Quizartinib

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 for Adverse Events version 4.03 (NCI CTCAE v4.03). QTcF between 450 ms and 480 ms (Grade 1) Continue VANFLYTA dose. QTcF between 481 ms and 500 ms (Grade 2) Reduce the dose of VANFLYTA (see Table 3 ) without interruption. Resume VANFLYTA at the previous dose in the next cycle if QTcF has decreased to less than 450 ms. Monitor the patient closely for QT prolongation during the first cycle at the increased dose. QTcF greater than 500 ms (Grade 3) Interrupt VANFLYTA. Resume VANFLYTA at a reduced dose (see Table 3 ) when QTcF returns to less than 450 ms. Maintain the 26.5 mg once daily dose during maintenance if QTcF greater than 500 ms was observed during induction or consolidation. Recurrent QTcF greater than 500 ms (Grade 3) Permanently discontinue VANFLYTA if QTcF greater than 500 ms recurs despite appropriate dose 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 VANFLYTA. Grade 3 or 4 non-hematologic adverse reactions Interrupt VANFLYTA. Resume treatment at the previous dose if adverse reaction improves to Grade 1 or less. Resume treatment at a reduced dose (see Table 3 ) if adverse reaction improves to Grade 2. Discontinue if Grade 3 or 4 adverse reaction persists beyond 28 days. Grade 3 or 4 hypokalemia (<3 mmol/L) or hypomagnesemia (<0.4 mmol/L or <0.9 mg/dL) Interrupt VANFLYTA. Correct hypokalemia and hypomagnesemia according to institutional guidelines. VANFLYTA may be restarted at the previous dose when the adverse reaction improves to Grade 2 or less without symptoms. Grade 4 neutropenia or thrombocytopenia after achieving remission Recommend bone marrow evaluation. Reduce VANFLYTA dose (see Table 3 ). Table 3: Recommended Dosage Adjustments for Adverse Reactions for VANFLYTA 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 2.4 Dosage Modifications for Strong CYP3A Inhibitors Reduce the dosage of VANFLYTA when used concomitantly with strong CYP3A inhibitors as shown in Table 4. If the current dosage is 17.7 mg once daily, interrupt VANFLYTA treatment for the duration of strong CYP3A inhibitor use. After discontinuation of a strong CYP3A inhibitor for 5 half-lives, resume the VANFLYTA dose that was taken before initiating the strong inhibitor [see Drug Interactions (7) ] . Table 4: Dosage Adjustments for Concomitant Use with Strong CYP3A Inhibitors 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

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 Between Arms of ≥2% Compared to Placebo) in the Clinical Trial Body System Adverse Reaction VANFLYTA + Chemotherapy (N=265) PLACEBO + Chemotherapy (N=268) All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Blood and Lymphatic System Disorders Febrile neutropenia Including fatalities. 44 43 42 41 Neutropenia Includes other related terms. 29 26 14 12 Thrombocytopenia 18 13 13 12 Anemia 11 6 7 5 Gastrointestinal Disorders Diarrhea Diarrhea includes colitis, diarrhea, enteritis, enterocolitis, gastroenteritis, and neutropenic colitis. 42 8 39 8 Mucositis Mucositis includes anal inflammation, anal ulcer, anorectal discomfort, aphthous ulcer, laryngeal inflammation, laryngeal pain, mucosal inflammation, edema mucosal, esophageal pain, esophageal ulcer, esophagitis, oral blood blister, oral disorder, oral mucosa erosion, oral mucosal blistering, oral mucosal erythema, oral pain, oropharyngeal pain, pharyngeal inflammation, proctalgia, proctitis, stomatitis, tongue ulceration, and vaginal ulceration. 38 5 33 4.1 Nausea 34 1.5 31 1.9 Abdominal pain 30 2.3 22 1.1 Vomiting 25 0 20 1.5 Dyspepsia 11 0.4 9 0.7 Infections and Infestations Sepsis Sepsis includes acinetobacter infection, bacteremia, bacterial sepsis, corynebacterium bacteremia, device related bacteremia, device related sepsis, enterobacter sepsis, enterococcal bacteremia, enterococcal sepsis, escherichia bacteremia, escherichia sepsis, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal bacteremia, pulmonary sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, staphylococcal sepsis, stenotrophomonas sepsis, streptococcal sepsis, and streptococcal bacteremia. , 30 19 26 20 Upper respiratory tract infection 21 2.6 12 3 Fungal infection Fungal infection includes aspergillosis oral, aspergillus infection, bronchopulmonary aspergillosis, candida infection, candida sepsis, fungal infection, fungal sepsis, fungal skin infection, fusarium infection, gastrointestinal candidiasis, hepatic infection fungal, hepatosplenic candidiasis, lower respiratory tract infection fungal, mucormycosis, oral candidiasis, oral fungal infection, oropharyngeal candidiasis, systemic candida, systemic mycosis, tinea cruris, and vulvovaginal candidiasis. , 16 6 10 3 Herpesvirus infection Herpesvirus infection includes disseminated varicella zoster virus infection, genital herpes, herpes simplex, herpesvirus infection, herpes zoster, oral herpes, and varicella zoster virus infection. 14 2.6 8 1.9 Nervous System Disorders Headache 28 0 20 0.7 Hepatobiliary disorders Hypertransaminasemia Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatic enzymes increased, and hypertransaminasemia. 19 7 14 6 Metabolism and Nutrition Disorders Decreased appetite 17 4.9 13 1.9 Respiratory, Thoracic and Mediastinal Disorders Epistaxis 15 1.1 11 0.4 Psychiatric Disorders Insomnia 14 0 11 0 Investigations Electrocardiogram QT prolonged 14 3 4.1 1.1 Eye Disorders Eye irritation Eye irritation includes dry eye, eye inflammation, eye irritation, eye pain, eye pruritus, foreign body sensation in eyes, keratitis, and ulcerative keratitis. 11 0 7 0 Laboratory Abnormalities Prolonged thrombocytopenia or neutropenia in the absence of active leukemia lasting past cycle day 42 of induction cycle 1 were noted in 8% of patients on the VANFLYTA plus chemotherapy arm and 4% of patients in the placebo plus chemotherapy arm. Table 6: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with Newly Diagnosed FLT3-ITD positive AML (with a Difference Between Arms of ≥2% Compared to Placebo) in the Clinical Trial Laboratory Abnormality VANFLYTA + Chemotherapy The denominator used to calculate the rate varied from 199 to 260 in VANFLYTA + Chemotherapy and from 187 to 267 in PLACEBO + Chemotherapy based on the number of patients with a baseline value and at least one post-treatment value. PLACEBO + Chemotherapy All Grades% Grades 3 or 4% All Grades% Grades 3 or 4% Lymphocytes decreased 60 57 55 51 Potassium decreased 59 22 56 18 Albumin decreased 53 1.6 45 4.3 Phosphorus decreased 52 22 48 19 Alkaline phosphatase increased 51 1.6 47 1.9 Magnesium decreased 44 2 42 1.1 Calcium decreased 33 2.4 27 1.6 Creatine phosphokinase increased 26 2.5 7 0.5 Potassium increased 15 1.2 11 0.8 Magnesium increased 14 2.8 9 1.2 Sodium increased 13 0 10 0.4 Other Clinical Trials Clinically relevant adverse reactions in <10% of patients who received quizartinib for relapsed or refractory FLT3-ITD positive AML, an indication for which VANFLYTA is not approved, included differentiation syndrome (5%) and acute febrile neutrophilic dermatosis (3%).

12.3 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 quizartinib concentrations were achieved at Day 15 following once daily dosage in patients with AML. Quizartinib exposure (AUC and C max ) increased proportionally in the dose range of 26.5 mg (0.75 times the recommended 35.4 mg induction dose) to 79.5 mg (2.25 times the recommended 35.4 mg induction dose) in healthy subjects and 17.7 mg (0.5 times the recommended 35.4 mg induction dose) to 53 mg (1.5 times the recommended 35.4 mg induction dose) in patients with AML. Table 8: Pharmacokinetic Properties of Quizartinib and AC886 Quizartinib AC886 General Information Steady state exposure following 35.4 mg VANFLYTA once daily during induction therapy in patients with newly diagnosed AML C max 140 ng/mL (71%) 163 ng/mL (52%) AUC 0-24h 2,680 ng∙h/mL (85%) 3,590 ng∙h/mL (51%) Steady state exposure following 35.4 mg VANFLYTA once daily during consolidation therapy in patients with newly diagnosed AML C max 204 ng/mL (64%) 172 ng/mL (47%) AUC 0-24h 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 C max 529 ng/mL (60%) 262 ng/mL (48%) AUC 0-24h 10,200 ng∙h/mL (75%) 5,790 ng∙h/mL (46%) Accumulation ratio Mean (±SD) (AUC 0-24h ) 5.4 (4.4) 8.7 (6.8) 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 T max ) of 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, respectively. Elimination Total body clearance of quizartinib in healthy subjects was estimated to be 2.23 L/hour (29%). The mean (SD) effective half-lives (t 1/2 ) 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. Excretion Following a single radiolabeled dose of quizartinib 53 mg to healthy subjects, 76.3% of the total radioactivity was recovered in feces (4% unchanged) and 1.64% in urine. 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 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 [see Use in Specific Populations (8.6) ] . 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 [see Use in Specific Populations (8.7) ] . Drug Interaction Studies and Model-Informed Approaches Clinical Studies Strong CYP3A Inhibitors The AUC of quizartinib increased by 94% and the C max 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 C max by 60%. Moderate CYP3A Inhibitors A clinically significant change in quizartinib and AC886 exposure (C max and AUC inf ) was not observed following coadministration of a single quizartinib dose with fluconazole (a moderate CYP3A inhibitor). Strong or Moderate CYP3A Inducers The AUC inf of quizartinib decreased by 90% and C max 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 C max 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) Enzymes Quizartinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Quizartinib does not induce CYP3A4, CYP1A2, or CYP2B6. AC886 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2C19, or CYP3A4. AC886 does not induce CYP3A4, CYP1A2, or CYP2B6. Other Metabolic Pathways Quizartinib inhibits UGT1A1. Transporters Quizartinib is a substrate for P-gp but not for BCRP, OATP1B1, OATP1B3, OCT1, OAT2, MATE1, or MRP2. AC886 is a substrate for BCRP but not for OATP1B1, OATP1B3, MATE1, or MRP2. Quizartinib inhibits BCRP and inhibition of this transporter at the recommended dosage cannot be excluded.