DOSAGE & ADMINISTRATION SECTION.

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) Recommended dosage in adults: 2.3) 40 mg orally once daily 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 >=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 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 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 PatientsThe recommended dosage of VORANIGO in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity.. Pediatric Patients 12 Years and OlderThe recommended dosage of VORANIGO in pediatric patients 12 years and older is based on body weight:Patients weighing >=40 kg: 40 mg orally once dailyPatients weighing <40 kg: 20 mg orally once dailyContinue treatment with VORANIGO until disease progression or unacceptable toxicity.. Patients weighing >=40 kg: 40 mg orally once daily. Patients weighing <40 kg: 20 mg orally once daily. AdministrationSwallow VORANIGO tablets whole with water with or without food [see Clinical Pharmacology (12.3)] Do not split, crush or chew tablets. Missed DoseTake VORANIGO tablets at about the same time each day. If dose is missed, take the missed dose as soon as possible within hours. If dose is missed by more than hours, skip the missed dose and take the next dose at the scheduled time.. VomitingIf vomiting occurs after taking dose, do not take 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 ReactionsDosage ReductionRecommended Dose and ScheduleAdult patients and Pediatric patients 12 years and older weighing at least 40 kgFirst20 mg once dailySecond10 mg once dailyPediatric patients 12 years and older weighing less than 40 kgFirst10 mg once dailyPermanently 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 ReactionsAdverse ReactionSeverity Management and Dosage ModificationsHepatotoxicity (Elevation of ALT or AST) [see Warnings and Precautions (5.1)] Grade ALT or AST increase >ULN to x ULN without concurrent total bilirubin >2 ULN Continue VORANIGO at current dose. Monitor liver laboratory tests weekly until recovery to Grade 1. Grade ALT or AST >3 to x ULN without concurrent total bilirubin >2 ULN First Occurrence: Withhold VORANIGO until recovery to Grade <= 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 <= or baseline, and resume VORANIGO at reduced dose [see Table 1] Grade ALT or AST >5 to 20 ULN without concurrent total bilirubin >2 ULN First Occurrence: Withhold VORANIGO until recovery to Grade <= 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 or Any ALT or AST >3 to 20 ULN with concurrent total bilirubin >2 ULN First Occurrence: Withhold VORANIGO until recovery to Grade <= or baseline. Resume VORANIGO at reduced dose [see Table 1] Recurrence: Permanently discontinue VORANIGO. Grade Any ALT or AST >20 ULN Permanently discontinue VORANIGO.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3First Occurrence: Withhold VORANIGO until recovery to Grade <= or baseline. Resume VORANIGO at reduced dose [see Table 1] Recurrence: Permanently discontinue VORANIGO. Grade 4Permanently discontinue VORANIGO.Abbreviations: ALT Alanine aminotransferase; AST Aspartate aminotransferase; ULN Upper limit of normala Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Recovery in <=28 days, resume VORANIGO at the same dose.. Recovery in >28 days, resume VORANIGO at reduced dose [see Table 1] . Recovery in <=28 days, resume VORANIGO at reduced dose [see Table 1]. If not recovered in <=28 days, permanently discontinue VORANIGO.. Resume VORANIGO at reduced dose [see Table 1] . Resume VORANIGO at reduced dose [see Table 1].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Hepatotoxicity [see Warnings and Precautions (5.1)] 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 or (>=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 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 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 or laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).. INDIGOThe safety of VORANIGO was evaluated in 330 patients with Grade 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: to 30 months) with 153 patients (92%) exposed to VORANIGO for at least months and 89 (53%) exposed for at least 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 or (>=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 and 4.Table 3: Adverse Reactions (>=5%) in Patients with Grade IDH1/2 Mutant Glioma Who Received VORANIGO Compared with Placebo in the INDIGO TrialVORANIGO 40 mg daily (n=167) Placebo n=163) Adverse Reaction All Grades (%)Grades or (%)All Grades (%)Grades or (%)General DisordersFatigue 370.6361.2Infections and InfestationsCOVID-19330290Nervous System DisordersSeizure 164.2153.7Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain 260251.8Gastrointestinal DisordersDiarrhea 250.6170.6Constipation130120Abdominal pain 130120Decreased appetite903.70a Adverse reactions are based on NCI CTCAE v5.0. Grouped term includes asthenia. Grouped term includes partial seizures, generalized tonic-clonic seizure, epilepsy, clonic convulsion, and simple partial seizures. Grouped term includes arthralgia, back pain, non-cardiac chest pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, arthritis, and musculoskeletal stiffness. Grouped term includes feces soft and frequent bowel movements. Grouped term includes abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. Table 4: Select Laboratory Abnormalities (>=5%) That Worsened from Baseline in Patients with Grade IDH1/2 Mutant Glioma Who Received VORANIGO in the INDIGO TrialVORANIGO 40 mg daily N=167 Placebo N=163 ParameterAll Grades (% ) Grades 3 or (% ) All Grades (% ) Grades 3 or (% ) ChemistryIncreased ALT5910250Increased AST464.8200Increased Creatinine110.670Decreased Calcium10070Increased Glucose 1004.30Increased GGT383101.8Decreased Phosphate 80.64.90Increased Potassium230.6200Increased ALP101.270.6HematologyIncreased Hemoglobin1303.10Decreased Lymphocytes111.880.6Decreased Leukocytes130.6120.6Decreased Neutrophils142.4121.8Decreased Platelets1204.30Abbreviations: AST Aspartate Aminotransferase; ALT Alanine Aminotransferase; GGT Gamma-Glutamyl Transferase; ALP Alkaline Phosphatasea 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. Includes adverse reaction term hyperglycemia. Includes adverse reaction terms hypophosphatemia and blood phosphorus decreased.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with vorasidenib. Vorasidenib and its major circulating metabolite, AGI-69460, were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Vorasidenib and AGI-69460 were not clastogenic in an in vitro human lymphocyte micronucleus assay, or an in vivo rat bone marrow micronucleus assay. AGI-69460 did not induce DNA damage in rat liver in the in vivo comet assay.Fertility studies in animals have not been conducted with vorasidenib. In repeat-dose toxicity studies up to 13 weeks in duration with oral administration of vorasidenib in rats, adverse effects in female reproductive organs included atrophy, decreased/absent corpora lutea, increased atretic follicles, and interstitial cell vacuolation of the ovaries, atrophy, hypertrophy, and metaplasia of the uterus, hyperplasia of the cervix, atrophy, hyperplasia, and mucification of the vagina, and estrous cycle variations at doses >=3 mg/kg/day (>=12 times the exposure based on AUC in humans at the highest recommended dose). Adverse effects in male reproductive organs in rats included tubular degeneration and atrophy of the testes, degeneration of seminiferous tubules, cellular debris in the epididymides, epithelial atrophy and inflammation in the prostate, and atrophy in the seminal vesicles at doses >=3 mg/kg/day (>=12 times the exposure based on AUC in humans at the highest recommended dose). Findings in the male rats were not reversible. In the 4-week repeat-dose toxicity studies in monkeys, oral administration of vorasidenib led to adverse effects in male and female reproductive organs including fibrotic hypoplasia of the testes in males at doses >=10 mg/kg/day (approximately 17 times the exposure based on AUC in humans at the highest recommended dose) and decreased uterine weights in females at doses >=10 mg/kg/day (approximately 22 times the exposure based on AUC in humans at the highest recommended dose). Findings in male and female monkeys were reversible.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Vorasidenib is small molecule inhibitor that targets isocitrate dehydrogenase-1 and (IDH1 and IDH2) enzymes. In vitro, vorasidenib inhibited the IDH1 wild type and mutant variants, including R132H and the IDH2 wild type and mutant variants. In cell-based and in vivo tumor models expressing IDH1 or IDH2 mutated proteins, vorasidenib decreased production of 2-hydroxyglutarate (2-HG) and partially restored cellular differentiation.. 12.2 Pharmacodynamics. Exposure-Response RelationshipsVorasidenib decreases 2-HG tumor concentrations in patients with IDH1 or IDH2 mutated glioma. Relative to tumors from patients in the untreated group, the posterior median percentage reduction (95% credible interval) in tumor 2-HG was 64% (22%, 88%) to 93% (76%, 98%) in tumors from patients who received vorasidenib at exposures that were 0.3 to 0.8 times the exposure observed with the highest recommended dosage.The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of vorasidenib have not been fully characterized.. Cardiac ElectrophysiologyWhen the recommended dose of VORANIGO is administered hour prior to meal, mean increase in the QTc interval >20 msec is unlikely. There is insufficient information to characterize the QTc effects of VORANIGO at higher vorasidenib concentrations, e.g., when administered with meal or when co-administered with moderate CYP1A2 inhibitor [see Clinical Pharmacology (12.3)] . 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 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%) max is 133 ng/mL (73%) and AUC is 1,988 hong/mL (95%). Steady state is achieved within 28 days of once daily dosing and the mean accumulation ratio of AUC is 4.4. AbsorptionThe median (minimum, maximum) time to maximum plasma concentrations (t max) at steady state is hours (0.5 to hours). The mean absolute bioavailability of vorasidenib is 34%.. Food EffectA high-fat and high-calorie (total 800-1,000 calories, of which 500-600 from fat) meal increased vorasidenib max 3.1-fold and AUC 1.4-fold, compared to the fasting conditions. low-fat and low-calorie (total 400-500 calories, of which 100-125 from fat) meal increased vorasidenib max 2.3-fold and AUC 1.4-fold, compared to the fasting conditions. DistributionThe mean (CV%) volume of distribution at steady state of vorasidenib is 3,930 (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.. EliminationThe mean (CV%) steady state terminal half-life is 10 days (57%) and oral clearance is 14 L/h (56%).. MetabolismVorasidenib 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.. ExcretionFollowing single oral radiolabeled dose of vorasidenib, 85% of the dose was recovered in feces (56% unchanged) and 4.5% was recovered in urine.. Specific PopulationsNo 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 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 PatientsThe 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 max 1.3-fold and AUC 2.5-fold. Concomitant use with fluvoxamine (strong CYP1A2 inhibitor) is predicted to increase vorasidenib 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 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 StudiesVorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4.Vorasidenib is not substrate of P-gp, BCRP, or OATP1B1 and OATP1B3.Vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-gp and OATP1B1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of VORANIGO was evaluated in the INDIGO trial (Study AG881-C-004), randomized, multicenter, double-blind, placebo-controlled study of 331 patients (NCT04164901). Eligible patients were required to have IDH1- or IDH2-mutant Grade astrocytoma or oligodendroglioma with prior surgery including biopsy, sub-total resection, or gross total resection. Patients were required to have measurable, non-enhancing disease; patients with centrally confirmed minimal, non-nodular, non-measurable enhancement were eligible. Patients who received prior anti-cancer treatment, including chemotherapy or radiation therapy were excluded. Patients were randomized to receive either VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. IDH1 or IDH2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.Randomization was stratified by local 1p19q status (co-deleted or not co-deleted) and baseline tumor size (diameter >=2 cm or <2 cm). Patients who were randomized to placebo were allowed to cross over to receive VORANIGO after documented radiographic disease progression. Tumor assessments were performed every 12 weeks.A total of 331 patients were randomized, 168 to the VORANIGO arm and 163 to the placebo arm. The median age was 40 years (range: 16 to 71); 57% were male; 78% were White, 4% were Asian, 1% were Black or African American and 16% had race not reported; 78% were not Hispanic or Latino; 52% oligodendroglioma and 48% astrocytoma; 79% had one prior surgery and 21% had >=2 prior surgeries. In the VORANIGO arm, 14% of patients had biopsy, 48% had sub-total resection and 51% had gross-total resection. The majority of IDH1 mutations consisted of R132H (87%). The other alleles were reported as follows: R132C (5%), R132G (3%), R132L (1%), and R132S (1%). IDH2 mutations consisted of R172K (2%) and R172G (1%).The major efficacy outcome was progression-free survival (PFS) as evaluated by blinded independent review committee (BIRC) per modified Response Assessment in Neuro-Oncology for Low Grade Glioma (RANO-LGG) criteria.Efficacy results are summarized in Table and Figure 1.Table 7: Efficacy Results for the INDIGO Trial (Study AG881-C-004)Efficacy ParameterVORANIGO 40 mg daily (n=168) Placebo (n=163) CI Confidence IntervalProgression-Free Survival (PFS)Number of Events, (%)Progressive disease47 (28)88 (54)Death00Hazard ratio (95% CI)a0.39 (0.27, 0.56)p-valueb<0.0001a Stratified Cox proportional hazard model, stratified by 1p19q status and baseline tumor size. Based on one-sided stratified log-rank test compared to the pre-specified of 0.000359 (one-sided). Figure 1: Kaplan-Meier Curve for Progression-Free Survival per BIRC for the INDIGO TrialThe major efficacy analyses are supported by prospectively defined key secondary outcome measure time to next intervention (defined as the time from randomization to the initiation of first subsequent anticancer therapy or death due to any cause). The median time to next intervention was not reached for patients in the VORANIGO arm and 17.8 months for patients in the placebo arm (HR=0.26; 95% CI: [0.15, 0.43], <0.0001).. 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.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 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 or laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).. INDIGOThe safety of VORANIGO was evaluated in 330 patients with Grade 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: to 30 months) with 153 patients (92%) exposed to VORANIGO for at least months and 89 (53%) exposed for at least 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 or (>=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 and 4.Table 3: Adverse Reactions (>=5%) in Patients with Grade IDH1/2 Mutant Glioma Who Received VORANIGO Compared with Placebo in the INDIGO TrialVORANIGO 40 mg daily (n=167) Placebo n=163) Adverse Reaction All Grades (%)Grades or (%)All Grades (%)Grades or (%)General DisordersFatigue 370.6361.2Infections and InfestationsCOVID-19330290Nervous System DisordersSeizure 164.2153.7Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain 260251.8Gastrointestinal DisordersDiarrhea 250.6170.6Constipation130120Abdominal pain 130120Decreased appetite903.70a Adverse reactions are based on NCI CTCAE v5.0. Grouped term includes asthenia. Grouped term includes partial seizures, generalized tonic-clonic seizure, epilepsy, clonic convulsion, and simple partial seizures. Grouped term includes arthralgia, back pain, non-cardiac chest pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, arthritis, and musculoskeletal stiffness. Grouped term includes feces soft and frequent bowel movements. Grouped term includes abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. Table 4: Select Laboratory Abnormalities (>=5%) That Worsened from Baseline in Patients with Grade IDH1/2 Mutant Glioma Who Received VORANIGO in the INDIGO TrialVORANIGO 40 mg daily N=167 Placebo N=163 ParameterAll Grades (% ) Grades 3 or (% ) All Grades (% ) Grades 3 or (% ) ChemistryIncreased ALT5910250Increased AST464.8200Increased Creatinine110.670Decreased Calcium10070Increased Glucose 1004.30Increased GGT383101.8Decreased Phosphate 80.64.90Increased Potassium230.6200Increased ALP101.270.6HematologyIncreased Hemoglobin1303.10Decreased Lymphocytes111.880.6Decreased Leukocytes130.6120.6Decreased Neutrophils142.4121.8Decreased Platelets1204.30Abbreviations: AST Aspartate Aminotransferase; ALT Alanine Aminotransferase; GGT Gamma-Glutamyl Transferase; ALP Alkaline Phosphatasea 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. Includes adverse reaction term hyperglycemia. Includes adverse reaction terms hypophosphatemia and blood phosphorus decreased.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP1A2 Inhibitors: Avoid concomitant use of strong and moderate CYP1A2 inhibitors. 7.1) CYP1A2 Inducers: Avoid concomitant use of moderate CYP1A2 inducers and smoking tobacco. 7.1) Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration change can reduce efficacy. 7.2) Hormonal Contraception: If concomitant use cannot be avoided, use with nonhormonal contraception methods. 7.2) CYP1A2 Inhibitors: Avoid concomitant use of strong and moderate CYP1A2 inhibitors. 7.1) CYP1A2 Inducers: Avoid concomitant use of moderate CYP1A2 inducers and smoking tobacco. 7.1) Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration change can reduce efficacy. 7.2) Hormonal Contraception: If concomitant use cannot be avoided, use with nonhormonal contraception methods. 7.2) 7.1 Effect of Other Drugs on VORANIGO. Table 5: Effect of Other Drugs on VORANIGOStrong and Moderate CYP1A2 InhibitorsClinical ImpactConcomitant use of VORANIGO with strong or moderate CYP1A2 inhibitor may increase vorasidenib plasma concentrations [see Clinical Pharmacology (12.3)] which may increase the risk of adverse reactions. Prevention or ManagementAvoid concomitant use of VORANIGO with strong and moderate CYP1A2 inhibitors.If concomitant use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4)] Moderate CYP1A2 InducersClinical ImpactConcomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco may decrease vorasidenib plasma concentrations [see Clinical Pharmacology (12.3)] which may reduce the anti-tumor activity of VORANIGO. Prevention or ManagementAvoid concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco.. Concomitant use of VORANIGO with strong or moderate CYP1A2 inhibitor may increase vorasidenib plasma concentrations [see Clinical Pharmacology (12.3)] which may increase the risk of adverse reactions. Avoid concomitant use of VORANIGO with strong and moderate CYP1A2 inhibitors.. If concomitant use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4)] . Concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco may decrease vorasidenib plasma concentrations [see Clinical Pharmacology (12.3)] which may reduce the anti-tumor activity of VORANIGO. Avoid concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco.. 7.2 Effect of VORANIGO on Other Drugs. Table 6: Effect of VORANIGO on Other DrugsCertain CYP3A SubstratesClinical ImpactConcomitant use of VORANIGO with CYP3A substrates may decrease plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)] Prevention or ManagementAvoid concomitant use of VORANIGO with CYP3A substrates, where minimal concentration change may lead to reduced therapeutic effect.Hormonal ContraceptionClinical ImpactConcomitant use of VORANIGO may decrease the concentrations of hormonal contraceptives, which may lead to contraception failure and/or an increase in breakthrough bleeding [see Clinical Pharmacology (12.3)] Prevention or ManagementIf concomitant use cannot be avoided, use with nonhormonal contraception methods.. Concomitant use of VORANIGO with CYP3A substrates may decrease plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)] . Avoid concomitant use of VORANIGO with CYP3A substrates, where minimal concentration change may lead to reduced therapeutic effect.. Concomitant use of VORANIGO may decrease the concentrations of hormonal contraceptives, which may lead to contraception failure and/or an increase in breakthrough bleeding [see Clinical Pharmacology (12.3)] . If concomitant use cannot be avoided, use with nonhormonal contraception methods.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. HepatotoxicityInform patients of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity to their healthcare provider [see Warnings and Precautions (5.1)] . Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)] Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for months after the last dose [see Use in Specific Populations (8.3)] since VORANIGO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)] Advise males with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for months after the last dose [see Use in Specific Populations (8.3)]. LactationAdvise women not to breastfeed during treatment with VORANIGO and for months after the last dose [see Use in Specific Populations (8.2)] . InfertilityAdvise females and males of reproductive potential that VORANIGO may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)] . Drug InteractionsAdvise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the counter drugs, vitamins and herbal products [see Drug Interactions (7)]. Advise patients and caregivers to inform their healthcare provider if they currently smoke tobacco as it may affect how well VORANIGO works [see Drug Interactions (7)]. Instructions for Taking VORANIGOAdvise patients to swallow tablets whole with glass of water, with or without food, and to not split, crush or chew VORANIGO tablets [see Dosage and Administration (2.3)] If patient misses dose by less than hours, instruct patients to take the missed dose right away. If patient misses dose by or more hours, instruct patients to skip the dose for that day. Advise patients to take the next dose at the usual time [see Dosage and Administration (2.3)] If patient vomits dose, instruct patients not to take another dose. Advise patients to take the next dose at the usual time [see Dosage and Administration (2.3)] . Manufactured for Servier Pharmaceuticals LLC, Boston, MA 02210Servier and the Servier logo are trademarks of Les Laboratoires Servier.VORANIGO (R) is registered trademark of Servier Pharmaceuticals LLC, wholly owned, indirect subsidiary of Les Laboratoires Servier. Oncomine(TM) Dx Target Test is trademark of Life Sciences Corporation, part of Thermo Fisher Scientific Inc.(C) 2026 Servier Pharmaceuticals LLC.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with vorasidenib. Vorasidenib and its major circulating metabolite, AGI-69460, were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Vorasidenib and AGI-69460 were not clastogenic in an in vitro human lymphocyte micronucleus assay, or an in vivo rat bone marrow micronucleus assay. AGI-69460 did not induce DNA damage in rat liver in the in vivo comet assay.Fertility studies in animals have not been conducted with vorasidenib. In repeat-dose toxicity studies up to 13 weeks in duration with oral administration of vorasidenib in rats, adverse effects in female reproductive organs included atrophy, decreased/absent corpora lutea, increased atretic follicles, and interstitial cell vacuolation of the ovaries, atrophy, hypertrophy, and metaplasia of the uterus, hyperplasia of the cervix, atrophy, hyperplasia, and mucification of the vagina, and estrous cycle variations at doses >=3 mg/kg/day (>=12 times the exposure based on AUC in humans at the highest recommended dose). Adverse effects in male reproductive organs in rats included tubular degeneration and atrophy of the testes, degeneration of seminiferous tubules, cellular debris in the epididymides, epithelial atrophy and inflammation in the prostate, and atrophy in the seminal vesicles at doses >=3 mg/kg/day (>=12 times the exposure based on AUC in humans at the highest recommended dose). Findings in the male rats were not reversible. In the 4-week repeat-dose toxicity studies in monkeys, oral administration of vorasidenib led to adverse effects in male and female reproductive organs including fibrotic hypoplasia of the testes in males at doses >=10 mg/kg/day (approximately 17 times the exposure based on AUC in humans at the highest recommended dose) and decreased uterine weights in females at doses >=10 mg/kg/day (approximately 22 times the exposure based on AUC in humans at the highest recommended dose). Findings in male and female monkeys were reversible.. 13.2 Animal Toxicology and Pharmacology. In repeat-dose toxicity studies, oral administration of vorasidenib to rats for 28 days led to ototoxicity findings of reversible neutrophil infiltration of the epithelial lining of the middle ear and Eustachian tube at doses >3 mg/kg/day (>12-times the human exposure based on the AUC at the highest recommended dose). Additional findings in 28-day ototoxicity study included edema in the tympanic cavity at doses >30 mg/kg/day. In addition, oral administration of vorasidenib to monkeys for 13 weeks resulted in dilated cardiomyopathy and secondary congestive heart failure at dose of 20 mg/kg/day (105 times the human exposure based on the AUC at the highest recommended dose). Skeletal muscle was target organ in the repeat dose toxicology studies in rats and monkeys at doses >=13 times the AUC in patients at the highest recommended dose. Findings included decreased hind limb muscle tone, abnormal gait with limited hind limb usage, and low carriage, associated with small size and atrophy of the muscle in rats and necrosis and mononuclear/mixed cell infiltrates in the muscle in monkeys.

PHARMACOKINETICS SECTION.

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 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%) max is 133 ng/mL (73%) and AUC is 1,988 hong/mL (95%). Steady state is achieved within 28 days of once daily dosing and the mean accumulation ratio of AUC is 4.4. AbsorptionThe median (minimum, maximum) time to maximum plasma concentrations (t max) at steady state is hours (0.5 to hours). The mean absolute bioavailability of vorasidenib is 34%.. Food EffectA high-fat and high-calorie (total 800-1,000 calories, of which 500-600 from fat) meal increased vorasidenib max 3.1-fold and AUC 1.4-fold, compared to the fasting conditions. low-fat and low-calorie (total 400-500 calories, of which 100-125 from fat) meal increased vorasidenib max 2.3-fold and AUC 1.4-fold, compared to the fasting conditions. DistributionThe mean (CV%) volume of distribution at steady state of vorasidenib is 3,930 (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.. EliminationThe mean (CV%) steady state terminal half-life is 10 days (57%) and oral clearance is 14 L/h (56%).. MetabolismVorasidenib 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.. ExcretionFollowing single oral radiolabeled dose of vorasidenib, 85% of the dose was recovered in feces (56% unchanged) and 4.5% was recovered in urine.. Specific PopulationsNo 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 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 PatientsThe 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 max 1.3-fold and AUC 2.5-fold. Concomitant use with fluvoxamine (strong CYP1A2 inhibitor) is predicted to increase vorasidenib 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 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 StudiesVorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4.Vorasidenib is not substrate of P-gp, BCRP, or OATP1B1 and OATP1B3.Vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-gp and OATP1B1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] VORANIGO can cause fetal harm when administered to pregnant woman. There are no available data on VORANIGO use in pregnant women to inform drug-associated risk. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity at >=8 times the human exposure based on the AUC at the highest recommended dose (see Data) Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study, vorasidenib was administered to pregnant rats via oral gavage at dose levels of 10, 25, and 75 mg/kg/day during the period of organogenesis (gestation days to 17). Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose). Malformation of heart occurred in rat at dose of 25 mg/kg (approximately 97 times the human exposure based on the AUC at the highest recommended dose). Dose-related delayed ossification of bones and short ribs associated with decreased fetal body weights was observed at 10 and 25 mg/kg/day in the absence of maternal toxicity and at 75 mg/kg/day. The dose of 10 mg/kg/day is >=45 times the human exposure based on the AUC at the highest recommended dose.In an embryo-fetal development study, oral administration of vorasidenib to pregnant rabbits at dose levels of 2, 6, and 18 mg/kg/day during the period of organogenesis (gestation days to 19) resulted in maternal toxicity at all doses (>=1.5 times the human exposure based on the AUC at the highest recommended dose) and caused higher incidence of late resorptions at 18 mg/kg/day as well as decreased fetal weights and delayed ossification at doses >=6 mg/kg/day (>=8 times the human exposure based on the AUC at the highest recommended dose).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 08/2024PATIENT INFORMATIONVORANIGO (R) (vo-rah-NEE-goh) (vorasidenib) tablets, for oral use What is VORANIGOVORANIGO is prescription medicine used to treat adults and children 12 years of age and older with certain types of brain tumors called astrocytoma or oligodendroglioma with an isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation, following surgery. Your healthcare provider will perform test to make sure that VORANIGO is right for you. It is not known if VORANIGO is safe and effective in children under 12 years of age. Before taking VORANIGO, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave kidney problems or are on dialysissmoke tobaccoare pregnant or plan to become pregnant. VORANIGO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before you start treatment with VORANIGO.You should use effective nonhormonal birth control during treatment with VORANIGO and for months after the last dose. VORANIGO may affect how hormonal contraceptives (birth control) work and cause them to not work well. Talk to your healthcare provider about birth control methods that may be right for you during treatment with VORANIGO.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with VORANIGO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with VORANIGO and for months after the last dose.Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant during your treatment with VORANIGO. are breastfeeding or plan to breastfeed. It is not known if VORANIGO passes into breast milk. Do not breastfeed during treatment with VORANIGO and for months after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. VORANIGO may affect the way other medicines work and other medicines may affect how VORANIGO works. Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine. How should take VORANIGOTake VORANIGO exactly as your healthcare provider tells you.Do not change your dose or stop taking VORANIGO without talking to your healthcare provider. Take VORANIGO time day about the same time each day.Swallow VORANIGO tablets whole with water. Do not split, crush or chew the tablets. VORANIGO can be taken with or without food.If you miss dose of VORANIGO by less than hours, take the missed dose right away. If you miss dose by more than hours, skip the dose for that day. Take your next dose at your usual time. If you vomit after taking VORANIGO, do not take an extra dose. Take your next dose at your usual time. What are the possible side effects of VORANIGO VORANIGO may cause serious side effects, including: Liver problems. Changes in liver function blood tests may happen during treatment with VORANIGO and can be serious. Your healthcare provider will do blood tests to check your liver function before and during treatment with VORANIGO. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems: yellowing of your skin or the white part of your eyes (jaundice)dark tea-colored urineloss of appetitepain on the upper right side of your stomach areafeeling very tired or weakThe most common side effects of VORANIGO include:increased liver enzyme levels in the bloodlack of energy, tirednessheadacheCOVID-19muscle aches or stiffnessdiarrheanauseaseizureYour healthcare provider may change your dose, temporarily stop or permanently stop treatment with VORANIGO if you have certain side effects.VORANIGO may affect fertility in females and males, which may affect the ability to have children. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of VORANIGO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store VORANIGOStore VORANIGO at room temperature between 68F to 77F (20C to 25C).VORANIGO comes with desiccant canisters (drying agent) in the bottle to help keep the medicine dry (protect from moisture). Do not remove the desiccant canisters from the bottle. Do not swallow the desiccant canisters. The VORANIGO bottle has child resistant cap.Keep VORANIGO and all medicines out of reach of children.General information about the safe and effective use of VORANIGO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VORANIGO for condition for which it was not prescribed. Do not give VORANIGO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VORANIGO that is written for health professionals. What are the ingredients in VORANIGOActive ingredient: vorasidenib Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose and sodium lauryl sulfate Tablet coating: hypromellose, lactose monohydrate, macrogol and titanium dioxide Black printing ink: black iron oxide, hypromellose and propylene glycol Manufactured for Servier Pharmaceuticals LLC, Boston, MA 02210 Servier and the Servier logo are trademarks of Les Laboratoires Servier. VORANIGO (R) is registered trademark of Servier Pharmaceuticals LLC, wholly owned, indirect subsidiary of Les Laboratoires Servier. (C) 2024 Servier Pharmaceuticals LLC For more information, go to www.VORANIGO.com or call 1-800-807-6124. have liver problems. have kidney problems or are on dialysis. smoke tobacco. are pregnant or plan to become pregnant. VORANIGO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before you start treatment with VORANIGO.You should use effective nonhormonal birth control during treatment with VORANIGO and for months after the last dose. VORANIGO may affect how hormonal contraceptives (birth control) work and cause them to not work well. Talk to your healthcare provider about birth control methods that may be right for you during treatment with VORANIGO.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with VORANIGO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with VORANIGO and for months after the last dose.Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant during your treatment with VORANIGO. Your healthcare provider will do pregnancy test before you start treatment with VORANIGO.. You should use effective nonhormonal birth control during treatment with VORANIGO and for months after the last dose. VORANIGO may affect how hormonal contraceptives (birth control) work and cause them to not work well. Talk to your healthcare provider about birth control methods that may be right for you during treatment with VORANIGO.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with VORANIGO.. You should use effective birth control during treatment with VORANIGO and for months after the last dose.. Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant during your treatment with VORANIGO.. are breastfeeding or plan to breastfeed. It is not known if VORANIGO passes into breast milk. Do not breastfeed during treatment with VORANIGO and for months after the last dose. Take VORANIGO exactly as your healthcare provider tells you.. Do not change your dose or stop taking VORANIGO without talking to your healthcare provider. Take VORANIGO time day about the same time each day.. Swallow VORANIGO tablets whole with water. Do not split, crush or chew the tablets. VORANIGO can be taken with or without food.. If you miss dose of VORANIGO by less than hours, take the missed dose right away. If you miss dose by more than hours, skip the dose for that day. Take your next dose at your usual time. If you vomit after taking VORANIGO, do not take an extra dose. Take your next dose at your usual time. Liver problems. Changes in liver function blood tests may happen during treatment with VORANIGO and can be serious. Your healthcare provider will do blood tests to check your liver function before and during treatment with VORANIGO. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems: yellowing of your skin or the white part of your eyes (jaundice)dark tea-colored urineloss of appetitepain on the upper right side of your stomach areafeeling very tired or weak. yellowing of your skin or the white part of your eyes (jaundice). dark tea-colored urine. loss of appetite. pain on the upper right side of your stomach area. feeling very tired or weak. increased liver enzyme levels in the blood. lack of energy, tiredness. headache. COVID-19. muscle aches or stiffness. diarrhea. nausea. seizure. Store VORANIGO at room temperature between 68F to 77F (20C to 25C).. VORANIGO comes with desiccant canisters (drying agent) in the bottle to help keep the medicine dry (protect from moisture). Do not remove the desiccant canisters from the bottle. Do not swallow the desiccant canisters. The VORANIGO bottle has child resistant cap.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) Infertility: May impair fertility in males and females. 8.3) Lactation: Advise not to breastfeed. 8.2) Infertility: May impair fertility in males and females. 8.3) 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] VORANIGO can cause fetal harm when administered to pregnant woman. There are no available data on VORANIGO use in pregnant women to inform drug-associated risk. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity at >=8 times the human exposure based on the AUC at the highest recommended dose (see Data) Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study, vorasidenib was administered to pregnant rats via oral gavage at dose levels of 10, 25, and 75 mg/kg/day during the period of organogenesis (gestation days to 17). Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose). Malformation of heart occurred in rat at dose of 25 mg/kg (approximately 97 times the human exposure based on the AUC at the highest recommended dose). Dose-related delayed ossification of bones and short ribs associated with decreased fetal body weights was observed at 10 and 25 mg/kg/day in the absence of maternal toxicity and at 75 mg/kg/day. The dose of 10 mg/kg/day is >=45 times the human exposure based on the AUC at the highest recommended dose.In an embryo-fetal development study, oral administration of vorasidenib to pregnant rabbits at dose levels of 2, 6, and 18 mg/kg/day during the period of organogenesis (gestation days to 19) resulted in maternal toxicity at all doses (>=1.5 times the human exposure based on the AUC at the highest recommended dose) and caused higher incidence of late resorptions at 18 mg/kg/day as well as decreased fetal weights and delayed ossification at doses >=6 mg/kg/day (>=8 times the human exposure based on the AUC at the highest recommended dose).. 8.2 Lactation. Risk SummaryThere are no data on the presence of vorasidenib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Because of the potential for adverse reactions in breastfed children from VORANIGO, advise women not to breastfeed during treatment with VORANIGO and for months after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on animal embryo-fetal toxicity studies, VORANIGO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)] . Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to starting VORANIGO [see Use in Specific Populations (8.1)] . Contraception. FemalesAdvise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for months after the last dose. VORANIGO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)] . MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for months after the last dose.. InfertilityBased on findings in animals, VORANIGO may impair fertility in females and males of reproductive potential. The effects on female and male fertility were not reversible in rats [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use. The safety and effectiveness of VORANIGO have been established in pediatric patients aged 12 years and older for the treatment of Grade IDH1- or IDH2-mutant astrocytoma or oligodendroglioma. Use of VORANIGO for this indication in this age group is supported by evidence from an adequate and well-controlled study of VORANIGO in adult and pediatric patients with additional population pharmacokinetic data demonstrating that age had no clinically meaningful effect on the pharmacokinetics of vorasidenib. In addition, the course of IDH1- or IDH2-mutant astrocytoma or oligodendroglioma is sufficiently similar between adults and pediatric patients to allow extrapolation of pharmacokinetic data in adults to pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)] The exposure of vorasidenib in pediatric patients 12 years and older is predicted to be within range of exposure observed in adults at the recommended dosages [see Clinical Pharmacology (12.3)] The safety and effectiveness of VORANIGO have not been established in pediatric patients younger than 12 years of age for any indication.. 8.5 Geriatric Use. Of the 167 patients who were randomized and received VORANIGO 40 mg once daily in the INDIGO trial, 1.2% (2 patients) were 65 years or older. Clinical studies of VORANIGO did not include sufficient numbers of patients aged >=65 to determine whether they respond differently from younger subjects.. 8.6 Renal Impairment. No dosage adjustment is recommended for patients with creatinine clearance (CL cr) >40 mL/min. The pharmacokinetics and safety of vorasidenib in patients with CL cr <=40 mL/min or renal impairment requiring dialysis have not been studied [see Clinical Pharmacology (12.3)] For patients with CL cr <=40 mL/min or who require dialysis, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] . 8.7 Hepatic Impairment. No dosage adjustment is recommended for patients with mild or moderate (Child-Pugh Class or B) hepatic impairment [see Clinical Pharmacology (12.3)] The pharmacokinetics and safety of vorasidenib in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. For patients with severe hepatic impairment, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis. Monitor liver function tests every weeks during the first months of treatment, then monthly for the first years of treatment, and as clinically indicated. Withhold, reduce the dose or discontinue VORANIGO based on severity. 2.3, 5.1) Embryo-Fetal Toxicity: VORANIGO can cause fetal harm. Advise patients of the potential risk to fetus and to use effective nonhormonal contraception. 5.2, 8.1, 8.3) Hepatotoxicity: VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis. Monitor liver function tests every weeks during the first months of treatment, then monthly for the first years of treatment, and as clinically indicated. Withhold, reduce the dose or discontinue VORANIGO based on severity. 2.3, 5.1) Embryo-Fetal Toxicity: VORANIGO can cause fetal harm. Advise patients of the potential risk to fetus and to use effective nonhormonal contraception. 5.2, 8.1, 8.3) 5.1 Hepatotoxicity. VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis.In the pooled safety population [see Adverse Reactions (6.1)] 58% of patients treated with VORANIGO experienced increased ALT and 44% of patients experienced increased AST. Grade or increased ALT or AST occurred in 9% and 4.8% of patients respectively. Among these patients, 4.1% (10/244) had concurrent Grade to ALT or AST elevations. total of 34% of patients treated with VORANIGO had increased gamma-glutamyl transferase (GGT), of these 2.2% were Grade or 4. Bilirubin increases occurred in 4.8% of patients treated with VORANIGO, with 0.4% Grade or 4. Nine percent of patients treated with VORANIGO had increased alkaline phosphatase, with 0.9% Grade or 4. Two patients met the laboratory criteria for Hys Law and had concurrent elevations in ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal; these events were associated with cases of autoimmune hepatitis and hepatic failure. The median time to first onset of increased ALT or AST was 57 days (range: to 1049).Acute hepatitis occurred in the postmarketing setting.Permanent discontinuation of VORANIGO was required for 2.9% of patients with ALT elevations, 1.6% of AST elevations, and 0.4% of GGT elevations. Dosage reductions of VORANIGO were required for 7% of patients with ALT elevations, 1.2% of AST elevations, and 0.4% of GGT elevations. Dosage interruptions were required in 14% of patients with ALT elevations, 6% of AST elevations, and 1.6% of GGT elevations.Monitor liver laboratory tests (AST, ALT, GGT, total bilirubin and alkaline phosphatase) prior to the start of VORANIGO, every weeks during the first months of treatment, then monthly for the first years of treatment, and as clinically indicated, with more frequent testing in patients who develop transaminase elevations.Reduce the dose, withhold, or permanently discontinue VORANIGO based on severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. 5.2 Embryo-Fetal Toxicity. Based on findings from animal studies, VORANIGO can cause fetal harm when administered to pregnant woman. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats during the period of organogenesis caused embryo-fetal toxicities at doses >=45 times the human exposure based on the area under the concentration-time curve (AUC) at the highest recommended dose. Oral administration of vorasidenib to pregnant rabbits during the period of organogenesis resulted in embryo-fetal toxicity at doses >=8 times the human exposure based on the AUC at the highest recommended dose.Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for months after the last dose, since VORANIGO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)] Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].