Ivosidenib

1 INDICATIONS AND USAGE TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy ( 1.1 ). Relapsed or refractory AML For the treatment of adult patients with relapsed or refractory AML ( 1.2 ). Relapsed or refractory Myelodysplastic Syndromes (MDS) For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes ( 1.3 ). Locally Advanced or Metastatic Cholangiocarcinoma For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated ( 1.4 ). 1.1 Newly Diagnosed Acute Myeloid Leukemia TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.1) ]. 1.2 Relapsed or Refractory Acute Myeloid Leukemia TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.2) ] . 1.3 Relapsed or Refractory Myelodysplastic Syndromes TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ] . 1.4 Locally Advanced or Metastatic Cholangiocarcinoma TIBSOVO is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) , and Clinical Studies (14.4) ] .

2 DOSAGE AND ADMINISTRATION 500 mg orally once daily with or without food until disease progression or unacceptable toxicity ( 2.2 ). Avoid a high-fat meal. 2.1 Patient Selection Select patients for treatment with TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )]. Information on FDA-approved tests for the detection of IDH1 mutations in AML, MDS, and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )] . For patients with AML or MDS without disease progression or unacceptable toxicity, continue TIBSOVO for a minimum of 6 months to allow time for clinical response. Administer TIBSOVO with or without food. Do not administer TIBSOVO with a high-fat meal [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. Do not split, crush, or chew TIBSOVO tablets. Administer TIBSOVO tablets orally about the same time each day. If a dose of TIBSOVO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. Newly Diagnosed AML (Combination Regimen) Start TIBSOVO administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m 2 subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle [see Clinical Studies (14.1) ] . Refer to the Prescribing Information for azacitidine for additional dosing information. 2.3 Monitoring and Dosage Modifications for Toxicities Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy [see Warnings and Precautions (5.2) ] . Manage any abnormalities promptly . Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Recommended Dosage Modifications for TIBSOVO Adverse Reactions Recommended Action Differentiation syndrome [see Warnings and Precautions (5.1) ] If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days . Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids . Resume TIBSOVO when signs and symptoms improve to Grade 2 or lower. Noninfectious leukocytosis (white blood cell [WBC] count greater than 25 × 10 9 /L or an absolute increase in total WBC of greater than 15 × 10 9 /L from baseline) Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt TIBSOVO if leukocytosis is not improved with hydroxyurea, and then resume TIBSOVO at 500 mg daily when leukocytosis has resolved. QTc interval greater than 480 msec to 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Interrupt TIBSOVO. Restart TIBSOVO at 500 mg once daily after the QTc interval returns to less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. QTc interval greater than 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects . Interrupt TIBSOVO. Resume TIBSOVO at a reduced dose of 250 mg once daily when QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. Consider re-escalating the dose of TIBSOVO to 500 mg daily if an alternative etiology for QTc prolongation can be identified. QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Warnings and Precautions (5.2) ] Discontinue TIBSOVO permanently. Guillain-Barré syndrome [see Warnings and Precautions (5.3) ] Discontinue TIBSOVO permanently. Other Grade 3 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening; grading based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. adverse reactions As monotherapy in AML and MDS : Interrupt TIBSOVO until toxicity resolves to Grade 2 or lower. Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade 1 or lower. If Grade 3 or higher toxicity recurs, discontinue TIBSOVO. In cholangiocarcinoma, or in AML in combination with azacitidine : Interrupt TIBSOVO until toxicity resolves to Grade 1 or lower, or baseline, then resume at 500 mg daily (Grade 3 toxicity) or 250 mg daily (Grade 4 toxicity). If Grade 3 toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily. If Grade 3 toxicity recurs (a third time), or Grade 4 toxicity recurs, discontinue TIBSOVO. Patients with AML or MDS Assess blood counts and blood chemistries prior to the initiation of TIBSOVO, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. 2.4 Dosage Modification for Use with Strong CYP3A4 Inhibitors If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the TIBSOVO dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome in AML and MDS [see Warnings and Precautions (5.1) ] QTc Interval Prolongation [see Warnings and Precautions (5.2) ] Guillain-Barré Syndrome [see Warnings and Precautions (5.3) ] The most common adverse reactions including laboratory abnormalities (≥ 25%) in patients with AML are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia ( 6.1 ). The most common adverse reactions including laboratory abnormalities (≥25%) in patients with relapsed or refractory MDS are creatinine increased, hemoglobin decrease, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash ( 6.1 ). The most common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash ( 6.1 ). The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals at 1-800-807-6124 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. Acute Myeloid Leukemia In AML, the safety population reflects exposure to TIBSOVO at 500 mg daily in combination with azacitidine or as monotherapy in patients in Studies AG120-C-009 (N=71) and AG120-C-001 (N=213), respectively [see Clinical Studies (14.1 and 14.2) ] . In this safety population, the most common adverse reactions including laboratory abnormalities (≥ 25% in either trial) were leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphatase decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia. Newly Diagnosed AML TIBSOVO in Combination with Azacitidine The safety of TIBSOVO was evaluated in AML patients treated in combination with azacitidine, in Study AG120-C-009 [see Clinical Studies (14.1) ] . Patients received at least one dose of either TIBSOVO 500 mg daily (N=71) or placebo (N=73). Among patients who received TIBSOVO in combination with azacitidine, the median duration of exposure to TIBSOVO was 6 months (range 0 to 33 months). Thirty-four patients (48%) were exposed to TIBSOVO for at least 6 months and 22 patients (31%) were exposed for at least 1 year. Common (≥ 5%) serious adverse reactions in patients who received TIBSOVO in combination with azacitidine included differentiation syndrome (8%). Fatal adverse reactions occurred in 4% of patients who received TIBSOVO in combination with azacitidine, due to differentiation syndrome (3%) and one case of cerebral ischemia. Adverse reactions leading to discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%). The most common (>5%) adverse reactions leading to dose interruption of TIBSOVO were neutropenia (25%), electrocardiogram QT prolonged (7%), and thrombocytopenia (7%). Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%). The most common adverse reactions and laboratory abnormalities observed in Study AG120-C-009 are shown in Tables 2 and 3. Table 2: Adverse Reactions (≥10%) in Patients with AML Who Received TIBSOVO + azacitidine with a Difference Between Arms of ≥ 2% Compared with Placebo + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Body System Adverse Reaction All Grades n (%) Grade ≥3 n (%) All Grades n (%) Grade ≥3 n (%) Gastrointestinal disorders Nausea 30 (42) 2 (3) 28 (38) 3 (4) Vomiting Grouped term includes vomiting and retching. 29 (41) 0 20 (27) 1 (1) Investigations Electrocardiogram QT prolonged 14 (20) 7 (10) 5 (7) 2 (3) Psychiatric Disorders Insomnia 13 (18) 1 (1) 9 (12) 0 Blood system and lymphatic system disorders Differentiation Syndrome 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. 11 (15) 7 (10) 6 (8) 6 (8) Leukocytosis Grouped term includes leukocytosis, white blood cell count increased. 9 (13) 0 1 (1) 0 Vascular disorders Hematoma Grouped term includes hematoma, eye hematoma, catheter site hematoma, oral mucosa hematoma, spontaneous hematoma, application site hematoma, injection site hematoma, periorbital hematoma. 11 (15) 0 3 (4) 0 Hypertension Grouped term includes blood pressure increased, essential hypertension, and hypertension. 9 (13) 3 (4) 6 (8) 4 (5) Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes pain in extremity, arthralgia, back pain, musculoskeletal stiffness, cancer pain, and neck pain. 21 (30) 3 (4) 6 (8) 1 (1) Respiratory, thoracic and mediastinal disorders Dyspnea Grouped term includes dyspnea, dyspnea exertional, hypoxia, respiration failure. 14 (20) 2 (3) 11 (15) 4 (5) Nervous system disorders Headache 8 (11) 0 2 (3) 0 Table 3: Select Laboratory Abnormalities Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. , The denominator used to calculate percentages is the number of treated subjects who can be evaluated for CTCAE criteria for each parameter in each arm. (≥10%) That Worsened from Baseline in Patients with AML Who Received TIBSOVO + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Parameter All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) Hematology Parameters Leukocytes decreased 46 (65) 39 (55) 47 (64) 42 (58) Platelets decreased 41 (58) 30 (42) 52 (71) 42 (58) Hemoglobin decreased 40 (56) 33 (46) 48 (66) 42 (58) Neutrophils decreased 18 (25) 16 (23) 25 (35) 23 (32) Lymphocytes increased 17 (24) 1 (1) 7 (10) 1 (1) Chemistry Parameters Glucose increased 40 (56) 9 (13) 34 (47) 8 (11) Phosphate decreased 29 (41) 7 (10) 25 (34) 9 (12) Aspartate Aminotransferase increased 26 (37) 0 17 (23) 0 Magnesium decreased 25 (35) 0 19 (26) 0 Alkaline Phosphatase increased 23 (32) 0 21 (29) 0 Potassium increased 17 (24) 2 (3) 9 (12) 1 (1) TIBSOVO Monotherapy 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 4. Table 4: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Newly Diagnosed AML in AG120-C-001 TIBSOVO (500 mg daily) N=28 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) Gastrointestinal disorders Diarrhea 17 (61) 2 (7) Nausea 10 (36) 2 (7) Abdominal pain Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 8 (29) 1 (4) Constipation 6 (21) 1 (4) Vomiting 6 (21) 1 (4) Mucositis Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 6 (21) 0 Dyspepsia 3 (11) 0 General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 14 (50) 4 (14) Edema Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 12 (43) 0 Metabolism and nutrition disorders Decreased appetite 11 (39) 1 (4) Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 10 (36) 2 (7) Differentiation Syndrome 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. 7 (25) 3 (11) Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 9 (32) 1 (4) Myalgia Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 7 (25) 1 (4) Respiratory, thoracic, and mediastinal disorders Dyspnea Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. 8 (29) 1 (4) Cough Grouped term includes cough, productive cough, and upper airway cough syndrome. 4 (14) 0 Investigations Electrocardiogram QT prolonged 6 (21) 3 (11) Weight decreased 3 (11) 0 Nervous system disorders Dizziness 6 (21) 0 Neuropathy Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. 4 (14) 0 Headache 3 (11) 0 Skin and subcutaneous tissue disorders Pruritus 4 (14) 1 (4) Rash 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. 4 (14) 1 (4) Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 5. Table 5: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly Diagnosed AML Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. in AG120-C-001 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 6. Table 6: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Relapsed or Refractory AML TIBSOVO (500 mg daily) N=179 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 69 (39) 6 (3) Edema Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 57 (32) 2 (1) Pyrexia 41 (23) 2 (1) Chest pain Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain 29 (16) 5 (3) Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 68 (38) 15 (8) Differentiation Syndrome 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. 34 (19) 23 (13) Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 64 (36) 8 (4) Myalgia Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 33 (18) 1 (1) Gastrointestinal disorders Diarrhea 60 (34) 4 (2) Nausea 56 (31) 1 (1) Mucositis Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 51 (28) 6 (3) Constipation 35 (20) 1 (1) Vomiting Grouped term includes vomiting and retching. 32 (18) 2 (1) Abdominal pain Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 29 (16) 2 (1) Respiratory, thoracic, and mediastinal disorders Dyspnea Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 59 (33) 16 (9) Cough Grouped term includes cough, productive cough, and upper airway cough syndrome. 40 (22) 1 (<1) Pleural effusion 23 (13) 5 (3) Investigations Electrocardiogram QT prolonged 46 (26) 18 (10) Skin and subcutaneous tissue disorders Rash 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. 46 (26) 4 (2) Metabolism and nutrition disorders Decreased appetite 33 (18) 3 (2) Tumor lysis syndrome 14 (8) 11 (6) Nervous system disorders Headache 28 (16) 0 Neuropathy Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barré syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 21 (12) 2 (1) Vascular disorders Hypotension Grouped term includes hypotension and orthostatic hypotension. 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 7. Table 7: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML 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 n (%) Grade ≥ 3 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) Relapsed or Refractory Myelodysplastic Syndromes The safety of TIBSOVO was evaluated in 19 adults with relapsed or refractory MDS treated with 500 mg daily in AG120-C-001 [see Clinical Studies (14.3) ] . The median duration of exposure to TIBSOVO was 9.3 months (range 3.3 to 78.8 months). Fourteen patients (74%) were exposed to TIBSOVO for at least 6 months and 8 patients (42%) were exposed for at least 1 year. Serious adverse reactions in ≥ 5% included differentiation syndrome (11%), fatigue (5%), and rash (5%). Permanent discontinuation of TIBSOVO due to an adverse reaction occurred in 5% of patients. The adverse reaction which resulted in permanent discontinuation of TIBSOVO was fatigue. Adverse reactions leading to dosage interruption of TIBSOVO occurred in 16% of patients. Adverse reactions which required dosage interruption in ≥ 5% were differentiation syndrome, leukocytosis, and rash. Dose reductions of TIBSOVO due to an adverse reaction occurred in 16% of patients. Adverse reactions which required a dose reduction in ≥ 5% included differentiation syndrome, fatigue, and rash. The most common (≥ 25%) adverse reactions, including laboratory abnormalities, were creatinine increased, hemoglobin decrease, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash. Table 8 summarizes the adverse reactions in AG120-C-001. Table 8: Adverse Reactions ≥ 10% in Patients with Relapsed or Refractory MDS in AG120-C-001 TIBSOVO (500 mg daily) N=19 Body System Adverse Reaction All Grades % Grade 3 or 4 % Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, pain in extremity, flank pain, joint swelling, and neck pain. 42 16 Myalgia Grouped term includes myalgia, muscle spasms, muscle discomfort, and musculoskeletal chest pain. 26 0 General disorders and administration site conditions Fatigue Grouped term includes fatigue and asthenia. 37 11 Respiratory, thoracic, and mediastinal disorders Cough 32 0 Dyspnea Grouped term includes dyspnea and dyspnea exertional. 21 0 Gastrointestinal disorders Diarrhea 32 0 Mucositis Grouped term includes oropharyngeal pain, gingivitis, mouth ulceration, stomatitis. 26 5 Constipation 16 0 Nausea 16 0 Skin and subcutaneous tissue disorders Pruritus 26 0 Rash Grouped term includes rash, catheter site erythema, and urticaria. 26 0 Metabolism and nutrition disorders Decreased appetite 26 0 Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and white blood cell count increased. 16 5 Differentiation Syndrome 11 0 Nervous system disorders Headache 16 0 Vascular disorders Hypertension 16 16 Investigations Electrocardiogram QT prolonged 11 0 Table 9 summarizes laboratory abnormalities in AG120-C-001. Table 9: Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients with Relapsed or Refractory MDS in AG120-C-001 TIBSOVO Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. N=19 Laboratory Abnormality All Grades % Grade 3 or 4 % Creatinine increased 95 5 Hemoglobin decreased 42 32 Albumin decreased 37 0 Aspartate Aminotransferase increased 37 5 Sodium decreased 32 5 Phosphate decreased 26 5 Alanine Aminotransferase increased 21 5 Bilirubin increased 21 0 Magnesium decreased 21 0 Alkaline Phosphatase increased 16 0 Potassium increased 16 0 Locally Advanced or Metastatic Cholangiocarcinoma The safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005 [see Clinical Studies (14.4) ] . Patients received at least one dose of either TIBSOVO 500 mg daily (N=123) or placebo (N=59). The median duration of treatment was 2.8 months (range 0.1 to 34.4 months) with TIBSOVO. Serious adverse reactions occurred in 34% of patients receiving TIBSOVO. Serious adverse reactions in ≥2% of patients in the TIBSOVO arm were pneumonia, ascites, hyperbilirubinemia, and jaundice cholestatic. Fatal adverse reactions occurred in 4.9% of patients receiving TIBSOVO, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%). TIBSOVO was permanently discontinued in 7% of patients. The most common adverse reactions leading to permanent discontinuation was acute kidney injury (1.6%). Dose interruptions due to adverse reactions occurred in 29% of patients treated with TIBSOVO. The most common (>2%) adverse reactions leading to dose interruption were hyperbilirubinemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue. Dose reductions of TIBSOVO due to an adverse reaction occurred in 4.1% of patients. Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3.3%) and neuropathy peripheral (0.8%). The most common adverse reactions (≥15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Adverse reactions and laboratory abnormalities observed in Study AG120-C-005 are shown in Tables 10 and 11. Table 10: Adverse Reactions Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005 TIBSOVO (500 mg daily) N=123 Placebo N=59 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 53 (43) 4 (3) 18 (31) 3 (5) Gastrointestinal disorders Nausea 51 (41) 3 (2) 17 (29) 1 (2) Diarrhea 43 (35) 0 10 (17) 0 Abdominal pain Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, epigastric discomfort, abdominal tenderness, and gastrointestinal pain. 43 (35) 3 (2) 13 (22) 2 (3) Ascites 28 (23) 11 (9) 9 (15) 4 (7) Vomiting Grouped term includes vomiting and retching. 28 (23) 3 (2) 12 (20) 0 Respiratory, thoracic, and mediastinal disorders Cough Grouped term includes cough and productive cough. 33 (27) 0 5 (9) 0 Metabolism and nutrition disorders Decreased appetite 30 (24) 2 (2) 11 (19) 0 Blood and lymphatic system disorders Anemia 22 (18) 8 (7) 3 (5) 0 Skin and subcutaneous tissue disorders Rash Grouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity. 19 (15) 1 (1) 4 (7) 0 Nervous system disorders Headache 16 (13) 0 4 (7) 0 Neuropathy peripheral Grouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paresthesia. 13 (11) 0 0 0 Investigations Electrocardiogram QT prolonged 12 (10) 2 (2) 2 (3) 0 Table 11: Selected Laboratory Abnormalities Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown. TIBSOVO (500 mg daily) N=123 Placebo N=59 Parameter All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) AST increased 41 (34) 5 (4) 14 (24) 1 (2) Bilirubin increased 36 (30) 15 (13) 11 (19) 2 (3) Hemoglobin decreased 48 (40) 8 (7) 14 (25) 0

12.3 Pharmacokinetics The AUC and C max of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). The following ivosidenib pharmacokinetic parameters (Table 12) were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady state), unless otherwise specified. The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML, relapsed or refractory AML, and relapsed or refractory MDS, and were lower in patients with cholangiocarcinoma. Table 12: Pharmacokinetics of ivosidenib Newly diagnosed AML treated with a combination of TIBSOVO and azacitidine Relapsed or refractory AML treated with TIBSOVO Relapsed or refractory MDS treated with TIBSOVO Cholangiocarcinoma treated with TIBSOVO PK parameters Single dose C max (ng/mL) PK parameters expressed as mean (%CV). 4,820 (39%) 4,503 (38%) 4,020 (31%) 4,060 (45%) Steady state C max (ng/mL) 6,145 (34%) 6,551 (44%) 5,820 (37%) 4,799 (33%) Steady state AUC (ng∙hr/mL) 106,326 (41%) 117,348 (50%) 103,770 (40%) 86,382 (34%) Steady state PK Within 14 days Accumulation C max 1.2 1.5 1.4 1.2 AUC 1.6 1.9 2 1.5 Absorption Median T max (hr) 2 3 3 2 Effect of Food Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories). C max 1.98-fold (90% CI: 1.79, 2.19) AUC 1.24-fold (90% CI: 1.16, 1.33) Distribution In vitro protein binding 92 to 96% Apparent volume of distribution at steady state (L) 504 (22%) 403 (35%) 552 (26%) 706 (45%) Elimination Apparent clearance at steady state (L/hr) 4.6 (35%) 5.6 (35%) 5.1 (35%) 6.1 (31%) Terminal half-life at steady state (hr) 98 (42%) 58 (42%) 96 (43%) 129 (102%) Metabolism Plasma Data from a single radiolabeled ivosidenib dose in healthy subjects. >92% of total radioactivity as ivosidenib Metabolic pathways Major CYP3A4 Minor N-dealkylation and hydrolytic pathways Excretion Urine 17% (10% as unchanged ivosidenib) Feces 77% (67% as unchanged ivosidenib) Specific Populations No clinically significant effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, mild or moderate hepatic impairment (Child-Pugh A or B) or mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m 2 , MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis or severe hepatic impairment (Child-Pugh C) is unknown. Drug Interaction Studies Clinical Studies and Model-Based Approaches Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib Co-administration of 250 mg ivosidenib with a strong CYP3A4 inhibitor (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC by 269% (90% CI: 245%, 295%) with no change in C max in healthy subjects . Co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) increases ivosidenib single-dose AUC by 173% with no change in C max . Co-administration of fluconazole following multiple daily ivosidenib doses is predicted to increase ivosidenib steady-state C max by 152% and AUC by 190% . Effect of Strong CYP3A4 Inducers on Ivosidenib Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% . Effect of Ivosidenib on CYP3A4 Substrates Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates, including certain azole anti-fungal agents, is expected to decrease CYP3A4 substrate steady-state AUC . Effect of Gastric Acid Reducing Agents on Ivosidenib No clinically significant ivosidenib pharmacokinetic differences were observed following co-administration with gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids). In vitro Studies Metabolic Pathways Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 . Drug Transporter Systems Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3. Ivosidenib is an inhibitor of OAT3 and P-gp. Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2.