REZLIDHIA

WARNING: DIFFERENTIATION SYNDROME Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution [see Warnings and Precautions ( 5.1 )] . WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate corticosteroids and hemodynamic monitoring until symptom resolution. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Monitor liver function tests during treatment with REZLIDHIA. If hepatotoxicity occurs, interrupt and reduce or discontinue REZLIDHIA. ( 2.3 , 5.2 ) 5.1 Differentiation Syndrome REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% (25/153) of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients [see Adverse Reactions (6.1)]. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dosage interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence [see Dosage and Administration ( 2.3 )] . 5.2 Hepatotoxicity REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity [see Adverse Reactions ( 6.1 )] . One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin. Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity [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 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] 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 (≥20%) adverse reactions, including laboratory abnormalities, are aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Relapsed or Refractory AML The safety of REZLIDHIA 150 mg administered twice daily was evaluated in 153 adults with relapsed or refractory AML with an IDH1 mutation [see Clinical Studies ( 14.1 )] . Among the 153 patients who received REZLIDHIA, 35% were exposed for at least 6 months and 21% were exposed for at least 1 year. The median duration of exposure to REZLIDHIA was 4.7 months (range: 0.1 to 34 months). Serious adverse reactions occurred in 25% of patients who received REZLIDHIA. Serious adverse reactions in ≥5% included differentiation syndrome (9%) and transaminitis (6%). Fatal adverse reactions occurred in 1% of patients who received REZLIDHIA, due to differentiation syndrome. Permanent discontinuation of REZLIDHIA due to an adverse reaction occurred in 8% of patients. Adverse reactions leading to permanent discontinuation in ≥1% of patients included transaminitis, differentiation syndrome, and gallbladder disorders. Dosage interruptions of REZLIDHIA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in >5% of patients included transaminitis and differentiation syndrome. Dose reductions of REZLIDHIA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reductions in ≥2% of patients included transaminitis. The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis. Table 2 summarizes the adverse reactions in the clinical trial for relapsed or refractory AML. Table 2: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory AML in the Clinical Trial Olutasidenib 150 mg BID N=153 Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Nausea 38 0 Constipation 26 0 Mucositis Mucositis includes gingival hypertrophy, gingivitis, gingivitis ulcerative, oral disorder, colitis, mouth ulceration, stomatitis, tongue ulceration, oral pain, oropharyngeal pain, pharyngitis, proctalgia, and colitis ischemic. 23 3 Diarrhea 20 1 Abdominal pain Includes multiple similar adverse reaction terms. 18 1 Vomiting 17 1 General Disorders and Administration Site Conditions Fatigue/malaise 36 3 Pyrexia 24 1 Edema 18 3 Musculoskeletal and Connective Tissue Disorders Arthralgia Arthralgia grouped term includes arthralgia, bone pain, back pain, neck pain, pain in extremity, arthritis, joint effusion, joint range of motion decreased, and joint swelling. 28 3 Blood System and Lymphatic Disorders Leukocytosis 25 9 Differentiation syndrome Includes fatal adverse reaction. ' Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. 16 8 Respiratory, Thoracic and Mediastinal Disorders Dyspnea ' Dyspnea grouped term includes acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, oxygen saturation decreased, respiratory distress, respiratory failure. 24 5 Cough 17 1 Skin and subcutaneous tissue disorders Rash 24 1 Investigations Transaminitis Transaminitis grouped term includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal, liver function test increased, transaminases increased, hepatitis acute, and blood alkaline phosphatase increased. 20 12 Metabolism and Nutrition Disorders Decreased appetite 16 2 Nervous System Disorders Headache 13 0 Vascular Disorders Hypertension 10 5 Clinically relevant adverse reactions in <10% of patients who received REZLIDHIA include: Gallbladder disorders: biliary tract disorder, biliary colic, cholangitis, and cholestasis Electrocardiogram QT prolonged Table 3 summarizes the laboratory abnormalities in the clinical trial for relapsed or refractory AML. Table 3: Most Common (≥10%) New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML in the Clinical Trial Olutasidenib The denominator used to calculate the rate varied from 143 to 152 based on the number of patients with a baseline value and at least one post-treatment value. Parameter All Grades (%) Grade 3 or 4 (%) Aspartate aminotransferase increased 47 10 Alanine aminotransferase increased 46 13 Potassium decreased 46 9 Sodium decreased 42 7 Alkaline phosphatase increased 42 7 Creatinine increased 38 2 Lymphocytes increased 26 3 Bilirubin increased 26 2 Uric acid increased 25 3 Lipase increased 24 8

<table ID="t2" width="100%" styleCode="Noautorules"><caption>Table 2: Adverse Reactions (&#x2265;10%) in Patients with Relapsed or Refractory AML in the Clinical Trial</caption><col width="60%" align="left"/><col width="20%" align="center"/><col width="20%" align="center"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td styleCode="Toprule Botrule Rrule" colspan="2"><content styleCode="bold">Olutasidenib 150 mg BID N=153</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 (%)</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">Grade 3 or 4</content> <content styleCode="bold">(%)</content></td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Nausea</td><td styleCode="Botrule Rrule">38</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Constipation</td><td styleCode="Botrule Rrule">26</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Mucositis<footnote ID="table_2_footnote2">Mucositis includes gingival hypertrophy, gingivitis, gingivitis ulcerative, oral disorder, colitis, mouth ulceration, stomatitis, tongue ulceration, oral pain, oropharyngeal pain, pharyngitis, proctalgia, and colitis ischemic.</footnote></td><td styleCode="Botrule Rrule">23</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Diarrhea</td><td styleCode="Botrule Rrule">20</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Abdominal pain<footnote ID="table_2_footnote1">Includes multiple similar adverse reaction terms.</footnote></td><td styleCode="Botrule Rrule">18</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Vomiting </td><td styleCode="Botrule Rrule">17</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" colspan="3"><content styleCode="bold">General Disorders and Administration Site Conditions </content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Fatigue/malaise<footnoteRef IDREF="table_2_footnote1"/></td><td styleCode="Botrule Rrule">36</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Pyrexia</td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Edema<footnoteRef IDREF="table_2_footnote1"/></td><td styleCode="Botrule Rrule">18</td><td styleCode="Botrule Rrule">3</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">Arthralgia<footnote ID="table_2_footnote3">Arthralgia grouped term includes arthralgia, bone pain, back pain, neck pain, pain in extremity, arthritis, joint effusion, joint range of motion decreased, and joint swelling.</footnote></td><td styleCode="Botrule Rrule">28</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Blood System and Lymphatic Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Leukocytosis</td><td styleCode="Botrule Rrule">25</td><td styleCode="Botrule Rrule">9</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Differentiation syndrome<footnote ID="table_2_footnote0">Includes fatal adverse reaction.</footnote>^&apos;<footnote ID="table_2_footnote4">Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain.</footnote></td><td styleCode="Botrule Rrule">16</td><td styleCode="Botrule Rrule">8</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">Dyspnea<footnoteRef IDREF="table_2_footnote0"/>^&apos;<footnote ID="table_2_footnote5">Dyspnea grouped term includes acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, oxygen saturation decreased, respiratory distress, respiratory failure.</footnote></td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">5</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Cough<footnoteRef IDREF="table_2_footnote1"/></td><td styleCode="Botrule Rrule">17</td><td styleCode="Botrule Rrule">1</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">Rash<footnoteRef IDREF="table_2_footnote1"/></td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">1</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">Transaminitis<footnote ID="table_2_footnote6">Transaminitis grouped term includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal, liver function test increased, transaminases increased, hepatitis acute, and blood alkaline phosphatase increased.</footnote></td><td styleCode="Botrule Rrule">20</td><td styleCode="Botrule Rrule">12</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">16</td><td styleCode="Botrule Rrule">2</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">Headache</td><td styleCode="Botrule Rrule">13</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td colspan="3" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Vascular Disorders</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Hypertension<footnoteRef IDREF="table_2_footnote1"/></td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">5</td></tr></tbody></table>

<table ID="t3" width="100%" styleCode="Noautorules"><caption>Table 3: Most Common (&#x2265;10%) New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML in the Clinical Trial</caption><col width="40%" align="left"/><col width="20%" align="center"/><col width="20%" align="center"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td styleCode="Toprule Botrule Rrule" colspan="2"><content styleCode="bold">Olutasidenib</content><footnote ID="table_3_footnote1">The denominator used to calculate the rate varied from 143 to 152 based on the number of patients with a baseline value and at least one post-treatment value.</footnote></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 (%)</content></td><td styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 3 or 4 (%)</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Aspartate aminotransferase increased</td><td styleCode="Botrule Rrule">47</td><td styleCode="Botrule Rrule">10</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Botrule Rrule">46</td><td styleCode="Botrule Rrule">13</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Potassium decreased</td><td styleCode="Botrule Rrule">46</td><td styleCode="Botrule Rrule">9</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Sodium decreased</td><td styleCode="Botrule Rrule">42</td><td styleCode="Botrule Rrule">7</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Alkaline phosphatase increased</td><td styleCode="Botrule Rrule">42</td><td styleCode="Botrule Rrule">7</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Creatinine increased</td><td styleCode="Botrule Rrule">38</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Lymphocytes increased</td><td styleCode="Botrule Rrule">26</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Bilirubin increased</td><td styleCode="Botrule Rrule">26</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Uric acid increased</td><td styleCode="Botrule Rrule">25</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Lipase increased</td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">8</td></tr></tbody></table>