VORANIGO tablets contain vorasidenib, an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor. Vorasidenib is present as the hemicitric acid hemihydrate co-crystal. The chemical name of the co-crystal is 6-(6-chloropyridin-2-yl)- N 2 , N 4 -bis[(2 R )-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine, 2-hydroxypropane-1,2,3-tricarboxylic acid, hydrate (2:1:1). It has the following chemical structure: The molecular formula is C 14 H 13 ClF 6 N 6 • ½ C 6 H 8 O 7• ½ H 2 O and the molecular weight is 519.8 g/mol. Vorasidenib hemicitric acid hemihydrate is a white to off-white solid practically insoluble in aqueous solutions between pH 1.2 to 6.8. VORANIGO is available as a 10 mg and 40 mg strength film-coated tablet for oral administration. The strengths reflect the amount of active ingredient vorasidenib in each tablet. Each tablet core contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose and sodium lauryl sulfate. The tablet coating includes hypromellose, lactose monohydrate, macrogol and titanium dioxide. Each tablet is printed with black ink that contains black iron oxide, hypromellose and propylene glycol. Chemical Structure

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 . 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.

Tablets: 10 mg: White to off-white, round film-coated tablet imprinted with "10" in black ink on one side and plain on the other side. Each tablet contains 10 mg of vorasidenib. 40 mg: White to off-white, oblong film-coated tablet imprinted with "40" in black ink on one side and plain on the other side. Each tablet contains 40 mg of vorasidenib. Tablets: 10 mg and 40 mg.

Recommended dosage in adults: 40 mg orally once daily Recommended dosage in pediatric patients 12 years of age and older based on body weight: ≥40 kg : 40 mg orally once daily <40 kg : 20 mg orally once daily Take with or without food

Recommended Evaluation Before Initiating VORANIGO Before initiating VORANIGO, evaluate blood chemistry and liver laboratory tests

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 . 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

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 . 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

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) 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 . Recurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline, and resume VORANIGO at reduced dose . 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 . 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 . Recurrence: Permanently discontinue VORANIGO. Grade 4 Any ALT or AST >20 × ULN Permanently discontinue VORANIGO. Other Adverse Reactions Grade 3 First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline. Resume VORANIGO at reduced dose . Recurrence: Permanently discontinue VORANIGO. Grade 4 Permanently discontinue VORANIGO.

Hepatotoxicity : Monitor liver function tests every 2 weeks during the first 2 months of treatment, then monthly for the first 2 years of treatment, and as clinically indicated. Withhold, reduce the dose or discontinue VORANIGO based on severity. Embryo-Fetal Toxicity : VORANIGO can cause fetal harm. Advise patients of the potential risk to a 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 , 58% of patients treated with VORANIGO experienced increased ALT and 44% of patients experienced increased AST. Grade 3 or 4 increased ALT or AST occurred in 9% and 4.8% of patients respectively. Among these patients, 4.1% (10/244) had concurrent Grade 3 to 4 ALT or AST elevations. A total of 34% of patients treated with VORANIGO had increased gamma-glutamyl transferase (GGT), of these 2.2% were Grade 3 or 4. Bilirubin increases occurred in 4.8% of patients treated with VORANIGO, with 0.4% Grade 3 or 4. Nine percent of patients treated with VORANIGO had increased alkaline phosphatase, with 0.9% Grade 3 or 4. Two patients met the laboratory criteria for Hy's 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: 1 to 1049). 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 2 weeks during the first 2 months of treatment, then monthly for the first 2 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

Embryo-Fetal Toxicity Based on findings from animal studies, VORANIGO can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for 3 months after the last dose, since VORANIGO can render some hormonal contraceptives ineffective . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for 3 months after the last dose .

CYP1A2 Inhibitors : Avoid concomitant use of strong and moderate CYP1A2 inhibitors. CYP1A2 Inducers : Avoid concomitant use of moderate CYP1A2 inducers and smoking tobacco. Certain CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where a minimal concentration change can reduce efficacy. Hormonal Contraception : If concomitant use cannot be avoided, use with nonhormonal contraception methods

Effect of Other Drugs on VORANIGO Table 5: Effect of Other Drugs on VORANIGO Strong and Moderate CYP1A2 Inhibitors Clinical Impact Concomitant use of VORANIGO with a strong or moderate CYP1A2 inhibitor may increase vorasidenib plasma concentrations , which may increase the risk of adverse reactions. Prevention or Management 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 . Moderate CYP1A2 Inducers Clinical Impact Concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco may decrease vorasidenib plasma concentrations , which may reduce the anti-tumor activity of VORANIGO. Prevention or Management Avoid concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco

Effect of VORANIGO on Other Drugs Table 6: Effect of VORANIGO on Other Drugs Certain CYP3A Substrates Clinical Impact Concomitant use of VORANIGO with CYP3A substrates may decrease plasma concentrations of CYP3A substrates. Prevention or Management Avoid concomitant use of VORANIGO with CYP3A substrates, where a minimal concentration change may lead to reduced therapeutic effect. Hormonal Contraception Clinical Impact Concomitant use of VORANIGO may decrease the concentrations of hormonal contraceptives, which may lead to contraception failure and/or an increase in breakthrough bleeding. Prevention or Management If concomitant use cannot be avoided, use with nonhormonal contraception methods.