ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Differentiation Syndrome in AML [see Warnings and Precautions (5.1)] QTc Interval Prolongation [see Warnings and Precautions (5.2)] Guillain-Barre Syndrome [see Warnings and Precautions (5.3)] Differentiation Syndrome in AML [see Warnings and Precautions (5.1)] QTc Interval Prolongation [see Warnings and Precautions (5.2)] Guillain-Barre Syndrome [see Warnings and Precautions (5.3)] The most common adverse reactions (>=20%) in patients with AML were fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, electrocardiogram QT prolonged, rash, cough, decreased appetite, myalgia, constipation, and pyrexia (6.1).The most common laboratory abnormalities (>=20%) in patients with AML were hemoglobin decreased, calcium decreased, sodium decreased, magnesium decreased, uric acid increased, potassium decreased, alkaline phosphatase increased, aspartate aminotransferase increased, phosphate decreased, and creatinine increased (6.1).The most common adverse reactions (>=15%) in patients with cholangiocarcinoma were 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 were hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased.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 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 LeukemiaThe safety of TIBSOVO as single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001 [see Clinical Studies (14.1 and 14.2)]. The median age of TIBSOVO treated patients was 68 (range 18-87) with 68% >= 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received TIBSOVO, 37% were exposed for months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in >= 20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia.. Newly Diagnosed AMLThe 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 months and patients (21%) were exposed for at least 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 dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES.The most common adverse reactions reported in the trial are shown in Table 2.Table 2:Adverse Reactions Reported in >= 10% (Any Grade) or >= 5% (Grade >= 3) of Patients with Newly Diagnosed AMLTIBSOVO (500 mg daily) N=28Body System Adverse ReactionAll Grades (%)Grade >= n (%)Gastrointestinal disordersDiarrhea17 (61)2 (7)Nausea10 (36)2 (7)Abdominal painGrouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. (29)1 (4)Constipation6 (21)1 (4)Vomiting6 (21)1 (4)MucositisGrouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. (21)0Dyspepsia3 (11)0General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 14 (50)4 (14)EdemaGrouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 12 (43)0Metabolism and nutrition disordersDecreased appetite11 (39)1 (4)Blood system and lymphatic system disordersLeukocytosisGrouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 10 (36)2 (7)Differentiation SyndromeDifferentiation 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. (25)3 (11)Musculoskeletal and connective tissue disordersArthralgiaGrouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. (32)1 (4)MyalgiaGrouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. (25)1 (4)Respiratory, thoracic, and mediastinal disordersDyspneaGrouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. (29)1 (4)CoughGrouped term includes cough, productive cough, and upper airway cough syndrome. (14)0InvestigationsElectrocardiogram QT prolonged6 (21)3 (11)Weight decreased3 (11)0Nervous system disordersDizziness6 (21)0NeuropathyGrouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. (14)0Headache3 (11)0Skin and subcutaneous tissue disordersPruritis4 (14)1 (4)RashGrouped 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. (14)1 (4)Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 3.Table 3: Most Common (>= 10%) or >= 5% (Grade >= 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly Diagnosed AMLLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=28ParameterAll Grades (%)Grade >= n (%)Hemoglobin decreased15 (54)12 (43)Alkaline phosphatase increased13 (46)0Potassium decreased12 (43)3 (11)Sodium decreased11 (39)1 (4)Uric acid increased8 (29)1 (4)Aspartate aminotransferase increased8 (29)1 (4)Creatinine increased8 (29)0Magnesium decreased7 (25)0Calcium decreased7 (25)1 (4)Phosphate decreased6 (21)2 (7)Alanine aminotransferase increased4 (14)1 (4). Relapsed or Refractory AMLThe 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 months and 16 patients (9%) were exposed for at least 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 dose reduction due to an adverse reaction. Adverse reactions leading to 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-Barre syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).The most common adverse reactions reported in the trial are shown in Table 4.Table 4: Adverse Reactions Reported in >= 10% (Any Grade) or >= 5% (Grade >= 3) of Patients with Relapsed or Refractory AMLTIBSOVO (500 mg daily) N=179Body System Adverse ReactionAll Grades (%)Grade >= n (%)General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 69 (39)6 (3)EdemaGrouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 57 (32)2 (1)Pyrexia41 (23)2 (1)Chest painGrouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain. 29 (16)5 (3)Blood system and lymphatic system disordersLeukocytosisGrouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 68 (38)15 (8)Differentiation SyndromeDifferentiation 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 disordersArthralgiaGrouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 64 (36)8 (4)MyalgiaGrouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 33 (18)1 (1)Gastrointestinal disordersDiarrhea60 (34)4 (2)Nausea56 (31)1 (1)MucositisGrouped 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)Constipation35 (20)1 (1)VomitingGrouped term includes vomiting and retching. 32 (18)2 (1)Abdominal painGrouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 29 (16)2 (1)Respiratory, thoracic, and mediastinal disordersDyspneaGrouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 59 (33)16 (9)CoughGrouped term includes cough, productive cough, and upper airway cough syndrome. 40 (22)1 (<1)Pleural effusion23 (13)5 (3)InvestigationsElectrocardiogram QT prolonged46 (26)18 (10)Skin and subcutaneous tissue disordersRashGrouped 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 disordersDecreased appetite33 (18)3 (2)Tumor lysis syndrome14 (8)11 (6)Nervous system disordersHeadache28 (16)0NeuropathyGrouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barre syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 21 (12)2 (1)Vascular disordersHypotensionGrouped 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 5.Table 5: Most Common (>= 10%) or >= 5% (Grade >= 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AMLLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=179ParameterAll Grades (%)Grade >= n (%)Hemoglobin decreased108 (60)83 (46)Sodium decreased69 (39)8 (4)Magnesium decreased68 (38)0Uric acid increased57 (32)11 (6)Potassium decreased55 (31)11 (6)Alkaline phosphatase increased49 (27)1 (1)Aspartate aminotransferase increased49 (27)1 (1)Phosphate decreased45 (25)15 (8)Creatinine increased42 (23)2 (1)Alanine aminotransferase increased26 (15)2 (1)Bilirubin increased28 (16)1 (1). Locally Advanced or Metastatic CholangiocarcinomaThe safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005 [see Clinical Studies (14.3)]. 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 and 7.Table 6:Adverse Reactions Occurring in >= 10% of Patients Receiving TIBSOVO in Study AG120-C-005TIBSOVO (500 mg daily) N=123Placebo N=59Body System Adverse ReactionAll Grades (%)Grade >= n (%)All Grades (%)Grade >= n (%)General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 53 (43)4 (3)18 (31)3 (5)Gastrointestinal disordersNausea51 (41)3 (2)17 (29)1 (2)Diarrhea43 (35)010 (17)0Abdominal painGrouped 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)Ascites28 (23)11 (9)9 (15)4 (7)VomitingGrouped term includes vomiting and retching. 28 (23)3 (2)12 (20)0Respiratory, thoracic, and mediastinal disordersCoughGrouped term includes cough and productive cough. 33 (27)05 (9)0Metabolism and nutrition disordersDecreased appetite30 (24)2 (2)11 (19)0Blood and lymphatic system disordersAnemia22 (18)8 (7)3 (5)0Skin and subcutaneous tissue disordersRashGrouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity. 19 (15)1 (1)4 (7)0Nervous system disordersHeadache16 (13)04 (7)0Neuropathy peripheralGrouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paraesthesia. 13 (11)000InvestigationsElectrocardiogram QT prolonged12 (10)2 (2)2 (3)0Table 7:Selected Laboratory Abnormalities Occurring in >= 10% of Patients Receiving TIBSOVO in Study AG120-C-005Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown. TIBSOVO (500 mg daily) N=123Placebo N=59ParameterAll Grades (%)Grade >= n (%)All Grades (%)Grade >= n (%)AST increased41 (34)5 (4)14 (24)1 (2)Bilirubin increased36 (30)15 (13)11 (19)2 (3)Hemoglobin decreased48 (40)8 (7)14 (25)0.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ivosidenib is small molecule inhibitor that targets the mutant isocitrate dehydrogenase (IDH1) enzyme. In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions.Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2- HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.In patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C, ivosidenib reduced 2-HG levels.. 12.2 Pharmacodynamics. Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies and cholangiocarcinoma to levels similar to those observed at baseline in healthy subjects. In bone marrow of patients with hematological malignancies and in tumor biopsy of patients with cholangiocarcinoma, the mean [% coefficient of variation (%CV)] reduction in 2-HG concentrations were 93.1% (11.1%) and 82.2% (32.4%), respectively.. Cardiac ElectrophysiologyThe mean increase in QTc was 17 msec (UCI: 20 ms) following administration of TIBSOVO 500 mg in patients with newly diagnosed AML and patients with relapsed or refractory AML. The increase in QTc interval was concentration-dependent [see Warnings and Precautions (5.2)]. similar mean increase of 17 ms following administration of TIBSOVO 500 mg daily was observed in patients with solid tumors, including patients with cholangiocarcinoma. Co- administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.. 12.3 Pharmacokinetics. The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as 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 cholangiocarcinoma.In patients with AML, the mean (%CV) peak plasma concentration (Cmax) is 4,503 ng/mL (38%) after single dose, and 6,551 ng/mL (44%) at steady-state. The mean steady-state area under the concentration time curve (AUC) is 117,348 nghr/mL (50%). In patients with cholangiocarcinoma, the mean Cmax is 4,060 ng/mL (45%) after single dose, and 4,799 ng/mL (33%) at steady-state. The mean steady-state AUC is 86,382 nghr/mL (34%).The AUC and Cmax of ivosidenib increase in less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax in patients with AML and approximately 1.5 for AUC and 1.2 for Cmax in patients with cholangiocarcinoma over one month. Steady-state plasma levels are reached within 14 days.. AbsorptionThe median time to Cmax is approximately hours in patients with AML and hours in patients with cholangiocarcinoma.. Effect of FoodFollowing administration of single dose in healthy subjects, high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%. DistributionThe mean (%CV) apparent central volume of distribution (Vc/F) of ivosidenib at steady-state is 234 (47%) in patients with AML and 222 (26%) in patients with cholangiocarcinoma. Protein binding of ivosidenib ranges from 92 to 96% in vitro.. EliminationIn patients with AML, the mean (%CV) apparent clearance (CL/F) of ivosidenib at steady state is 5.6 L/hour (35%) with mean terminal half-life of 58 hours (42%). In patients with cholangiocarcinoma, the mean apparent clearance of ivosidenib at steady state is 6.1 L/hour (31%) with mean terminal half-life of 129 hours (102%).. MetabolismIvosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.. ExcretionAfter single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).. Specific PopulationsNo clinically meaningful 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, or mild or moderate renal impairment (eGFR >= 30 mL/min/1.73m2, MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis is unknown.. Patients with Hepatic ImpairmentFollowing single dose of TIBSOVO 500 mg, the geometric mean ratio (90% confidence interval) of ivosidenib systemic exposure (AUC0-INF) in subjects with mild hepatic impairment (Child-Pugh A) was 0.85 (0.62, 1.15) and moderate hepatic impairment (Child-Pugh B) was 0.71 (0.48, 1.05) as compared to that in subjects with normal hepatic function. The pharmacokinetics of ivosidenib in patients with 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 IvosidenibItraconazole was used as strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax In regard to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with TIBSOVO in patients (see Effect of Ivosidenib on CYP3A4 Substrates).Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in Cmax. In regard to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state Cmax to 152% of control and AUC to 190% of control [see Drug Interactions (7.1)]. Effect of Strong CYP3A4 Inducers on IvosidenibCo-administration of ivosidenib with strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% [see Drug Interactions (7.1)]. Effect of Ivosidenib on CYP3A4 SubstratesIvosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to clinically relevant extent [see Drug Interactions (7.2)]. Effect of Gastric Acid Reducing Agents on IvosidenibGastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.. In vitro Studies. Metabolic PathwaysIvosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes [see Drug Interactions (7.2)]. Drug Transporter SystemsIvosidenib is substrate for P-glycoprotein (P-gp). Ivosidenib is not substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Newly Diagnosed AML. The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by local or central diagnostic test and confirmed retrospectively using the Abbott RealTime(TM) IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of >= 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin 1.5 times the upper limit of normal, or creatinine clearance 45 mL/min. TIBSOVO was given orally at starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following TIBSOVO treatment.The baseline demographic and disease characteristics are shown in Table 8.Table 8:Baseline Demographic and Disease Characteristics in Patients with Newly Diagnosed AML (Study AG120-C-001)Demographic and Disease CharacteristicsTIBSOVO (500 mg daily) N=28ECOG PS: Eastern Cooperative Oncology Group Performance Status. ELN: European Leukemia NetDemographicsAge (Years) Median (Min, Max)77 (64, 87)Age Categories, (%)<65 years1 (4)>=65 years to <75 years8 (29)>= 75 years19 (68)Sex, (%)Male 15 (54)Female13 (46)Race, (%)White24 (86)Black or African American2 (7)Asian0Native Hawaiian/Other Pacific Islander0Other/Not provided2 (7)Disease CharacteristicsECOG PS, (%)06 (21)116 (57)25 (18)31 (4)IDH1 Mutation, (%)Using confirmatory Abbott RealTime IDH1 assay testing results. R132C24 (86)R132G1 (4)R132H2 (7)R132L1 (4)R132S0ELN Risk Category, (%)Favorable0Intermediate9 (32)Adverse19 (68)Transfusion Dependent at BaselinePatients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO., (%)17 (61)Type of AML, (%)De novo AML6 (21)AML-MRCAML with myelodysplasia-related changes. 19 (68) Therapy-related AML3 (11)Prior Hypomethylating Agent for AntecedentHematologic Disorder13 (46)Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 9. The median follow-up was 8.1 months (range, 0.6 to 40.9 months) and median treatment duration was 4.3 months (range, 0.3 to 40.9 months).Table 9:Efficacy Results in Patients with Newly Diagnosed AML (Study AG120-C- 001)EndpointTIBSOVO (500 mg daily) N=28CI: confidence interval, NE: not estimableCRCR (complete remission) was defined as <5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC] >1,000/microliter). (%)8 (28.6) 95% CI (13.2, 48.7) Median DOCRDOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier. indicates censored observation. (months) NEThe median durations of CR and CR+CRh were not estimable, with patients (41.7%) who achieved CR or CRh remaining on TIBSOVO treatment (treatment duration range: 20.3 to 40.9 months). 95% CI (4.2, NE)CRhCRh (complete remission with partial hematological recovery) was defined as <5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). (%) (14.3) 95% CI (4.0, 32.7) Observed DOCRh (months) 2.8, 4.6, 8.3, 15.7+CR+CRh (%)12 (42.9) 95% CI (24.5, 62.8) Median DOCR+CRh (months) NE 95% CI (4.2, NE)For patients who achieved CR or CRh, the median time to CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Of the 12 patients who achieved best response of CR or CRh, 11 (92%) achieved first response of CR or CRh within months of initiating TIBSOVO.Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, (54.5%) remained transfusion independent during any 56-day post- baseline period.. 14.2Relapsed or Refractory AML. The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by local or central diagnostic test and confirmed retrospectively using the Abbott RealTime(TM) IDH1 Assay. TIBSOVO was given orally at starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following TIBSOVO treatment.The baseline demographic and disease characteristics are shown in Table 10.Table 10:Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AML (Study AG120-C-001)Demographic and Disease CharacteristicsTIBSOVO (500 mg daily) N=174ECOG PS: Eastern Cooperative Oncology Group Performance Status.DemographicsAge (Years) Median (Min, Max)67 (18, 87)Age Categories, (%)<65 years63 (36)>=65 years to <75 years71 (41)>= 75 years40 (23)Sex, (%)Male 88 (51)Female86 (49)Race, (%)White108 (62)Black or African American10 (6)Asian6 (3)Native Hawaiian/Other Pacific Islander1 (1)Other/Not provided49 (28)Disease CharacteristicsECOG PS, (%)036 (21)197 (56)239 (22)32 (1)IDH1 Mutation, (%)Using confirmatory Abbott RealTime IDH1 assay testing results. R132C102 (59)R132H43 (25)R132G12 (7)R132S10 (6)R132L7 (4)Cytogenetic Risk Status, (%)Intermediate104 (60)Poor47 (27)Missing/Unknown23 (13)Relapse TypePrimary refractory64 (37)Refractory relapse45 (26)Untreated relapse65 (37)Relapse Number064 (37)183 (48)221 (12)>= 36 (3)Prior Stem Cell Transplantation for AML, (%)40 (23)Transfusion Dependent at BaselinePatients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO., (%)110 (63)Median Number of Prior Therapies (Min, Max)2 (1, 6)Type of AML, (%)De novo AML 116 (67)Secondary AML58 (33)Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 9. The median follow-up was 8.3 months (range, 0.2 to 39.5 months) and median treatment duration was 4.1 months (range, 0.1 to 39.5 months).Table 11:Efficacy Results in Patients with Relapsed or Refractory AML (Study AG120-C-001)EndpointTIBSOVO (500 mg daily) N=174CI: confidence intervalCRCR (complete remission) was defined as <5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC] >1,000/microliter). (%)43 (24.7) 95% CI (18.5, 31.8) Median DOCRDOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier. (months) 10.1 95% CI (6.5, 22.2)CRhCRh (complete remission with partial hematological recovery) was defined as <5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). (%)14 (8.0) 95% CI (4.5, 13.1) Median DOCRh (months) 3.6 95% CI (1, 5.5)CR+CRhCR+CRh rate appeared to be consistent across all baseline demographic and baseline disease characteristics with the exception of number of prior regimens. (%)57 (32.8) 95% CI (25.8, 40.3) Median DOCR+CRh (months) 8.2 95% CI (5.6, 12)For patients who achieved CR or CRh, the median time to CR or CRh was months (range, 0.9 to 5.6 months). Of the 57 patients who achieved best response of CR or CRh, all achieved first response of CR or CRh within months of initiating TIBSOVO.Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.. 14.3Locally Advanced or Metastatic Cholangiocarcinoma. The efficacy of TIBSOVO was evaluated in randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-005, NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following at least but not more than prior regimens, including at least one gemcitabine- or 5-FU-containing regimen. Patients were randomized to receive either TIBSOVO 500 mg orally once daily or matched placebo until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 or 2). Eligible patients who were randomized to placebo were allowed to cross over to receive TIBSOVO after documented radiographic disease progression. Patients with IDH1 mutations were selected using central diagnostic next generation sequencing assay. Tumor imaging assessments were performed every weeks for the first assessments and every weeks thereafter.The major efficacy outcome measure was Progression Free Survival (PFS) as determined by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.The median age was 62 years (range: 33 to 83); 63% were female; 57% were White, 12% Asian, 1.1% Black, 0.5% Native Hawaiian/Other Pacific Islander, 0.5% American Indian or Alaska Native, 28% race missing/not reported; and 37% had an ECOG performance status of (37%) or (62%). All patients received at least prior line of systemic therapy and 47% received two prior lines. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Across both arms, 70% patients had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.1% had an R132H mutation, and 1.6% had an R132S mutation.The efficacy results are shown in Table 12 and Figure 1. The study demonstrated statistically significant improvement in PFS.Table 12:Efficacy Results in Patients with Locally Advanced or Metastatic CholangiocarcinomaEndpointTIBSOVO (500 mg daily)PlaceboIRC: Independent Review Committee; CI: Confidence IntervalProgression-Free Survival by IRC AssessmentN=124N=61 Events, (%)76 (61)50 (82) Progressive Disease64 (52)44 (72) Death12 (10)6 (10) Hazard ratio (95% CI)Hazard ratio is calculated from stratified Cox regression model. Stratified by number of prior lines of therapy. 0.37 (0.25, 0.54) p-valueP-value is calculated from the one-sided stratified log-rank test. Stratified by number of prior lines of therapy. <0.0001Objective Response Rate, (%)3 (2.4)0Overall SurvivalOS results are based on the final analysis of OS (based on 150 deaths) which occurred 16 months after the final analysis of PFS. The median OS (95% CI) for TIBSOVO was 10.3 (7.8, 12.4) months; and placebo was 7.5 (4.8, 11.1) months without adjusting for crossover. In the analysis of OS, 70% of the patients randomized to placebo had crossed over to receive TIBSOVO after radiographic disease progression. N=126N=61 Deaths, (%)100 (79)50 (82) Hazard ratio (95% CI) 0.79 (0.56, 1.12) p-value 0.093Figure 1: Kaplan-Meier Plot of Progression-Free Survival per Independent Review Committee. Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LeukemiaThe safety of TIBSOVO as single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001 [see Clinical Studies (14.1 and 14.2)]. The median age of TIBSOVO treated patients was 68 (range 18-87) with 68% >= 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received TIBSOVO, 37% were exposed for months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in >= 20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia.. Newly Diagnosed AMLThe 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 months and patients (21%) were exposed for at least 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 dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES.The most common adverse reactions reported in the trial are shown in Table 2.Table 2:Adverse Reactions Reported in >= 10% (Any Grade) or >= 5% (Grade >= 3) of Patients with Newly Diagnosed AMLTIBSOVO (500 mg daily) N=28Body System Adverse ReactionAll Grades (%)Grade >= n (%)Gastrointestinal disordersDiarrhea17 (61)2 (7)Nausea10 (36)2 (7)Abdominal painGrouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. (29)1 (4)Constipation6 (21)1 (4)Vomiting6 (21)1 (4)MucositisGrouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. (21)0Dyspepsia3 (11)0General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 14 (50)4 (14)EdemaGrouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 12 (43)0Metabolism and nutrition disordersDecreased appetite11 (39)1 (4)Blood system and lymphatic system disordersLeukocytosisGrouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 10 (36)2 (7)Differentiation SyndromeDifferentiation 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. (25)3 (11)Musculoskeletal and connective tissue disordersArthralgiaGrouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. (32)1 (4)MyalgiaGrouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. (25)1 (4)Respiratory, thoracic, and mediastinal disordersDyspneaGrouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. (29)1 (4)CoughGrouped term includes cough, productive cough, and upper airway cough syndrome. (14)0InvestigationsElectrocardiogram QT prolonged6 (21)3 (11)Weight decreased3 (11)0Nervous system disordersDizziness6 (21)0NeuropathyGrouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. (14)0Headache3 (11)0Skin and subcutaneous tissue disordersPruritis4 (14)1 (4)RashGrouped 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. (14)1 (4)Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 3.Table 3: Most Common (>= 10%) or >= 5% (Grade >= 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly Diagnosed AMLLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=28ParameterAll Grades (%)Grade >= n (%)Hemoglobin decreased15 (54)12 (43)Alkaline phosphatase increased13 (46)0Potassium decreased12 (43)3 (11)Sodium decreased11 (39)1 (4)Uric acid increased8 (29)1 (4)Aspartate aminotransferase increased8 (29)1 (4)Creatinine increased8 (29)0Magnesium decreased7 (25)0Calcium decreased7 (25)1 (4)Phosphate decreased6 (21)2 (7)Alanine aminotransferase increased4 (14)1 (4). Relapsed or Refractory AMLThe 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 months and 16 patients (9%) were exposed for at least 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 dose reduction due to an adverse reaction. Adverse reactions leading to 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-Barre syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).The most common adverse reactions reported in the trial are shown in Table 4.Table 4: Adverse Reactions Reported in >= 10% (Any Grade) or >= 5% (Grade >= 3) of Patients with Relapsed or Refractory AMLTIBSOVO (500 mg daily) N=179Body System Adverse ReactionAll Grades (%)Grade >= n (%)General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 69 (39)6 (3)EdemaGrouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 57 (32)2 (1)Pyrexia41 (23)2 (1)Chest painGrouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain. 29 (16)5 (3)Blood system and lymphatic system disordersLeukocytosisGrouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 68 (38)15 (8)Differentiation SyndromeDifferentiation 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 disordersArthralgiaGrouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 64 (36)8 (4)MyalgiaGrouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 33 (18)1 (1)Gastrointestinal disordersDiarrhea60 (34)4 (2)Nausea56 (31)1 (1)MucositisGrouped 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)Constipation35 (20)1 (1)VomitingGrouped term includes vomiting and retching. 32 (18)2 (1)Abdominal painGrouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 29 (16)2 (1)Respiratory, thoracic, and mediastinal disordersDyspneaGrouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 59 (33)16 (9)CoughGrouped term includes cough, productive cough, and upper airway cough syndrome. 40 (22)1 (<1)Pleural effusion23 (13)5 (3)InvestigationsElectrocardiogram QT prolonged46 (26)18 (10)Skin and subcutaneous tissue disordersRashGrouped 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 disordersDecreased appetite33 (18)3 (2)Tumor lysis syndrome14 (8)11 (6)Nervous system disordersHeadache28 (16)0NeuropathyGrouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barre syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 21 (12)2 (1)Vascular disordersHypotensionGrouped 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 5.Table 5: Most Common (>= 10%) or >= 5% (Grade >= 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AMLLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. TIBSOVO (500 mg daily) N=179ParameterAll Grades (%)Grade >= n (%)Hemoglobin decreased108 (60)83 (46)Sodium decreased69 (39)8 (4)Magnesium decreased68 (38)0Uric acid increased57 (32)11 (6)Potassium decreased55 (31)11 (6)Alkaline phosphatase increased49 (27)1 (1)Aspartate aminotransferase increased49 (27)1 (1)Phosphate decreased45 (25)15 (8)Creatinine increased42 (23)2 (1)Alanine aminotransferase increased26 (15)2 (1)Bilirubin increased28 (16)1 (1). Locally Advanced or Metastatic CholangiocarcinomaThe safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005 [see Clinical Studies (14.3)]. 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 and 7.Table 6:Adverse Reactions Occurring in >= 10% of Patients Receiving TIBSOVO in Study AG120-C-005TIBSOVO (500 mg daily) N=123Placebo N=59Body System Adverse ReactionAll Grades (%)Grade >= n (%)All Grades (%)Grade >= n (%)General disorders and administration site conditionsFatigueGrouped term includes asthenia and fatigue. 53 (43)4 (3)18 (31)3 (5)Gastrointestinal disordersNausea51 (41)3 (2)17 (29)1 (2)Diarrhea43 (35)010 (17)0Abdominal painGrouped 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)Ascites28 (23)11 (9)9 (15)4 (7)VomitingGrouped term includes vomiting and retching. 28 (23)3 (2)12 (20)0Respiratory, thoracic, and mediastinal disordersCoughGrouped term includes cough and productive cough. 33 (27)05 (9)0Metabolism and nutrition disordersDecreased appetite30 (24)2 (2)11 (19)0Blood and lymphatic system disordersAnemia22 (18)8 (7)3 (5)0Skin and subcutaneous tissue disordersRashGrouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity. 19 (15)1 (1)4 (7)0Nervous system disordersHeadache16 (13)04 (7)0Neuropathy peripheralGrouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paraesthesia. 13 (11)000InvestigationsElectrocardiogram QT prolonged12 (10)2 (2)2 (3)0Table 7:Selected Laboratory Abnormalities Occurring in >= 10% of Patients Receiving TIBSOVO in Study AG120-C-005Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown. TIBSOVO (500 mg daily) N=123Placebo N=59ParameterAll Grades (%)Grade >= n (%)All Grades (%)Grade >= n (%)AST increased41 (34)5 (4)14 (24)1 (2)Bilirubin increased36 (30)15 (13)11 (19)2 (3)Hemoglobin decreased48 (40)8 (7)14 (25)0.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 500 mg orally once daily with or without food until disease progression or unacceptable toxicity (2.2). Avoid high-fat meal.. 2.1Patient Selection. Acute Myeloid LeukemiaSelect patients for the treatment of AML with TIBSOVO based on the presence of IDH1 mutations in the blood or bone marrow [see Clinical Studies (14.1)]. Patients with AML without IDH1 mutations at diagnosis should be retested at relapse because mutation in IDH1 may emerge during treatment and at relapse.. Locally Advanced or Metastatic CholangiocarcinomaSelect patients for the treatment of locally advanced or metastatic cholangiocarcinoma with TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.3)].Information on FDA-approved tests for the detection of IDH1 mutations in AML and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage. The recommended dose of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity.Administer TIBSOVO with or without food. Do not administer TIBSOVO with high-fat meal because of an increase in ivosidenib concentration [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Do not split or crush TIBSOVO tablets. Administer TIBSOVO tablets orally about the same time each day. If dose of TIBSOVO is vomited, do not administer replacement dose; wait until the next scheduled dose is due. If 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 doses within 12 hours.. Patients with Acute Myeloid LeukemiaFor patients without disease progression or unacceptable toxicity, treat for minimum of months to allow time for clinical response.. Patients with the Comorbidities of Severe Renal or Severe Hepatic ImpairmentTreatment with TIBSOVO has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO [see Use in Specific Populations (8.6, 8.7)]. 2.3Monitoring and Dose Modifications for Toxicities. Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly [see Adverse Reactions (6.1)]. Interrupt dosing or reduce dose for toxicities. See Table for dose modification guidelines.Table 1:Recommended Dose Modifications for TIBSOVOAdverse ReactionsRecommended ActionDifferentiation syndromeIf differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for minimum of days [see Warnings and Precautions (5.1)]. Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids [see Warnings and Precautions (5.1)]. Resume TIBSOVO when signs and symptoms improve to Grade 2Grade is mild, Grade is moderate, Grade is severe, Grade is life-threatening. or lower.Noninfectious leukocytosis (white blood cell [WBC] count greater than 25 109/L or an absolute increase in total WBC of greater than 15 109/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 msecMonitor and supplement electrolyte levels as clinically indicated [see Warnings and Precautions (5.2)].Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7.1)].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 weeks following resolution of QTc prolongation.QTc interval greater than 500 msecMonitor and supplement electrolyte levels as clinically indicated [see Warnings and Precautions (5.2)].Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7.1)]. Interrupt TIBSOVO.Resume TIBSOVO at 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 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 arrhythmiaDiscontinue TIBSOVO permanently [see Warnings and Precautions (5.2)].Guillain-Barre syndromeDiscontinue TIBSOVO permanently [see Warnings and Precautions (5.3)].Other Grade adverse reactionsAML:Interrupt TIBSOVO until toxicity resolves to Grade or lower.Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade or lower.If Grade or higher toxicity recurs, discontinue TIBSOVO.Cholangiocarcinoma:Interrupt TIBSOVO until toxicity resolves to Grade or lower, or baseline, then resume at 500 mg daily (Grade toxicity) or 250 mg daily (Grade toxicity).If Grade toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily.If Grade toxicity recurs (a third time), or Grade toxicity recurs, discontinue TIBSOVO. Differentiation syndrome. If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for minimum of days [see Warnings and Precautions (5.1)]. Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids [see Warnings and Precautions (5.1)]. Resume TIBSOVO when signs and symptoms improve to Grade 2Grade is mild, Grade is moderate, Grade is severe, Grade is life-threatening. or lower.. Noninfectious leukocytosis (white blood cell [WBC] count greater than 25 109/L or an absolute increase in total WBC of greater than 15 109/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. Monitor and supplement electrolyte levels as clinically indicated [see Warnings and Precautions (5.2)].. Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7.1)].. 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 weeks following resolution of QTc prolongation.. QTc interval greater than 500 msec. Monitor and supplement electrolyte levels as clinically indicated [see Warnings and Precautions (5.2)].. Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7.1)]. Interrupt TIBSOVO.. Resume TIBSOVO at 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 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. Discontinue TIBSOVO permanently [see Warnings and Precautions (5.2)].. Guillain-Barre syndrome. Discontinue TIBSOVO permanently [see Warnings and Precautions (5.3)].. Other Grade adverse reactions. Interrupt TIBSOVO until toxicity resolves to Grade or lower.. Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade or lower.. If Grade or higher toxicity recurs, discontinue TIBSOVO.. Interrupt TIBSOVO until toxicity resolves to Grade or lower, or baseline, then resume at 500 mg daily (Grade toxicity) or 250 mg daily (Grade toxicity).. If Grade toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily.. If Grade toxicity recurs (a third time), or Grade toxicity recurs, discontinue TIBSOVO.. Patients with Acute Myeloid LeukemiaAssess 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.. 2.4Dose Modification for Use with Strong CYP3A4 Inhibitors. If 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 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

DRUG INTERACTIONS SECTION.

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).. 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).. 7.1Effect of Other Drugs on Ivosidenib. Strong or Moderate CYP3A4 InhibitorsClinical ImpactCo-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 ManagementConsider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO.If co-administration of 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 InducersClinical ImpactCo-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3)]. Prevention or ManagementAvoid co-administration of strong CYP3A4 inducers with TIBSOVO.QTc Prolonging DrugsClinical ImpactCo-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2)]. Prevention or ManagementAvoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies.If co-administration of QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2)]. 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)]. Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO.. If co-administration of 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)]. Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid co-administration of strong CYP3A4 inducers with TIBSOVO.. Co-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2)]. Avoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies.. If co-administration of QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2)]. 7.2Effect 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. Do not administer TIBSOVO with itraconazole or ketoconazole (CYP3A4 substrates) 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. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Differentiation Syndrome in AMLAdvise patients with AML being treated with TIBSOVO of the risks of developing differentiation syndrome as early as day after start of therapy and during the first months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].. QTc Interval ProlongationInform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider [see Warnings and Precautions (5.2)]. Guillain-Barre SyndromeInform patients of symptoms that may be indicative of Guillain-Barre syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing. Advise patients to report these symptoms to their healthcare provider [see Warnings and Precautions (5.3)]. Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7)]. Tumor Lysis SyndromeAdvise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values [see Adverse Reactions (6.1)].. Gastrointestinal Adverse ReactionsAdvise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite, ascites and abdominal pain. Ask patients to report these events to their healthcare provider and advise patients how to manage them [see Adverse Reactions (6.1)]. LactationAdvise women not to breastfeed during treatment with TIBSOVO and for at least month after the final dose [see Use in Specific Populations (8.2)]. Dosing and Storage InstructionsAdvise patients to swallow tablets whole and to not split, crush, or chew TIBSOVO tablets.Advise patients to avoid taking TIBSOVO with high-fat meal.Instruct patients that if dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.Store TIBSOVO at room temperature from 20C to 25C (68F to 77F).. Advise patients to swallow tablets whole and to not split, crush, or chew TIBSOVO tablets.. Advise patients to avoid taking TIBSOVO with high-fat meal.. Instruct patients that if dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.. Store TIBSOVO at room temperature from 20C to 25C (68F to 77F).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as 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 cholangiocarcinoma.In patients with AML, the mean (%CV) peak plasma concentration (Cmax) is 4,503 ng/mL (38%) after single dose, and 6,551 ng/mL (44%) at steady-state. The mean steady-state area under the concentration time curve (AUC) is 117,348 nghr/mL (50%). In patients with cholangiocarcinoma, the mean Cmax is 4,060 ng/mL (45%) after single dose, and 4,799 ng/mL (33%) at steady-state. The mean steady-state AUC is 86,382 nghr/mL (34%).The AUC and Cmax of ivosidenib increase in less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax in patients with AML and approximately 1.5 for AUC and 1.2 for Cmax in patients with cholangiocarcinoma over one month. Steady-state plasma levels are reached within 14 days.. AbsorptionThe median time to Cmax is approximately hours in patients with AML and hours in patients with cholangiocarcinoma.. Effect of FoodFollowing administration of single dose in healthy subjects, high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%. DistributionThe mean (%CV) apparent central volume of distribution (Vc/F) of ivosidenib at steady-state is 234 (47%) in patients with AML and 222 (26%) in patients with cholangiocarcinoma. Protein binding of ivosidenib ranges from 92 to 96% in vitro.. EliminationIn patients with AML, the mean (%CV) apparent clearance (CL/F) of ivosidenib at steady state is 5.6 L/hour (35%) with mean terminal half-life of 58 hours (42%). In patients with cholangiocarcinoma, the mean apparent clearance of ivosidenib at steady state is 6.1 L/hour (31%) with mean terminal half-life of 129 hours (102%).. MetabolismIvosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.. ExcretionAfter single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).. Specific PopulationsNo clinically meaningful 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, or mild or moderate renal impairment (eGFR >= 30 mL/min/1.73m2, MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis is unknown.. Patients with Hepatic ImpairmentFollowing single dose of TIBSOVO 500 mg, the geometric mean ratio (90% confidence interval) of ivosidenib systemic exposure (AUC0-INF) in subjects with mild hepatic impairment (Child-Pugh A) was 0.85 (0.62, 1.15) and moderate hepatic impairment (Child-Pugh B) was 0.71 (0.48, 1.05) as compared to that in subjects with normal hepatic function. The pharmacokinetics of ivosidenib in patients with 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 IvosidenibItraconazole was used as strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax In regard to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with TIBSOVO in patients (see Effect of Ivosidenib on CYP3A4 Substrates).Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in Cmax. In regard to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state Cmax to 152% of control and AUC to 190% of control [see Drug Interactions (7.1)]. Effect of Strong CYP3A4 Inducers on IvosidenibCo-administration of ivosidenib with strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% [see Drug Interactions (7.1)]. Effect of Ivosidenib on CYP3A4 SubstratesIvosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to clinically relevant extent [see Drug Interactions (7.2)]. Effect of Gastric Acid Reducing Agents on IvosidenibGastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.. In vitro Studies. Metabolic PathwaysIvosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes [see Drug Interactions (7.2)]. Drug Transporter SystemsIvosidenib is substrate for P-glycoprotein (P-gp). Ivosidenib is not substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised Aug 2021MEDICATION GUIDETIBSOVO(R) (tib-SOH-voh) (ivosidenib tablets)What is the most important information should know about TIBSOVOTIBSOVO may cause serious side effects, including:Differentiation Syndrome. Differentiation syndrome is condition that affects your blood cells and may be life-threatening or lead to death if not treated. Differentiation syndrome in adults with acute myeloid leukemia (AML) has happened as early as day and up to months after starting TIBSOVO. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome during treatment with TIBSOVO:fevercoughtrouble breathingrashdecreased urinationdizziness or lightheadednessrapid weight gainswelling of your arms or legsIf you develop signs and symptoms of differentiation syndrome, your healthcare provider may treat you with corticosteroid medicine or medicine called hydroxyurea and may monitor you in the hospital.See What are the possible side effects of TIBSOVO for more information about side effects.What is TIBSOVOTIBSOVO is prescription medicine used to treat:acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation in:adults with newly diagnosed AML who are 75 years or older or who have health problems that prevent the use of certain chemotherapy treatments.adults with AML when the disease has come back or has not improved after previous treatment(s).adults with bile duct cancer (cholangiocarcinoma) that has spread:who have already received previous treatment(s) andwhose tumor has certain type of abnormal IDH1 mutationYour healthcare provider will perform test to make sure that TIBSOVO is right for you. It is not known if TIBSOVO is safe and effective in children.Before taking TIBSOVO, tell your healthcare provider about all of your medical conditions, including if you:have any heart problems, including condition called long QT syndrome.have problems with abnormal electrolytes, such as sodium, potassium, calcium or magnesium levels.have nervous system problems.have problems with your kidneys or are on dialysis.have any liver disorders, including cirrhosis.are pregnant or plan to become pregnant. TIBSOVO may cause harm to your unborn baby. You should avoid becoming pregnant during treatment with TIBSOVO. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with TIBSOVO.are breastfeeding or plan to breastfeed. It is not known if TIBSOVO passes into your breast milk. Do not breastfeed during your treatment with TIBSOVO and for at least month after your last dose of TIBSOVO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Especially tell your healthcare provider if you take hormonal contraceptives. TIBSOVO may affect how hormonal contraceptives work and may cause them to not work as well.How should take TIBSOVOTake TIBSOVO exactly as your healthcare provider tells you to.Do not change your dose or stop taking TIBSOVO without talking to your healthcare provider.Take TIBSOVO time day about the same time each day.Swallow TIBSOVO tablets whole. Do not split, crush, or chew the tablet.TIBSOVO can be taken with or without food.Do not take TIBSOVO with high-fat meal. An example of high-fat meal includes eggs fried in butter, strips of bacon, slices of white bread with butter, croissant with slice of cheese, and ounces of whole milk (approximately 1,000 calories and 58 grams of fat).If you vomit after taking dose of TIBSOVO, do not take an additional dose. Take your next dose at your usual time.If you miss dose of TIBSOVO or did not take it at the usual time, take your dose as soon as possible and at least 12 hours before your next dose. Return to your normal schedule the following day. Do not take doses of TIBSOVO within 12 hours.What are the possible side effects of TIBSOVO TIBSOVO may cause serious side effects, including:See What is the most important information should know about TIBSOVO Changes in the electrical activity of your heart called QTc prolongation. QTc prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will check the electrical activity of your heart with test called an electrocardiogram (ECG) during treatment with TIBSOVO. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint.Guillain-Barre syndrome has happened in people treated with TIBSOVO. Your healthcare provider will monitor you for nervous system problems and will permanently stop your treatment with TIBSOVO if you develop Guillain-Barre syndrome. Tell your healthcare provider right away if you develop any signs or symptoms of Guillain-Barre syndrome, including:weakness or tingling feeling in your legs, arms, or upper bodynumbness and pain on one side or both sides of your bodyany changes in your ability to see, touch, hear, or tasteburning or prickling sensationdifficulty breathingThe most common side effects of TIBSOVO in adults with AML include:fatiguejoint painhigh white blood cell countdiarrheaswelling of arms or legsnauseashortness of breathpain or sores in your mouth or throatirregular heart rhythm or heartbeat (QTc prolongation)rashcoughdecreased appetitemuscle painconstipationfeverhemoglobin decreased (anemia)decreased levels of electrolytes in the bloodchanges in liver or kidney function testsThe most common side effects of TIBSOVO in adults with Cholangiocarcinoma include:fatiguenauseaabdominal paindiarrheacoughdecreased appetitefluid and swelling in your stomach areavomitinghemoglobin decreased (anemia)rashchanges in liver function testsYour healthcare provider will do blood tests before you start and during treatment with TIBSOVO. Your healthcare provider may decrease, temporarily hold, or permanently stop your treatment with TIBSOVO if you develop certain side effects.TIBSOVO may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of TIBSOVO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TIBSOVOStore TIBSOVO at room temperature between 68F to 77F (20C to 25C).Keep TIBSOVO and all medicines out of the reach of children.General information about the safe and effective use of TIBSOVOMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not take TIBSOVO for conditions for which it was not prescribed. Do not give TIBSOVO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TIBSOVO that is written for healthcare professionals.What are the ingredients in TIBSOVO Active ingredient: ivosidenibInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating includes FD&C blue 2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin.Manufactured for Servier Pharmaceuticals LLC, Boston, MA 02210 Servier and the Servier logo are trademarks of Les Laboratoires Servier. TIBSOVO(R) is registered trademark of Servier Pharmaceuticals LLC, wholly owned, indirect subsidiary of Les Laboratoires Servier. (C) 2021 Servier Pharmaceuticals LLC AG-MG-004 For more information go to www.TIBSOVO.com or call 1-800-807-6124.. Differentiation Syndrome. Differentiation syndrome is condition that affects your blood cells and may be life-threatening or lead to death if not treated. Differentiation syndrome in adults with acute myeloid leukemia (AML) has happened as early as day and up to months after starting TIBSOVO. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome during treatment with TIBSOVO:. fever. cough. trouble breathing. rash. decreased urination. dizziness or lightheadedness. rapid weight gain. swelling of your arms or legs. acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation in:. adults with newly diagnosed AML who are 75 years or older or who have health problems that prevent the use of certain chemotherapy treatments.. adults with AML when the disease has come back or has not improved after previous treatment(s).. adults with bile duct cancer (cholangiocarcinoma) that has spread:. who have already received previous treatment(s) and. whose tumor has certain type of abnormal IDH1 mutation. have any heart problems, including condition called long QT syndrome.. have problems with abnormal electrolytes, such as sodium, potassium, calcium or magnesium levels.. have nervous system problems.. have problems with your kidneys or are on dialysis.. have any liver disorders, including cirrhosis.. are pregnant or plan to become pregnant. TIBSOVO may cause harm to your unborn baby. You should avoid becoming pregnant during treatment with TIBSOVO. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with TIBSOVO.. are breastfeeding or plan to breastfeed. It is not known if TIBSOVO passes into your breast milk. Do not breastfeed during your treatment with TIBSOVO and for at least month after your last dose of TIBSOVO.. Take TIBSOVO exactly as your healthcare provider tells you to.. Do not change your dose or stop taking TIBSOVO without talking to your healthcare provider.. Take TIBSOVO time day about the same time each day.. Swallow TIBSOVO tablets whole. Do not split, crush, or chew the tablet.. TIBSOVO can be taken with or without food.. Do not take TIBSOVO with high-fat meal. An example of high-fat meal includes eggs fried in butter, strips of bacon, slices of white bread with butter, croissant with slice of cheese, and ounces of whole milk (approximately 1,000 calories and 58 grams of fat).. If you vomit after taking dose of TIBSOVO, do not take an additional dose. Take your next dose at your usual time.. If you miss dose of TIBSOVO or did not take it at the usual time, take your dose as soon as possible and at least 12 hours before your next dose. Return to your normal schedule the following day. Do not take doses of TIBSOVO within 12 hours.. See What is the most important information should know about TIBSOVO Changes in the electrical activity of your heart called QTc prolongation. QTc prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will check the electrical activity of your heart with test called an electrocardiogram (ECG) during treatment with TIBSOVO. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint.. Guillain-Barre syndrome has happened in people treated with TIBSOVO. Your healthcare provider will monitor you for nervous system problems and will permanently stop your treatment with TIBSOVO if you develop Guillain-Barre syndrome. Tell your healthcare provider right away if you develop any signs or symptoms of Guillain-Barre syndrome, including:. weakness or tingling feeling in your legs, arms, or upper body. numbness and pain on one side or both sides of your body. any changes in your ability to see, touch, hear, or taste. burning or prickling sensation. difficulty breathing. fatigue. joint pain. high white blood cell count. diarrhea. swelling of arms or legs. nausea. shortness of breath. pain or sores in your mouth or throat. irregular heart rhythm or heartbeat (QTc prolongation). rash. cough. decreased appetite. muscle pain. constipation. fever. hemoglobin decreased (anemia). decreased levels of electrolytes in the blood. changes in liver or kidney function tests. fatigue. nausea. abdominal pain. diarrhea. cough. decreased appetite. fluid and swelling in your stomach area. vomiting. hemoglobin decreased (anemia). rash. changes in liver function tests. Store TIBSOVO at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed (8.2).. 8.1 Pregnancy. Risk SummaryBased on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform 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 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 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 DataIvosidenib administered to pregnant rats at 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 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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least month after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of TIBSOVO in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 34 patients with newly diagnosed AML treated with TIBSOVO, 97% were 65 years of age or older, and 56% were 75 years or older. Of the 179 patients with relapsed or refractory AML treated with TIBSOVO, 63% were 65 years of age or older and 22% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older.No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.. 8.6 Renal Impairment. No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR >= 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR 30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis are unknown [see Clinical Pharmacology (12.3)]. For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with TIBSOVO.. 8.7 Hepatic Impairment. No modification of the starting dose is recommended for patients with mild or moderate (Child- Pugh or B) hepatic impairment [see Clinical Pharmacology (12.3)]. The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.

WARNINGS AND PRECAUTIONS SECTION.

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-Barre Syndrome: Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barre syndrome (2.3, 5.3).. 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-Barre Syndrome: Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barre syndrome (2.3, 5.3).. 5.1Differentiation Syndrome in AML. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the patients with newly diagnosed AML who experienced differentiation syndrome, (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 day and up to 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 minimum of 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)]. 5.2QTc Interval Prolongation. Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology (12.2)] and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with TIBSOVO in the clinical trial (AG120-C-001), 9% were found to have QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of >= 450 msec (unless the QTc >= 450 msec was due to pre-existing bundle branch block) or with 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 QTc interval greater than 500 msec. and 5% of patients had an increase from baseline QTc greater than 60 msec. The clinical trial excluded patients with heart-rate corrected QT interval (using Fridericias 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-HT3 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) ].. 5.3Guillain-Barre Syndrome. Guillain-Barre syndrome can develop in patients treated with TIBSOVO. Guillain-Barre syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in study AG120-C-001.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- Barre syndrome [see Dosage and Administration (2.3)].