Vorasidenib

1 INDICATIONS AND USAGE VORANIGO is indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14) ] . VORANIGO is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage in adults: ( 2.3 ) 40 mg orally once daily Recommended dosage in pediatric patients 12 years of age and older based on body weight: ( 2.3 ) ≥40 kg : 40 mg orally once daily <40 kg : 20 mg orally once daily Take with or without food. ( 2.3 ) 2.1 Recommended Evaluation Before Initiating VORANIGO Before initiating VORANIGO, evaluate blood chemistry and liver laboratory tests [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. 2.2 Patient Selection Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment with VORANIGO based on the presence of IDH1 or IDH2 mutations in tumor specimens [see Clinical Studies (14) ] . Information on FDA-approved tests for detection of IDH1 or IDH2 mutations in Grade 2 astrocytoma or oligodendroglioma for selecting patients for treatment with VORANIGO is available at: https://www.fda.gov/CompanionDiagnostics. 2.3 Recommended Dosage and Administration Recommended Dosage Adult Patients The recommended dosage of VORANIGO in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity. Pediatric Patients 12 Years and Older The recommended dosage of VORANIGO in pediatric patients 12 years and older is based on body weight: Patients weighing ≥40 kg: 40 mg orally once daily Patients weighing <40 kg: 20 mg orally once daily Continue treatment with VORANIGO until disease progression or unacceptable toxicity. Administration Swallow VORANIGO tablets whole with water with or without food [see Clinical Pharmacology (12.3) ] . Do not split, crush or chew tablets. Missed Dose Take VORANIGO tablets at about the same time each day. If a dose is missed, take the missed dose as soon as possible within 6 hours. If a dose is missed by more than 6 hours, skip the missed dose and take the next dose at the scheduled time. Vomiting If vomiting occurs after taking a dose, do not take a replacement dose, and take the next dose at the scheduled time on the following day. 2.4 Dosage Modifications, Management and Monitoring for Adverse Reactions The recommended VORANIGO dosage reductions for adverse reactions are provided in Table 1. Table 1: Recommended VORANIGO Dosage Reductions for Adverse Reactions Dosage Reduction Recommended Dose and Schedule Adult patients and Pediatric patients 12 years and older weighing at least 40 kg First 20 mg once daily Second 10 mg once daily Pediatric patients 12 years and older weighing less than 40 kg First 10 mg once daily Permanently discontinue VORANIGO in patients unable to tolerate 10 mg once daily. The recommended management for adverse reactions and VORANIGO dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended VORANIGO Dosage Modifications and Management for Adverse Reactions Adverse Reaction Severity Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Management and Dosage Modifications Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal Hepatotoxicity (Elevation of ALT or AST) [see Warnings and Precautions (5.1) ] Grade 1 ALT or AST increase >ULN to 3 × ULN without concurrent total bilirubin >2 × ULN Continue VORANIGO at current dose. Monitor liver laboratory tests weekly until recovery to <Grade 1. Grade 2 ALT or AST >3 to 5 × ULN without concurrent total bilirubin >2 × ULN First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline. Recovery in ≤28 days, resume VORANIGO at the same dose. Recovery in >28 days, resume VORANIGO at reduced dose [see Table 1 ] . Recurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline, and resume VORANIGO at reduced dose [see Table 1 ] . Grade 3 ALT or AST >5 to 20 × ULN without concurrent total bilirubin >2 × ULN First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline. Recovery in ≤28 days, resume VORANIGO at reduced dose [see Table 1 ] . If not recovered in ≤28 days, permanently discontinue VORANIGO. Recurrence: Permanently discontinue VORANIGO. Grade 2 or 3 Any ALT or AST >3 to 20 × ULN with concurrent total bilirubin >2 × ULN First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline. Resume VORANIGO at reduced dose [see Table 1 ] . Recurrence: Permanently discontinue VORANIGO. Grade 4 Any ALT or AST >20 × ULN Permanently discontinue VORANIGO. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline. Resume VORANIGO at reduced dose [see Table 1 ] . Recurrence: Permanently discontinue VORANIGO. Grade 4 Permanently discontinue VORANIGO.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] The most common (≥15%) adverse reactions include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure. Grade 3 or 4 (≥2%) laboratory abnormalities were ALT increased, AST increased, GGT increased, and neutrophils decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions described in the WARNINGS AND PRECAUTIONS reflect exposure to VORANIGO 40 mg orally once daily until disease progression or unacceptable toxicity in the 244 patients with astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutation in trials AG881-C-002 (NCT02481154, n=11), AG120-881-001 (NCT03343197, n=14) and INDIGO (NCT04164901, n=167 randomized patients and n=52 crossover patients). Among the 244 patients who received VORANIGO, 78% were exposed for 6 months or longer and 44% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions were fatigue (33%), headache (28%), COVID-19 (28%), musculoskeletal pain (24%), diarrhea (21%), nausea (20%), and seizure (16%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%). INDIGO The safety of VORANIGO was evaluated in 330 patients with Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation who received at least one dose of either VORANIGO 40 mg daily (N=167) or placebo (N=163) in the INDIGO trial [see Clinical Studies (14) ] . Patients received VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. Among the 167 patients who were randomized and received VORANIGO, the median duration of exposure to VORANIGO was 12.7 months (range: 1 to 30 months) with 153 patients (92%) exposed to VORANIGO for at least 6 months and 89 (53%) exposed for at least 1 year. The demographics of patients randomized to VORANIGO were: median age 41 years (range: 21 to 71 years); 60% male, 74% White, 20% race not reported, 3% Asian, and 1.2% Black or African American; and 5% were Hispanic or Latino. Serious adverse reactions occurred in 7% of patients who received VORANIGO. The most common serious adverse reactions occurring in ≥2% of patients who received VORANIGO includes seizure (3%). Permanent discontinuation of VORANIGO due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of VORANIGO in ≥2% of patients included ALT increased (3%). Dosage interruptions of VORANIGO due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dose interruption in ≥5% of patients included ALT increased (14%), COVID-19 (9%), and AST increased (6%). Dose reductions of VORANIGO due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reduction in ≥5% of patients included ALT increased (8%). The most common (≥15%) adverse reactions were fatigue (37%), COVID-19 (33%), musculoskeletal pain (26%), diarrhea (25%), and seizure (16%). Grade 3 or 4 (≥2%) laboratory abnormalities were ALT increased (10%), AST increased (4.8%), GGT increased (3%) and neutrophil decreased (2.4%). Adverse reactions and select laboratory abnormalities reported in the INDIGO trial are shown in Tables 3 and 4. Table 3: Adverse Reactions (≥5%) in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO Compared with Placebo in the INDIGO Trial VORANIGO 40 mg daily (n=167) Placebo (n=163) Adverse Reaction Adverse reactions are based on NCI CTCAE v5.0. All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) General Disorders Fatigue Grouped term includes asthenia. 37 0.6 36 1.2 Infections and Infestations COVID-19 33 0 29 0 Nervous System Disorders Seizure Grouped term includes partial seizures, generalized tonic-clonic seizure, epilepsy, clonic convulsion, and simple partial seizures. 16 4.2 15 3.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Grouped term includes arthralgia, back pain, non-cardiac chest pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, arthritis, and musculoskeletal stiffness. 26 0 25 1.8 Gastrointestinal Disorders Diarrhea Grouped term includes feces soft and frequent bowel movements. 25 0.6 17 0.6 Constipation 13 0 12 0 Abdominal pain Grouped term includes abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. 13 0 12 0 Decreased appetite 9 0 3.7 0 Table 4: Select Laboratory Abnormalities (≥5%) That Worsened from Baseline in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO in the INDIGO Trial VORANIGO 40 mg daily N=167 Placebo N=163 Parameter All Grades Based on NCI CTCAE v5.0. (% The denominator used to calculate percentages is N, the number of subjects in the Safety Analysis Set within each treatment group. ) Grades 3 or 4 (% ) All Grades (% ) Grades 3 or 4 (% ) Abbreviations: AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; GGT = Gamma-Glutamyl Transferase; ALP = Alkaline Phosphatase Chemistry Increased ALT 59 10 25 0 Increased AST 46 4.8 20 0 Increased Creatinine 11 0.6 7 0 Decreased Calcium 10 0 7 0 Increased Glucose Includes adverse reaction term hyperglycemia. 10 0 4.3 0 Increased GGT 38 3 10 1.8 Decreased Phosphate Includes adverse reaction terms hypophosphatemia and blood phosphorus decreased. 8 0.6 4.9 0 Increased Potassium 23 0.6 20 0 Increased ALP 10 1.2 7 0.6 Hematology Increased Hemoglobin 13 0 3.1 0 Decreased Lymphocytes 11 1.8 8 0.6 Decreased Leukocytes 13 0.6 12 0.6 Decreased Neutrophils 14 2.4 12 1.8 Decreased Platelets 12 0 4.3 0

12.3 Pharmacokinetics Vorasidenib maximum plasma concentration (C max ) and AUC increased approximately proportionally over the dose range of 10 to 200 mg (0.2 to 4 times the exposure of the highest approved recommended dosage) following once daily administration of single and multiple doses. At the highest approved recommended dosage, steady state mean (CV%) C max is 133 ng/mL (73%) and AUC is 1,988 h•ng/mL (95%). Steady state is achieved within 28 days of once daily dosing and the mean accumulation ratio of AUC is 4.4. Absorption The median (minimum, maximum) time to maximum plasma concentrations (t max ) at steady state is 2 hours (0.5 to 4 hours). The mean absolute bioavailability of vorasidenib is 34%. Food Effect A high-fat and high-calorie (total 800-1,000 calories, of which 500-600 from fat) meal increased vorasidenib C max 3.1-fold and AUC 1.4-fold, compared to the fasting conditions. A low-fat and low-calorie (total 400-500 calories, of which 100-125 from fat) meal increased vorasidenib C max 2.3-fold and AUC 1.4-fold, compared to the fasting conditions. Distribution The mean (CV%) volume of distribution at steady state of vorasidenib is 3,930 L (40%). The protein binding is 97% in human plasma independent of vorasidenib concentrations in vitro. The brain tumor-to-plasma concentration ratio is 1.6. Elimination The mean (CV%) steady state terminal half-life is 10 days (57%) and oral clearance is 14 L/h (56%). Metabolism Vorasidenib is primarily metabolized by CYP1A2 with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. Non-CYP pathways may contribute up to 30% of its metabolism. Excretion Following a single oral radiolabeled dose of vorasidenib, 85% of the dose was recovered in feces (56% unchanged) and 4.5% was recovered in urine. Specific Populations No clinically significant effects on the pharmacokinetics of vorasidenib were observed based on age (16 to 75 years), sex, race (White, Black or African American, Asian, American Indian/Alaskan Native, Native Hawaiian or Other Pacific Islander), ethnicity (Hispanic and non-Hispanic), body weight (43.5 to 168 kg), mild or moderate hepatic impairment (Child-Pugh Class A or B) or CL cr >40 mL/min (as Cockcroft-Gault). The pharmacokinetics of vorasidenib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), in patients with CL cr ≤40 mL/min or in patients with renal impairment who require dialysis. Pediatric Patients The exposure of vorasidenib in pediatric patients ≥12 years of age is predicted to be within range of that observed in adults at the approved recommended dosage. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Vorasidenib Strong and Moderate CYP1A2 Inhibitors: Concomitant use of ciprofloxacin (moderate CYP1A2 inhibitor) increased vorasidenib plasma C max 1.3-fold and AUC 2.5-fold. Concomitant use with fluvoxamine (strong CYP1A2 inhibitor) is predicted to increase vorasidenib C max and AUC by ≥5-fold. Moderate CYP1A2 Inducers: Concomitant use with phenytoin or rifampicin (moderate CYP1A2 inducers) is predicted to decrease vorasidenib steady-state C max by 30% and AUC by 40%. Gastric Acid Reducing Agents: No clinically significant difference in vorasidenib pharmacokinetics was observed following concomitant use with omeprazole (an acid-reducing agent). Effect of Vorasidenib on Other Drugs CYP3A Substrates: Concomitant use of multiple doses of vorasidenib with CYP3A substrates is predicted to decrease the concentrations of these substrates. UGT1A4 Substrate: No clinically significant difference in lamotrigine pharmacokinetics was observed following the administration of lamotrigine with multiple doses of vorasidenib. P-gp and BCRP Substrates: No clinically significant difference in the pharmacokinetics of digoxin (P-gp substrate) or rosuvastatin (BCRP substrate) is predicted when used concomitantly with vorasidenib. In vitro Studies Vorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4. Vorasidenib is not a substrate of P-gp, BCRP, or OATP1B1 and OATP1B3. Vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-gp and OATP1B1.