FDA label 7618e704-4d61-4af1-8a05-1f521db4f309

WARNING: DIFFERENTIATION SYNDROME Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )]. WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution ( 5.1 , 6.1 ).

5 WARNINGS AND PRECAUTIONS QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, dose reduce or withhold, then resume dose or permanently discontinue TIBSOVO ( 2.3 , 5.2 ). Guillain-Barré Syndrome: Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome ( 2.3 , 5.3 ). 5.1 Differentiation Syndrome In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement [see Dosage and Administration ( 2.3 )] . If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe [see Dosage and Administration ( 2.3 )]. 5.2 QTc Interval Prolongation Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology ( 12.2 )] and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with TIBSOVO in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT 3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )] . Conduct monitoring of electrocardiograms (ECGs) and electrolytes [see Dosage and Administration ( 2.3 )] . In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration ( 2.3 )] . 5.3 Guillain-Barré Syndrome Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome [see Dosage and Administration ( 2.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] Guillain-Barré Syndrome [see Warnings and Precautions ( 5.3 )] 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 most common adverse reactions (≥20%) were fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, electrocardiogram QT prolonged, rash, cough, decreased appetite, myalgia, constipation, and pyrexia ( 6.1 ). The most common laboratory abnormalities (≥20%) were hemoglobin decreased, calcium decreased, sodium decreased, magnesium decreased, uric acid increased, potassium decreased, alkaline phosphatase increased, aspartate aminotransferase increased, phosphate decreased, and creatinine increased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals at 1-833-228-8474 and 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 of TIBSOVO as a single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001 [see Clinical Studies ( 14.1 and 14.2 )] . The median age of TIBSOVO treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received TIBSOVO, 37% were exposed for 6 months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in ≥ 20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia. Newly-Diagnosed AML The safety profile of single-agent TIBSOVO was studied in 28 adults with newly-diagnosed AML treated with 500 mg daily [see Clinical Studies ( 14.1 )] . The median duration of exposure to TIBSOVO was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to TIBSOVO for at least 6 months and 6 patients (21%) were exposed for at least 1 year. Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES). Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES. The most common adverse reactions reported in the trial are shown in Table 2 . Table 2: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Newly-Diagnosed AML 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 2 Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. 3 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 4 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 5 Grouped term includes asthenia and fatigue. 6 Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 7 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 8 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 9 Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. 10 Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. 11 Grouped term includes cough, productive cough, and upper airway cough syndrome. 12 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. TIBSOVO (500 mg daily) N=28 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) Blood System and Lymphatic System Disorders Leukocytosis 1 10 (36) 2 (7) Differentiation Syndrome 2 7 (25) 3 (11) Gastrointestinal Disorders Diarrhea 17 (61) 2 (7) Nausea 10 (36) 2 (7) Abdominal pain 3 8 (29) 1 (4) Constipation 6 (21) 1 (4) Vomiting 6 (21) 1 (4) Mucositis 4 6 (21) 0 Dyspepsia 3 (11) 0 General Disorders and Administration Site Conditions Fatigue 5 14 (50) 4 (14) Edema 6 12 (43) 0 Investigations Electrocardiogram QT prolonged 6 (21) 3 (11) Weight decreased 3 (11) 0 Metabolism and Nutrition Disorders Decreased appetite 11 (39) 1 (4) Musculoskeletal and Connective Tissue Disorders Arthralgia 7 9 (32) 1 (4) Myalgia 8 7 (25) 1 (4) Nervous System Disorders Dizziness 6 (21) 0 Neuropathy 9 4 (14) 0 Headache 3 (11) 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 10 8 (29) 1 (4) Cough 11 4 (14) 0 Skin and Subcutaneous Tissue Disorders Pruritis 4 (14) 1 (4) Rash 12 4 (14) 1 (4) Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 3 . Table 3: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly-Diagnosed AML 1 1 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=28 Parameter All Grades n (%) Grade ≥ 3 n (%) Hemoglobin decreased 15 (54) 12 (43) Alkaline phosphatase increased 13 (46) 0 Potassium decreased 12 (43) 3 (11) Sodium decreased 11 (39) 1 (4) Uric acid increased 8 (29) 1 (4) Aspartate aminotransferase increased 8 (29) 1 (4) Creatinine increased 8 (29) 0 Magnesium decreased 7 (25) 0 Calcium decreased 7 (25) 1 (4) Phosphate decreased 6 (21) 2 (7) Alanine aminotransferase increased 4 (14) 1 (4) Relapsed or Refractory AML The safety profile of single-agent TIBSOVO was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily [see Clinical Studies ( 14.2 )]. The median duration of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to TIBSOVO for at least 6 months and 16 patients (9%) were exposed for at least 1 year. Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML). The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%). The most common adverse reactions reported in the trial are shown in Table 4 . Table 4: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Relapsed or Refractory AML 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 2 Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. 3 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 4 Grouped term includes vomiting and retching. 5 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 6 Grouped term includes asthenia and fatigue. 7 Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 8 Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain. 9 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 10 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 11 Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barré syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 12 Grouped term includes cough, productive cough, and upper airway cough syndrome. 13 Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 14 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. 15 Grouped term includes hypotension and orthostatic hypotension. TIBSOVO (500 mg daily) N=179 Body System All Grades Grade ≥ 3 Adverse Reaction n (%) n (%) Blood System and Lymphatic System Disorders Leukocytosis 1 68 (38) 15 (8) Differentiation Syndrome 2 34 (19) 23 (13) Gastrointestinal Disorders Diarrhea 60 (34) 4 (2) Nausea 56 (31) 1 (1) Mucositis 3 51 (28) 6 (3) Constipation 35 (20) 1 (1) Vomiting 4 32 (18) 2 (1) Abdominal pain 5 29 (16) 2 (1) General Disorders and Administration Site Conditions Fatigue 6 69 (39) 6 (3) Edema 7 57 (32) 2 (1) Pyrexia 41 (23) 2 (1) Chest pain 8 29 (16) 5 (3) Investigations Electrocardiogram QT prolonged 46 (26) 18 (10) Metabolism and Nutrition Disorders Decreased appetite 33 (18) 3 (2) Tumor lysis syndrome 14 (8) 11 (6) Musculoskeletal and Connective Tissue Disorders Arthralgia 9 64 (36) 8 (4) Myalgia 10 33 (18) 1 (1) Nervous System Disorders Headache 28 (16) 0 Neuropathy 11 21 (12) 2 (1) Respiratory, Thoracic and Mediastinal Disorders Cough 12 40 (22) 1 (<1) Dyspnea 13 59 (33) 16 (9) Pleural effusion 23 (13) 5 (3) Skin and Subcutaneous Tissue Disorders Rash 14 46 (26) 4 (2) Vascular Disorders Hypotension 15 22 (12) 7 (4) Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 5 . Table 5: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML 1 1 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=179 Parameter All Grades Grade ≥ 3 n (%) n (%) Hemoglobin decreased 108 (60) 83 (46) Sodium decreased 69 (39) 8 (4) Magnesium decreased 68 (38) 0 Uric acid increased 57 (32) 11 (6) Potassium decreased 55 (31) 11 (6) Alkaline phosphatase increased 49 (27) 1 (1) Aspartate aminotransferase increased 49 (27) 1 (1) Phosphate decreased 45 (25) 15 (8) Creatinine increased 42 (23) 2 (1) Alanine aminotransferase increased 26 (15) 2 (1) Bilirubin increased 28 (16) 1 (1)

<table ID="table2" width="700" styleCode="Noautorules"><caption>Table 2: Adverse Reactions Reported in &#x2265; 10% (Any Grade) or &#x2265; 5% (Grade &#x2265; 3) of Patients with Newly-Diagnosed AML</caption><col width="60%" align="left"/><col width="20%" align="center"/><col width="20%" align="center"/><tfoot><tr valign="top"><td colspan="3" align="left"><paragraph styleCode="footnote">¹ Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.</paragraph><paragraph styleCode="footnote">² Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.</paragraph><paragraph styleCode="footnote">³ Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.</paragraph><paragraph styleCode="footnote">⁴ Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.</paragraph><paragraph styleCode="footnote">⁵ Grouped term includes asthenia and fatigue. </paragraph><paragraph styleCode="footnote">⁶ Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face.</paragraph><paragraph styleCode="footnote">⁷ Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.</paragraph><paragraph styleCode="footnote">⁸ Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal.</paragraph><paragraph styleCode="footnote">⁹ Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy.</paragraph><paragraph styleCode="footnote">¹⁰ Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. </paragraph><paragraph styleCode="footnote">¹¹ Grouped term includes cough, productive cough, and upper airway cough syndrome.</paragraph><paragraph styleCode="footnote">¹² Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer.</paragraph></td></tr></tfoot><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td styleCode="Toprule Botrule Rrule" colspan="2"><content styleCode="bold">TIBSOVO (500 mg daily) N=28</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"><content styleCode="bold">Body System</content> Adverse Reaction</td><td styleCode="Botrule Rrule"><content styleCode="bold">All Grades n (%)</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">Grade &#x2265; 3</content> <content styleCode="bold">n (%)</content></td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Blood System and Lymphatic System Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Leukocytosis¹</td><td styleCode="Botrule Rrule">10 (36)</td><td styleCode="Botrule Rrule">2 (7)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Differentiation Syndrome²</td><td styleCode="Botrule Rrule">7 (25)</td><td styleCode="Botrule Rrule">3 (11)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Diarrhea</td><td styleCode="Botrule Rrule">17 (61)</td><td styleCode="Botrule Rrule">2 (7)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Nausea</td><td styleCode="Botrule Rrule">10 (36)</td><td styleCode="Botrule Rrule">2 (7)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Abdominal pain³</td><td styleCode="Botrule Rrule">8 (29)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Constipation</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Vomiting</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Mucositis⁴</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Dyspepsia</td><td styleCode="Botrule Rrule">3 (11)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Fatigue⁵</td><td styleCode="Botrule Rrule">14 (50)</td><td styleCode="Botrule Rrule">4 (14)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Edema⁶</td><td styleCode="Botrule Rrule">12 (43)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Electrocardiogram QT prolonged</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">3 (11)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Weight decreased</td><td styleCode="Botrule Rrule">3 (11)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Decreased appetite</td><td styleCode="Botrule Rrule">11 (39)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Arthralgia⁷</td><td styleCode="Botrule Rrule">9 (32)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Myalgia⁸</td><td styleCode="Botrule Rrule">7 (25)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Dizziness</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Neuropathy⁹</td><td styleCode="Botrule Rrule">4 (14)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Headache</td><td styleCode="Botrule Rrule">3 (11)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Dyspnea¹⁰</td><td styleCode="Botrule Rrule">8 (29)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Cough¹¹</td><td styleCode="Botrule Rrule">4 (14)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Pruritis</td><td styleCode="Botrule Rrule">4 (14)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Rash¹²</td><td styleCode="Botrule Rrule">4 (14)</td><td styleCode="Botrule Rrule">1 (4)</td></tr></tbody></table>

<table ID="table3" width="600" styleCode="Noautorules"><caption>Table 3: Most Common (&#x2265; 10%) or &#x2265; 5% (Grade &#x2265; 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly-Diagnosed AML¹</caption><col width="40%" align="left"/><col width="20%" align="center"/><col width="20%" align="center"/><tfoot><tr valign="top"><td colspan="3" align="left"><paragraph styleCode="footnote">¹ Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.</paragraph></td></tr></tfoot><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td styleCode="Toprule Botrule Rrule" colspan="2"><content styleCode="bold">TIBSOVO (500 mg daily) N=28</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Parameter</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">All Grades n (%)</content></td><td styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade &#x2265; 3 n (%)</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Hemoglobin decreased</td><td styleCode="Botrule Rrule">15 (54)</td><td styleCode="Botrule Rrule">12 (43)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Alkaline phosphatase increased</td><td styleCode="Botrule Rrule">13 (46)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Potassium decreased</td><td styleCode="Botrule Rrule">12 (43)</td><td styleCode="Botrule Rrule">3 (11)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Sodium decreased</td><td styleCode="Botrule Rrule">11 (39)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Uric acid increased</td><td styleCode="Botrule Rrule">8 (29)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Aspartate aminotransferase increased</td><td styleCode="Botrule Rrule">8 (29)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Creatinine increased</td><td styleCode="Botrule Rrule">8 (29)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Magnesium decreased</td><td styleCode="Botrule Rrule">7 (25)</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Calcium decreased</td><td styleCode="Botrule Rrule">7 (25)</td><td styleCode="Botrule Rrule">1 (4)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Phosphate decreased</td><td styleCode="Botrule Rrule">6 (21)</td><td styleCode="Botrule Rrule">2 (7)</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Botrule Rrule">4 (14)</td><td styleCode="Botrule Rrule">1 (4)</td></tr></tbody></table>

<table ID="table4" width="700" styleCode="Noautorules"><caption>Table 4: Adverse Reactions Reported in &#x2265; 10% (Any Grade) or &#x2265; 5% (Grade &#x2265; 3) of Patients with Relapsed or Refractory AML</caption><col width="50%" align="left"/><col width="25%" align="center"/><col width="25%" align="center"/><tfoot><tr><td colspan="3" align="left"><paragraph styleCode="footnote">¹ Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.</paragraph><paragraph styleCode="footnote">² Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.</paragraph><paragraph styleCode="footnote">³ Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.</paragraph><paragraph styleCode="footnote">⁴ Grouped term includes vomiting and retching.</paragraph><paragraph styleCode="footnote">⁵ Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.</paragraph><paragraph styleCode="footnote">⁶ Grouped term includes asthenia and fatigue.</paragraph><paragraph styleCode="footnote">⁷ Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema.</paragraph><paragraph styleCode="footnote">⁸ Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain.</paragraph><paragraph styleCode="footnote">⁹ Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.</paragraph><paragraph styleCode="footnote">¹⁰ Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal.</paragraph><paragraph styleCode="footnote">¹¹ Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barr&#xE9; syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance.</paragraph><paragraph styleCode="footnote">¹² Grouped term includes cough, productive cough, and upper airway cough syndrome.</paragraph><paragraph styleCode="footnote">¹³ Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional.</paragraph><paragraph styleCode="footnote">¹⁴ Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer.</paragraph><paragraph styleCode="footnote">¹⁵ Grouped term includes hypotension and orthostatic hypotension.</paragraph></td></tr></tfoot><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">TIBSOVO (500 mg daily) N=179</content></td></tr><tr><td styleCode="Toprule Lrule Rrule"><content styleCode="bold">Body System</content></td><td styleCode="Toprule Lrule Rrule"><content styleCode="bold">All Grades</content></td><td styleCode="Toprule Lrule Rrule"><content styleCode="bold">Grade &#x2265; 3</content></td></tr><tr><td styleCode="Botrule Lrule Rrule">Adverse Reaction</td><td styleCode="Botrule Lrule Rrule"><content styleCode="bold">n (%)</content></td><td styleCode="Botrule Lrule Rrule"><content styleCode="bold">n (%)</content></td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Blood System and Lymphatic System Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Leukocytosis¹</td><td styleCode="Toprule Botrule Lrule Rrule">68 (38)</td><td styleCode="Toprule Botrule Lrule Rrule">15 (8)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Differentiation Syndrome²</td><td styleCode="Toprule Botrule Lrule Rrule">34 (19)</td><td styleCode="Toprule Botrule Lrule Rrule">23 (13)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Diarrhea</td><td styleCode="Toprule Botrule Lrule Rrule">60 (34)</td><td styleCode="Toprule Botrule Lrule Rrule">4 (2)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Nausea</td><td styleCode="Toprule Botrule Lrule Rrule">56 (31)</td><td styleCode="Toprule Botrule Lrule Rrule">1 (1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Mucositis³</td><td styleCode="Toprule Botrule Lrule Rrule">51 (28)</td><td styleCode="Toprule Botrule Lrule Rrule">6 (3)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Constipation</td><td styleCode="Toprule Botrule Lrule Rrule">35 (20)</td><td styleCode="Toprule Botrule Lrule Rrule">1 (1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Vomiting⁴</td><td styleCode="Toprule Botrule Lrule Rrule">32 (18)</td><td styleCode="Toprule Botrule Lrule Rrule">2 (1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Abdominal pain⁵</td><td styleCode="Toprule Botrule Lrule Rrule">29 (16)</td><td styleCode="Toprule Botrule Lrule Rrule">2 (1)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Fatigue⁶</td><td styleCode="Toprule Botrule Lrule Rrule">69 (39)</td><td styleCode="Toprule Botrule Lrule Rrule">6 (3)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Edema⁷</td><td styleCode="Toprule Botrule Lrule Rrule">57 (32)</td><td styleCode="Toprule Botrule Lrule Rrule">2 (1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Pyrexia</td><td styleCode="Toprule Botrule Lrule Rrule">41 (23)</td><td styleCode="Toprule Botrule Lrule Rrule">2 (1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Chest pain⁸</td><td styleCode="Toprule Botrule Lrule Rrule">29 (16)</td><td styleCode="Toprule Botrule Lrule Rrule">5 (3)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Electrocardiogram QT prolonged</td><td styleCode="Toprule Botrule Lrule Rrule">46 (26)</td><td styleCode="Toprule Botrule Lrule Rrule">18 (10)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Decreased appetite</td><td styleCode="Toprule Botrule Lrule Rrule">33 (18)</td><td styleCode="Toprule Botrule Lrule Rrule">3 (2)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Tumor lysis syndrome</td><td styleCode="Toprule Botrule Lrule Rrule">14 (8)</td><td styleCode="Toprule Botrule Lrule Rrule">11 (6)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Arthralgia⁹</td><td styleCode="Toprule Botrule Lrule Rrule">64 (36)</td><td styleCode="Toprule Botrule Lrule Rrule">8 (4)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Myalgia¹⁰</td><td styleCode="Toprule Botrule Lrule Rrule">33 (18)</td><td styleCode="Toprule Botrule Lrule Rrule">1 (1)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Headache</td><td styleCode="Toprule Botrule Lrule Rrule">28 (16)</td><td styleCode="Toprule Botrule Lrule Rrule">0</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Neuropathy¹¹</td><td styleCode="Toprule Botrule Lrule Rrule">21 (12)</td><td styleCode="Toprule Botrule Lrule Rrule">2 (1)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Cough¹²</td><td styleCode="Toprule Botrule Lrule Rrule">40 (22)</td><td styleCode="Toprule Botrule Lrule Rrule">1 (&lt;1)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Dyspnea¹³</td><td styleCode="Toprule Botrule Lrule Rrule">59 (33)</td><td styleCode="Toprule Botrule Lrule Rrule">16 (9)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Pleural effusion</td><td styleCode="Toprule Botrule Lrule Rrule">23 (13)</td><td styleCode="Toprule Botrule Lrule Rrule">5 (3)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Rash¹⁴</td><td styleCode="Toprule Botrule Lrule Rrule">46 (26)</td><td styleCode="Toprule Botrule Lrule Rrule">4 (2)</td></tr><tr><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Vascular Disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Hypotension¹⁵</td><td styleCode="Toprule Botrule Lrule Rrule">22 (12)</td><td styleCode="Toprule Botrule Lrule Rrule">7 (4)</td></tr></tbody></table>