 36 cycles For patients who proceed to hematopoietic stem cell transplantation (HSCT), VANFLYTA should be stopped 7 days before the start of a conditioning regimen. Administer VANFLYTA orally with or without food at approximately the same time each day. Swallow tablets whole. Do not cut, crush, or chew the tablets. If a dose of VANFLYTA is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of VANFLYTA is missed or not taken at the usual time, administer the dose as soon as possible on the same day and return to the usual schedule the following day. The patient should not take two doses on the same day. 2.3 Monitoring and Dosage Modifications for Adverse Reactions Initiate VANFLYTA only if QTcF is less than or equal to 450 ms [see Warnings and Precautions (5.1) ]. During induction and consolidation, perform ECGs prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated [see Warnings and Precautions (5.1) ]. During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dose initiation and escalation, and thereafter as clinically indicated. Escalate the dose only if QTcF is less than or equal to 450 ms [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ]. Correct electrolyte abnormalities (hypokalemia and hypomagnesemia), and if possible, avoid concomitant administration of drugs that prolong the QT interval [see Warnings and Precautions (5.1) ]. For recommended dosage modifications due to adverse reactions, see Table 2 . For dosage adjustments due to adverse reactions, see Table 3 . Table 2: Recommended Dosage Modifications for Adverse Reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] Adverse Reaction Recommended Action Grades are in accordance with National Cancer Institute Common Terminology Criteria …

3 DOSAGE FORMS AND STRENGTHS Tablets: 17.7 mg quizartinib, white, round, film-coated, debossed with "DSC511" 26.5 mg quizartinib, yellow, round, film-coated, debossed with "DSC512" Tablets: 17.7 mg or 26.5 mg of quizartinib. ( 3 )

4 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 [see Warnings and Precautions (5.1) ]. Contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. ( 4 , 5.1 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: QT Prolongation, Torsades de Pointes, and Cardiac Arrest [see Warnings and Precautions (5.1) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed FLT3-ITD positive AML 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, a randomized, double-blind clinical trial of VANFLYTA (n=265) or placebo (n=268) with chemotherapy [see Clinical Studies (14) ] . Among patients who received VANFLYTA, 38% were exposed for 6 months or longer and 30% were exposed for greater than one year. On the VANFLYTA plus chemotherapy arm, 65% and 44% of patients completed induction and consolidation therapy, respectively, compared to 65% and 34% of patients in the placebo plus chemotherapy arm. 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 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, upper respiratory tract infections, hypertransaminasemia, thrombocytopenia, decreased appetite, fungal infections, epistaxis, potassium increased, herpesvirus infections, insomnia, electrocardiogram QT prolonged, magnesium increased, sodium increased, dyspepsia, anemia, and eye irritation. Tables 5 and 6 summarize adverse reactions and laboratory abnormalities observed in patients receiving VANFLYTA in the clinical trial. Table 5: Adverse Reactions (≥10%) in Patients with Newly Diagnosed FLT3-ITD positive AML Who Received VANFLYTA (with a Difference Betwee …

7 DRUG INTERACTIONS Table 7: Effect of Other Drugs on VANFLYTA Strong CYP3A Inhibitors Clinical Impact VANFLYTA is a CYP3A substrate. Concomitant use of VANFLYTA with a strong CYP3A inhibitor increases quizartinib systemic exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of VANFLYTA adverse reactions. Prevention or Management Reduce the dosage of VANFLYTA [see Dosage and Administration (2.4) ]. Strong or Moderate CYP3A Inducers Clinical Impact Concomitant use of VANFLYTA with strong or moderate CYP3A inducers decreases quizartinib systemic exposure [see Clinical Pharmacology (12.3) ] , which may reduce VANFLYTA efficacy. Prevention or Management Avoid concomitant use of VANFLYTA with strong or moderate CYP3A inducers [see Clinical Pharmacology (12.3) ] . QT Interval Prolonging Drugs Clinical Impact 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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . Prevention or Management Monitor patients more frequently with ECG if co-administration of VANFLYTA with drugs known to prolong the QT interval is required. Examples of QT prolonging drugs include but are not limited to antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine, and tacrolimus. Breast Cancer Resistant Protein (BCRP) Substrates Clinical Impact Concomitant use of VANFLYTA with BCRP substrates may increase the risk of BCRP substrate-associated adverse reactions [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use of VANFLYTA with drugs that are BCRP substrates where possible. If concomitant use is unavoidable, monitor patients more frequently for BCRP substrate-associated adverse reactions and decrease the BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Strong CYP3A Inhibitors: Reduce the VANFLYTA dose. ( 2.4 , 7 ) Strong or Moderate CYP3A Inducers: Avoid concomitant use. ( 7 , 12.3 ) Breast Cancer Resistant Protein (BCRP) substrates: Avoid concomitant use. ( 7 , 12.3 )

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 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 [see Clinical Pharmacology (12.1) ] . There are no available data on VANFLYTA 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 ( see Data ). 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. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received oral doses of quizartinib of 0, 0.6, 2, or 6 mg/kg/day during the period of organogenesis. Administration of quizartinib at the dose of 6 mg/kg/day was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification). At this dose, the maternal systemic exposures (AUC) were approximately 3 times the human exposure at the MRHD of 53 mg/day. 8.2 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. 8.3 Females and Males of Reproductive Potential VANFLYTA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . 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 [see Nonclinical Toxicology (13.1) ] . Infertility Females Based on findings from animal studies, VANFLYTA may impair female fertility. These effects on fertility were reversible [see Nonclinical Toxicology (13.1) ] . Males Based on findings from animal studies, VANFLYTA may impair male fertility. These effects on fertility were reversible [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness of VANFLYTA have not been established in pediatric patients. 8.5 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 [see Clinical Studies (14) ] . No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger adult patients. 8.6 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 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 [see Clinical Pha …

12.1 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. 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.

11 DESCRIPTION VANFLYTA (quizartinib) is a kinase inhibitor for oral use. The chemical name of quizartinib dihydrochloride is N -(5- tert -butyl-isoxazol-3-yl)- N '-{4-[7-(2-(morpholin-4-ylethoxy)imidazo[2,1- b ][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride. Quizartinib dihydrochloride is a white to off-white solid with a molecular formula of C 29 H 32 N 6 O 4 S∙2 HCl and a molecular weight of 633.6 for the salt and 560.7 for the free base. The aqueous solubility of quizartinib dihydrochloride (pKa 4.75 and 3.16) decreases with increasing pH. It is very slightly soluble in aqueous media at pH 1 and practically insoluble or insoluble at pH 2 and higher. Quizartinib dihydrochloride is very slightly soluble in ethanol. The chemical structure of quizartinib dihydrochloride is: VANFLYTA is supplied as film-coated tablets containing 20 mg and 30 mg quizartinib dihydrochloride equivalent to 17.7 mg or 26.5 mg of quizartinib, respectively. The inactive ingredients in the tablet core are hydroxypropyl betadex, magnesium stearate, and microcrystalline cellulose. The tablet coating consists of hypromellose, talc, titanium dioxide, and triacetin. The 26.5 mg tablet coating also contains ferric oxide. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING VANFLYTA (quizartinib) is supplied as round, film-coated tablets, packaged in bottles with a child-resistant closure. Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Tablet Strength Tablet Description Package Configuration NDC 17.7 mg White, round, film-coated, debossed with "DSC511" , 28-count bottle 65597-504-28 14-count bottle 65597-504-04 26.5 mg Yellow, round, film-coated, debossed with "DSC512" 28-count bottle 65597-511-28 14-count bottle 65597-511-04