Daurismo

WARNING: EMBRYO-FETAL TOXICITY DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic in animals [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . Conduct pregnancy testing in females of reproductive potential prior to initiation of DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1 , 8.3) ] . Advise males of the potential risk of DAURISMO exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose to avoid potential drug exposure [see Warnings and Precautions (5.1) , Use in Specific Populations (8.3) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. • DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic in animals. ( 5.1 , 8.1 ) • Conduct pregnancy testing in females of reproductive potential prior to initiation of DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. ( 5.1 , 8.1 , 8.3 ) • Advise males of the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose to avoid potential drug exposure. ( 5.1 , 8.3 )

5 WARNINGS AND PRECAUTIONS • Blood Donation: Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose. ( 5.1 ) • QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc prolongation occurs, interrupt treatment with DAURISMO. ( 2.2 , 5.2 ) • Musculoskeletal Adverse Reactions: Obtain creatine phosphokinase (CPK) and serum creatinine levels prior to initiating DAURISMO and as indicated clinically thereafter. Temporary dose interruption, dose reduction, or discontinuation of DAURISMO may be required for musculoskeletal adverse reactions or serum CPK elevation. ( 2.2 , 5.3 ) 5.1 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women. In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg [see Use in Specific Populations (8.1 , 8.2) , Clinical Pharmacology (12.1) ] . Advise pregnant women of the potential risk to the fetus. Females of Reproductive Potential DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose [see Use in Specific Populations (8.2 , 8.3) ] . Males Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose [see Use in Specific Populations (8.3) ] . Blood Donation Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose of DAURISMO because their blood or blood products might be given to a female of reproductive potential. 5.2 QTc Interval Prolongation Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. Monitor electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (2.2) ] . Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7) , Clinical Pharmacology (12.2) ] . In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended. Interrupt DAURISMO if QTc increases to greater than 500 ms. Discontinue DAURISMO permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration (2.2) ] . 5.3 Musculoskeletal Adverse Reactions Musculoskeletal adverse reactions, which may be accompanied by CPK elevations, have occurred with DAURISMO and other drugs which inhibit the hedgehog (Hh) pathway. In BRIGHT AML 1003, musculoskeletal adverse reactions occurred in 45% of patients treated, with 2% (7/79) reported as Grade 3 or higher. The most frequent manifestations of musculoskeletal adverse reactions reported were musculoskeletal pain (30%) and muscle spasms (15%). Increased CPK laboratory values occurred in 16% of patients [see Adverse Reactions (6.1) ] . Obtain baseline CPK levels prior to initiating DAURISMO and as clinically indicated (e.g., if muscle symptoms are reported). Obtain CPK and serum creatinine levels at least weekly in patients with musculoskeletal adverse reactions with concurrent CPK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption, dose reduction, or discontinuation of DAURISMO may be required for musculoskeletal adverse reactions or serum CPK elevation [see Dosage and Administration (2.2) ] .

6 ADVERSE REACTIONS The following clinically-significant adverse reactions are described elsewhere in the labeling: • QTc Interval Prolongation [see Warnings and Precautions (5.2) ] • Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%) are anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 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. The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated [see Clinical Studies (14) ] . Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). The median duration of treatment in the DAURISMO with low-dose cytarabine arm was 83 days (range 3 to 972 days), and the median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year. Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with DAURISMO with low-dose cytarabine, and the most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%). Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in Table 3. Table 3. Adverse Reactions Occurring in ≥10% of Patients Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included. No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm. Within the First 90 Days of Therapy in BRIGHT AML 1003 Body System Adverse Reactions DAURISMO With Low-Dose Cytarabine N=84 Low-Dose Cytarabine N=41 All Grades % Grade ≥3 % All Grades % Grade ≥3 % Abbreviations: N = number of patients. Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse reactions include events that commenced within 28 days after the last treatment dose. Blood and lymphatic system disorder Anemia 43 41 42 37 Hemorrhage Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage, and subdural hematoma. 36 6 42 12 Febrile neutropenia 31 31 22 22 Thrombocytopenia 30 30 27 24 General disorders and administration site conditions Fatigue Fatigue includes asthenia and fatigue. 36 14 32 7 Edema Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face. 30 0 20 2 Mucositis Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis, oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation. 21 1 12 0 Pyrexia 18 1 22 2 Chest pain Chest pain includes chest pain and non-cardiac chest pain. 12 1 2 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck pain, and bone pain. 30 2 17 2 Muscle spasm Muscle spasms includes muscle spasms and muscle tightness. 15 0 5 0 Gastrointestinal disorders Nausea 29 1 12 2 Constipation 20 1 12 0 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower. 19 0 12 0 Diarrhea Diarrhea includes diarrhea, colitis, and gastroenteritis. 18 4 22 0 Vomiting 18 2 10 2 Respiratory thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure. 23 11 24 7 Cough Cough includes cough and productive cough. 18 0 15 2 Metabolism and nutrition disorders Decrease appetite 21 1 7 2 Nervous system disorders Dysgeusia Dysgeusia includes dysgeusia and ageusia. 21 0 2 0 Dizziness 18 1 7 0 Headache 12 0 10 2 Skin and subcutaneous tissue disorders Rash Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic. 20 2 7 2 Infection and infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, and lung infection. 19 15 24 22 Investigations Hyponatremia 11 6 0 0 Platelet count decreased 15 15 10 10 Weight decreased 13 0 2 0 White blood cell count decreased 11 11 5 2 Cardiac disorders Atrial arrhythmia Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia. 13 4 7 2 Renal and urinary disorders Renal insufficiency Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure. 19 5 10 0 The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades ≤2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003. Additional clinically-significant adverse reactions occurring in <10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include: • Dental disorders: loose tooth and toothache • Skin and subcutaneous tissue disorders: alopecia • Cardiac disorders: QT interval prolonged Changes in selected post-baseline laboratory values that were observed in patients with newly-diagnosed AML and other conditions for which DAURISMO is not indicated in the clinical trial are shown in Table 4. Table 4. Selected Laboratory Abnormalities (≥15%) Maximum severity based on the number of patients with available on-study laboratory data. Within the First 90 Days of Therapy in BRIGHT AML 1003 DAURISMO with Low-Dose Cytarabine Low-Dose Cytarabine Laboratory Abnormality N All Grades % Grade 3 or 4 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. % N All Grades % Grade 3 or 4 % Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Creatinine increased 81 96 1 40 80 5 Hyponatremia 81 54 7 39 41 8 Hypomagnesemia 81 33 0 39 23 0 AST increased 80 28 1 40 23 0 Blood bilirubin increased 80 25 4 39 33 3 ALT increased 80 24 0 40 28 3 Alkaline phosphatase increased 80 23 0 40 28 3 Hyperkalemia 81 16 1 40 8 3 CPK increased 38 16 0 17 6 0 Hypokalemia 81 15 0 40 23 0 The following laboratory abnormalities worsened (i.e. progressed from Grades ≤2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003: • hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients).

<table width="100%"><caption>Table 3. Adverse Reactions Occurring in &#x2265;10% of Patients<footnote ID="_RefID0EVVAE">Adverse reactions with &#x2265;10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included.</footnote><footnote ID="_RefID0EXVAE">No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm.</footnote> Within the First 90 Days of Therapy in BRIGHT AML 1003</caption><col width="22%"/><col width="22%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Body System</content></th><th align="center" styleCode="Rrule Toprule " valign="top"><content styleCode="bold">Adverse Reactions</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">DAURISMO With Low-Dose Cytarabine</content> <content styleCode="bold">N=84</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Low-Dose Cytarabine</content> <content styleCode="bold">N=41</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"/><th align="left" styleCode="Rrule Botrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade &#x2265;3</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade &#x2265;3</content> <content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="6" valign="top">Abbreviations: N = number of patients. Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse reactions include events that commenced within 28 days after the last treatment dose.</td></tr></tfoot><tbody><tr><td rowspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Blood and lymphatic system disorder</paragraph></td><td styleCode="Rrule Toprule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>37</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hemorrhage<footnote ID="_RefID0E3YAE">Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage, and subdural hematoma.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>31</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>31</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thrombocytopenia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td></tr><tr><td rowspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>General disorders and administration site conditions</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Fatigue<footnote ID="_RefID0EG1AE">Fatigue includes asthenia and fatigue.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Edema<footnote ID="_RefID0ET1AE">Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Mucositis<footnote ID="_RefID0EB2AE">Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis, oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chest pain<footnote ID="_RefID0E32AE">Chest pain includes chest pain and non-cardiac chest pain.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Musculoskeletal and connective tissue disorders</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Musculoskeletal pain<footnote ID="_RefID0EN3AE">Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck pain, and bone pain. </footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Muscle spasm<footnote ID="_RefID0E23AE">Muscle spasms includes muscle spasms and muscle tightness.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td rowspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal disorders</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Abdominal pain<footnote ID="_RefID0ED5AE">Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Diarrhea<footnote ID="_RefID0ER5AE">Diarrhea includes diarrhea, colitis, and gastroenteritis.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Respiratory thoracic and mediastinal disorders</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Dyspnea<footnote ID="_RefID0EP6AE">Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cough<footnote ID="_RefID0E46AE">Cough includes cough and productive cough.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Metabolism and nutrition disorders</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Decrease appetite</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td rowspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nervous system disorders</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Dysgeusia<footnote ID="_RefID0E4AAG">Dysgeusia includes dysgeusia and ageusia.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Skin and subcutaneous tissue disorders</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Rash<footnote ID="_RefID0EGCAG">Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Infection and infestations</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Pneumonia<footnote ID="_RefID0EWCAG">Pneumonia includes pneumonia, pneumonia aspiration, and lung infection.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>22</paragraph></td></tr><tr><td rowspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Investigations</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Hyponatremia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Platelet count decreased</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Weight decreased</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>White blood cell count decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cardiac disorders</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Atrial arrhythmia<footnote ID="_RefID0EZEAG">Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Renal and urinary disorders</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Renal insufficiency<footnote ID="_RefID0EIFAG">Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 4. Selected Laboratory Abnormalities (&#x2265;15%)<footnote ID="_Reft3f1">Maximum severity based on the number of patients with available on-study laboratory data.</footnote> Within the First 90 Days of Therapy in BRIGHT AML 1003</caption><col width="30%"/><col width="5%"/><col width="15%"/><col width="15%"/><col width="5%"/><col width="15%"/><col width="15%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="middle"/><th align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">DAURISMO with Low-Dose Cytarabine</content></th><th align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Low-Dose Cytarabine</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="bottom"><content styleCode="bold">Laboratory Abnormality</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">All Grades</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grade 3 or 4</content><footnote ID="_RefID0E5FAG">Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.</footnote> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">All Grades</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grade 3 or 4</content><footnoteRef IDREF="_RefID0E5FAG"/> <content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="7" valign="top">Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Creatinine increased</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>96</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>80</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hyponatremia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>54</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>AST increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>80</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Blood bilirubin increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>80</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>ALT increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>80</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Alkaline phosphatase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>80</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>CPK increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>