VANFLYTA

WARNING: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST VANFLYTA prolongs the QT interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2) ] . Prior to VANFLYTA 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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]. 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 [see Contraindications (4) and Warnings and Precautions (5.1) ] . 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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure [see Dosage and Administration (2.4) and Warnings and Precautions (5.1) ] . Because of the risk of QT prolongation, VANFLYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VANFLYTA REMS [see Warnings and Precautions (5.2) ] . WARNING: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST See full prescribing information for complete boxed warning. VANFLYTA prolongs the QT interval. ( 12.2 ) Prior to VANFLYTA administration and periodically, perform electrocardiograms (ECGs), monitor for hypokalemia or hypomagnesemia, and correct deficiencies. ( 2.3 , 5.1 ) 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. ( 4 , 5.1 ) 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. ( 2.3 , 5.1 ) Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. ( 2.3 , 5.1 ) Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. ( 2.4 , 5.1 ) VANFLYTA is available only through a restricted program called the VANFLYTA Risk Evaluation and Mitigation Strategy (REMS). ( 5.2 )

5 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. ( 2.3 , 5.1 ) 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. ( 5.3 , 8.1 , 8.3 ) 5.1 QT Prolongation, Torsades de Pointes, and Cardiac Arrest VANFLYTA 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 VANFLYTA that predicts the risk of cardiac arrhythmias is unclear. Inhibition of I Ks and I Kr may leave patients with limited reserve leading to a higher risk of QT prolongation and serious cardiac arrhythmias, including fatal outcomes [see Clinical Pharmacology (12.2) ] . Torsades de pointes, ventricular fibrillation, cardiac arrest, and sudden death have occurred in patients treated with VANFLYTA. Of the 1,081 patients with AML treated with VANFLYTA 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 [see Adverse Reactions (6.1) ] . These severe cardiac arrhythmias occurred predominantly during the induction phase. Of the 265 patients with newly diagnosed FLT3-ITD-positive AML treated with VANFLYTA 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 VANFLYTA if the QTcF interval is greater than 450 ms. Do not use VANFLYTA in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes [see Contraindications (4) ] . Perform an ECG and correct electrolyte abnormalities prior to initiation of treatment with VANFLYTA. During induction and consolidation, perform an ECG prior to initiation and then once weekly during VANFLYTA treatment 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 [see Dosage and Administration (2.3) ] . 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 VANFLYTA. 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 VANFLYTA with drugs known to prolong the QT interval is required [see Drug Interactions (7) ] . Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure [see Dosage and Administration (2.4) ] . Reduce VANFLYTA if QTc increases to greater than 480 ms and less than 500 ms. Interrupt and reduce VANFLYTA if QTc increases to greater than 500 ms. Permanently discontinue VANFLYTA in patients who develop recurrent QTc greater than 500 ms or QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration (2.3) ] . VANFLYTA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 VANFLYTA REMS VANFLYTA 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 [see Warnings and Precautions (5.1) ] . Notable requirements of the VANFLYTA REMS include the following: Prescribers must be certified in the VANFLYTA REMS by enrolling and completing training. Prescribers must counsel patients receiving VANFLYTA about the risk of QT prolongation, torsades de pointes, and cardiac arrest, and provide patients with a Patient Wallet Card. Pharmacies that dispense VANFLYTA must be certified with the VANFLYTA REMS and must verify prescribers are certified through the VANFLYTA REMS. Further information about the VANFLYTA REMS is available at www.VANFLYTAREMS.com or by telephone at 1-855-212-6670. 5.3 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, VANFLYTA 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 VANFLYTA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

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%).

<table width="80%"><caption>Table 5: Adverse Reactions (&#x2265;10%) in Patients with Newly Diagnosed FLT3-ITD positive AML Who Received VANFLYTA (with a Difference Between Arms of &#x2265;2% Compared to Placebo) in the Clinical Trial</caption><col width="32%" align="left" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Body System Adverse Reaction</th><th styleCode="Rrule" colspan="2">VANFLYTA + Chemotherapy (N=265)</th><th styleCode="Rrule" colspan="2">PLACEBO + Chemotherapy (N=268)</th></tr><tr><th styleCode="Rrule" align="center">All Grades %</th><th styleCode="Rrule">Grade 3 or 4 %</th><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grade 3 or 4 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Febrile neutropenia<footnote ID="ft1">Including fatalities.</footnote></td><td styleCode="Rrule">44</td><td styleCode="Rrule">43</td><td styleCode="Rrule">42</td><td styleCode="Rrule">41</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia<footnote ID="ft2">Includes other related terms.</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">26</td><td styleCode="Rrule">14</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">18</td><td styleCode="Rrule">13</td><td styleCode="Rrule">13</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">11</td><td styleCode="Rrule">6</td><td styleCode="Rrule">7</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea<footnote>Diarrhea includes colitis, diarrhea, enteritis, enterocolitis, gastroenteritis, and neutropenic colitis.</footnote></td><td styleCode="Rrule">42</td><td styleCode="Rrule">8</td><td styleCode="Rrule">39</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Mucositis<footnote>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.</footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">5</td><td styleCode="Rrule">33</td><td styleCode="Rrule">4.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">34</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">31</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">30</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">22</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">25</td><td styleCode="Rrule">0</td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspepsia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections and Infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sepsis<footnote>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.</footnote>^,<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">30</td><td styleCode="Rrule">19</td><td styleCode="Rrule">26</td><td styleCode="Rrule">20</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">21</td><td styleCode="Rrule">2.6</td><td styleCode="Rrule">12</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fungal infection<footnote>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.</footnote>^,<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">16</td><td styleCode="Rrule">6</td><td styleCode="Rrule">10</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Herpesvirus infection<footnote>Herpesvirus infection includes disseminated varicella zoster virus infection, genital herpes, herpes simplex, herpesvirus infection, herpes zoster, oral herpes, and varicella zoster virus infection.</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">2.6</td><td styleCode="Rrule">8</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">28</td><td styleCode="Rrule">0</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Hepatobiliary disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertransaminasemia<footnote>Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatic enzymes increased, and hypertransaminasemia.</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">7</td><td styleCode="Rrule">14</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Lrule Rrule">17</td><td styleCode="Lrule Rrule">4.9</td><td styleCode="Lrule Rrule">13</td><td styleCode="Lrule Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Epistaxis</td><td styleCode="Lrule Rrule">15</td><td styleCode="Lrule Rrule">1.1</td><td styleCode="Lrule Rrule">11</td><td styleCode="Lrule Rrule">0.4</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Electrocardiogram QT prolonged<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">14</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4.1</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Eye Disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Eye irritation<footnote>Eye irritation includes dry eye, eye inflammation, eye irritation, eye pain, eye pruritus, foreign body sensation in eyes, keratitis, and ulcerative keratitis.</footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="85%"><caption>Table 6: Select Laboratory Abnormalities (&#x2265;10%) That Worsened from Baseline in Patients with Newly Diagnosed FLT3-ITD positive AML (with a Difference Between Arms of &#x2265;2% Compared to Placebo) in the Clinical Trial</caption><col width="28%" align="left" valign="middle"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th styleCode="Botrule Rrule" colspan="2" valign="middle">VANFLYTA + Chemotherapy<footnote ID="ft3">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.</footnote></th><th styleCode="Botrule Rrule" colspan="2" valign="middle">PLACEBO + Chemotherapy<footnoteRef IDREF="ft3"/></th></tr><tr><th styleCode="Rrule" align="center" valign="middle">All Grades%</th><th styleCode="Rrule" valign="middle">Grades 3 or 4%</th><th styleCode="Rrule" valign="middle">All Grades%</th><th styleCode="Rrule" valign="middle">Grades 3 or 4%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocytes decreased</td><td styleCode="Rrule">60</td><td styleCode="Rrule">57</td><td styleCode="Rrule">55</td><td styleCode="Rrule">51</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Potassium decreased</td><td styleCode="Rrule">59</td><td styleCode="Rrule">22</td><td styleCode="Rrule">56</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Albumin decreased</td><td styleCode="Rrule">53</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">45</td><td styleCode="Rrule">4.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Phosphorus decreased</td><td styleCode="Rrule">52</td><td styleCode="Rrule">22</td><td styleCode="Rrule">48</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alkaline phosphatase increased</td><td styleCode="Rrule">51</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">47</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Magnesium decreased</td><td styleCode="Rrule">44</td><td styleCode="Rrule">2</td><td styleCode="Rrule">42</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Calcium decreased</td><td styleCode="Rrule">33</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">27</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatine phosphokinase increased</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Potassium increased</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Magnesium increased</td><td styleCode="Rrule">14</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">9</td><td styleCode="Rrule">1.2</td></tr><tr><td styleCode="Lrule Rrule">Sodium increased</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.4</td></tr></tbody></table>