TIBSOVO

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.

4 CONTRAINDICATIONS None. None ( 4 ).

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 AML and MDS 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 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. In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment. In the monotherapy clinical trial AG120-C-001, 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 [see Adverse Reactions (6.1) ] . 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. In the monotherapy clinical trial AG120-C-001, 11% (2/19) of patients with relapsed or refractory MDS treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 2 patients who experienced differentiation syndrome, both 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 and ventricular arrhythmias [see Clinical Pharmacology (12.2) ]. Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate corrected QT interval (using Fridericia's method) (QTcF) greater than 500 msec and 15 out of 69 (22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a QTcF ≥ 470 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Of the 265 patients with hematological malignancies, including patients with AML and MDS, treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 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 [see Adverse Reactions (6.1) ] . 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. Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study AG120-C-005), 2% were found to have a QTc interval greater than 500 msec and 5% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). 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 can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in 0.8% (2/265) of patients treated with TIBSOVO in study AG120-C-001 [see Adverse Reactions (6.1) ] . 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) ].

7 DRUG INTERACTIONS Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation ( 2.4 , 5.2 , 7.1 , 12.3 ). Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO ( 7.1 , 12.3 ). Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO ( 7.2 , 12.3 ). QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation ( 5.2 , 7.1 ). 7.1 Effect of Other Drugs on Ivosidenib Strong or Moderate CYP3A4 Inhibitors Clinical Impact Co-administration of TIBSOVO with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. Increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO. If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily [see Dosage and Administration (2.3) ]. Monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2) ] . Strong CYP3A4 Inducers Clinical Impact Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. Prevention or Management Avoid co-administration of strong CYP3A4 inducers with TIBSOVO. QTc Prolonging Drugs Clinical Impact Co-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management Avoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies. If co-administration of a QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [ see Warnings and Precautions (5.2) ]. 7.2 Effect of Ivosidenib on Other Drugs Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology (12.3) ] . Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 due to expected loss of antifungal efficacy. Co-administration of TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving TIBSOVO.

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

8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data ). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily. In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.