Voranigo Drug Information

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.

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. 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 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.

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. Resume VORANIGO at reduced dose.

Grade 4 Permanently discontinue VORANIGO.

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). Patients received VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.

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. 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 (≥ %). Adverse reactions and select laboratory abnormalities reported in the INDIGO trial are shown in Tables 3 and 4.

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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, VORANIGO can cause fetal harm when administered to a pregnant woman. There are no available data on VORANIGO use in pregnant women to inform a 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 respectively. 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 a rat at a 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 6 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).

Pediatric Use The safety and effectiveness of VORANIGO have been established in pediatric patients aged 12 years and older for the treatment of Grade 2 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.

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. The safety and effectiveness of VORANIGO have not been established in pediatric patients younger than 12 years of age for any indication.