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

2.4 Dosage Modifications, Management and Monitoring for Adverse Reactions

The recommended VORANIGO dosage reductions for adverse reactions are provided in Table 1.

The recommended management for adverse reactions and VORANIGO dosage modifications for adverse reactions are provided in Table 2.

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)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions described in the WARNINGS AND PRECAUTIONS reflect exposure to VORANIGO 40 mg orally once daily until disease progression or unacceptable toxicity in the 244 patients with astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutation in trials AG881-C-002 (NCT02481154, n=11), AG120-881-001 (NCT03343197, n=14) and INDIGO (NCT04164901, n=167 randomized patients and n=52 crossover patients). Among the 244 patients who received VORANIGO, 78% were exposed for 6 months or longer and 44% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions were fatigue (33%), headache (28%), COVID-19 (28%), musculoskeletal pain (24%), diarrhea (21%), nausea (20%), and seizure (16%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).

7.1 Effect of Other Drugs on VORANIGO

7.2 Effect of VORANIGO on Other Drugs

8.1 Pregnancy

8.2 Lactation

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)].

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 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 [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 (CLcr) >40 mL/min.

The pharmacokinetics and safety of vorasidenib in patients with CLcr ≤40 mL/min or renal impairment requiring dialysis have not been studied [see Clinical Pharmacology (12.3)]. For patients with CLcr ≤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 A 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)].

12.1 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Vorasidenib maximum plasma concentration (Cmax) and AUC increased approximately proportionally over the dose range of 10 to 200 mg (0.2 to 4 times the exposure of the highest approved recommended dosage) following once daily administration of single and multiple doses. At the highest approved recommended dosage, steady state mean (CV%) Cmax is 133 ng/mL (73%) and AUC is 1,988 h•ng/mL (95%). Steady state is achieved within 28 days of once daily dosing and the mean accumulation ratio of AUC is 4.4.

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 was not clastogenic in an in vitro human lymphocyte micronucleus assay, or an in vivo rat bone marrow micronucleus 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 a 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 a dose of 20 mg/kg/day (105 times the human exposure based on the AUC at the highest recommended dose). Skeletal muscle was a 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.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Hepatotoxicity

Inform 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 Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a 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 3 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 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with VORANIGO and for 2 months after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential that VORANIGO may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Drug Interactions

Advise 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 VORANIGO

Advise patients to swallow tablets whole with a glass of water, with or without food, and to not split, crush or chew VORANIGO tablets [see Dosage and Administration (2.3)].

If a patient misses a dose by less than 6 hours, instruct patients to take the missed dose right away. If a patient misses a dose by 6 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 a patient vomits a 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)].