vorasidenib 10 MG Oral Tablet [Voranigo]

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 )

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.

WARNINGS AND PRECAUTIONS 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. ( 2.3 , 5.1 ) 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 [see Adverse Reactions (6.1) ] , 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 [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 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 [see Drug Interactions (7.2) ] . 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 [see Use in Specific Populations (8.1 , 8.3) ] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Vorasidenib is a small molecule inhibitor that targets isocitrate dehydrogenase-1 and 2 (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.