Highlights

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Vorasidenib 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.

Dosage and administration

Recommended evaluation before initiating vorasidenib

Before initiating vorasidenib, evaluate blood chemistry and liver laboratory tests.

Patient selection

Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment with vorasidenib 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 vorasidenib is available at: www.fda.gov/CompanionDiagnostics.

Recommended dosage and administration

Recommended dosage.

Adult patients. The recommended dosage of vorasidenib 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 vorasidenib 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 vorasidenib until disease progression or unacceptable toxicity.

Administration. Swallow vorasidenib tablets whole with water with or without food. Do not split, crush or chew tablets.

Missed dose. Take vorasidenib 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 vorasidenib dosage reductions for adverse reactions are provided in Table 1.

Table 1. Recommended Vorasidenib Dosage Reductions for Adverse Reactions

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

Table 2. Recommended Vorasidenib Dosage Modifications and Management for Adverse Reactions

Dosage forms and strengths

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.

Contraindications

None.

Warnings and precautions

Hepatotoxicity

Vorasidenib 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 vorasidenib 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 vorasidenib 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 vorasidenib, with 0.4% Grade 3 or 4. Nine percent of patients treated with vorasidenib 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 more than three times the upper limit of normal and total bilirubin more than two 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 vorasidenib was required for 2.9% of patients with ALT elevations, 1.6% of AST elevations, and 0.4% of GGT elevations. Dosage reductions of vorasidenib 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 vorasidenib, 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 vorasidenib based on severity.

Embryo-fetal toxicity

Based on findings from animal studies, vorasidenib 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 or more 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 or more 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 vorasidenib and for 3 months after the last dose because vorasidenib can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vorasidenib and for 3 months after the last dose.

Adverse reactions

The following clinically significant adverse reaction was described elsewhere in the labeling: hepatotoxicity.

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 vorasidenib 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 vorasidenib, 78% were exposed for 6 months or longer, and 44% were exposed for more than 1 year. In this pooled safety population, the most common (15% or greater) 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% or greater) Grade 3 or 4 laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).

INDIGO. The safety of vorasidenib was evaluated in 330 patients with Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation who received at least one dose of either vorasidenib 40 mg daily (N=167) or placebo (N=163) in the INDIGO trial. Patients received vorasidenib 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 vorasidenib, the median duration of exposure to vorasidenib was 12.7 months (range: 1 to 30 months), with 153 patients (92%) exposed to vorasidenib for at least 6 months and 89 (53%) exposed for at least 1 year.

The demographics of patients randomized to vorasidenib 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 vorasidenib. The most common serious adverse reactions occurring in 2% or more of patients who received vorasidenib include seizure (3%).

Permanent discontinuation of vorasidenib due to an adverse reaction occurred in 3.6% of patients. Adverse reactions that resulted in permanent discontinuation of vorasidenib in 2% or more of patients included ALT increased (3%).

Dosage interruptions of vorasidenib due to an adverse reaction occurred in 30% of patients. Adverse reactions that required dose interruption in ≥5% of patients included ALT increased (14%), COVID-19 (9%), and AST increased (6%).

Dose reductions of vorasidenib due to an adverse reaction occurred in 11% of patients. Adverse reactions that required dose reduction in 5% or more 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 3 or 4 (2% or greater) 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 3 and 4.

Table 3. Adverse Reactions (greater than 5%) in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received Vorasidenib Compared with Placebo in the INDIGO Trial

Table 4. Select Laboratory Abnormalities (greater than 5%) That Worsened from Baseline in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received Vorasidenib in the INDIGO Trial

Drug interactions

Effect of other drugs on vorasidenib

Table 5. Effect of Other Drugs on Vorasidenib

Effect of vorasidenib on other drugs

Table 6. Effect of Vorasidenib on Other Drugs

Use in specific populations

Pregnancy

Risk Summary. Based on findings from animal studies and its mechanism of action, vorasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on vorasidenib 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 eight or more 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 data. In 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 6 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 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).

Lactation

Risk Summary. There 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 vorasidenib, advise women not to breastfeed during treatment with vorasidenib and for 2 months after the last dose.

Females and males of reproductive potential

Based on animal embryo-fetal toxicity studies, vorasidenib can cause fetal harm when administered to pregnant women.

Pregnancy testing. Verify pregnancy status in females of reproductive potential prior to starting vorasidenib.

Contraception.

Females. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with vorasidenib and for 3 months after the last dose. Vorasidenib can render some hormonal contraceptives ineffective.

Males. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vorasidenib and for 3 months after the last dose.

Infertility. Based on findings in animals, vorasidenib may impair fertility in females and males of reproductive potential. The effects on female and male fertility were not reversible in rats.

Pediatric use

The safety and effectiveness of vorasidenib 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 vorasidenib for this indication in this age group is supported by evidence from an adequate and well-controlled study of vorasidenib 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 the range of exposure observed in adults at the recommended dosages.

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

Geriatric use

Of the 167 patients who were randomized and received vorasidenib 40 mg once daily in the INDIGO trial, 1.2% (two patients) were 65 years or older. Clinical studies of vorasidenib did not include sufficient numbers of patients aged ≥65 to determine whether they respond differently from younger subjects.

Renal impairment

No dosage adjustment is recommended for patients with creatinine clearance (CLcr) greater than 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. For patients with CLcr 40 mL/min or less or who require dialysis, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended.

Hepatic impairment

No dosage adjustment is recommended for patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment.

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.

Clinical pharmacology

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.

Pharmacodynamics

Exposure-response relationships. Vorasidenib 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 electrophysiology. When the recommended dose of vorasidenib is administered 1 hour prior to a meal, a mean increase in the QTc interval longer than 20 msec is unlikely. There is insufficient information to characterize the QTc effects of vorasidenib at higher vorasidenib concentrations, eg, when administered with a meal or when co-administered with a moderate CYP1A2 inhibitor.

Pharmacokinetics

Vorasidenib maximum plasma concentration (C_max) and AUC increased approximately proportionally over the dose range of 10 to 200 mg (0.2 to four 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%) C_max 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.

Absorption. The median (minimum, maximum) time to maximum plasma concentrations (t_max) at steady state is 2 hours (0.5 to 4 hours).

The mean absolute bioavailability of vorasidenib is 34%.

Food effect. A high-fat and high-calorie (total 800 to 1,000 calories, of which 500 to 600 from fat) meal increased vorasidenib C_max 3.1-fold and AUC 1.4-fold, compared to the fasting conditions.

A low-fat and low-calorie (total 400 to 500 calories, of which 100 to 125 from fat) meal increased vorasidenib C_max 2.3-fold and AUC 1.4-fold, compared to the fasting conditions.

Distribution. The mean (CV%) volume of distribution at steady state of vorasidenib is 3,930 L (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.

Elimination. The mean (CV%) steady state terminal half-life is 10 days (57%), and oral clearance is 14 L/h (56%).

Metabolism. Vorasidenib 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.

Excretion. Following a single oral radiolabeled dose of vorasidenib, 85% of the dose was recovered in feces (56% unchanged), and 4.5% was recovered in urine.

Specific populations. No 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 A or B) or CLcr greater than 40 mL/min (as Cockcroft-Gault). The pharmacokinetics of vorasidenib have not been studied in patients with severe hepatic impairment (Child-Pugh Class C), in patients with CLcr 40 mL/min or less in patients with renal impairment who require dialysis.

Pediatric patients. The exposure of vorasidenib in pediatric patients 12 years of age or older is predicted to be within the 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 C_max 1.3-fold and AUC 2.5-fold.

Concomitant use with fluvoxamine (strong CYP1A2 inhibitor) is predicted to increase vorasidenib C_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 C_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 studies.

Vorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4.

Vorasidenib is not a substrate of P-gp, BCRP, or OATP1B1 and OATP1B3.

Vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-gp and OATP1B1.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and 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 or greater (12 or more 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 or greater (12 or more 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 or greater (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 or greater (approximately 22 times the exposure based on AUC in humans at the highest recommended dose). Findings in male and female monkeys were reversible.

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 greater than 3 mg/kg/day (more than 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 greater than 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 or more 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.

Clinical studies

The efficacy of vorasidenib was evaluated in the INDIGO trial (Study AG881-C-004), a randomized, multicenter, double-blind, placebo-controlled study of 331 patients (NCT04164901). Eligible patients were required to have IDH1- or IDH2-mutant Grade 2 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 vorasidenib 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 vorasidenib after documented radiographic disease progression. Tumor assessments were performed every 12 weeks.

A total of 331 patients were randomized, 168 to the vorasidenib 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 vorasidenib arm, 14% of patients had a biopsy, 48% had subtotal 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 a blinded independent review committee (BIRC) per modified Response Assessment in Neuro-Oncology for Low Grade Glioma (RANO-LGG) criteria.

The major efficacy analyses are supported by a 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 vorasidenib arm and 17.8 months for patients in the placebo arm (HR=0.26; 95% CI: [0.15, 0.43], p <0.0001).

For a summary of key efficacy results from this study, Table 7 and Figure 1 (on the DAILYMED website).

How supplied/storage and handling

How supplied. Vorasidenib® (vorasidenib) tablets are supplied in two strengths:

10 mg tablets: White to off-white, round film-coated tablet imprinted with "10" in black ink on one side and plain on the other side.

• Each carton contains one 30-count bottle of 10 mg tablets with desiccant canister(s) and child-resistant cap (NDC 72694-879-10)

40 mg tablets: White to off-white, oblong film-coated tablet imprinted with "40" in black ink on one side and plain on the other side.

• Each carton contains one 30-count bottle of 40 mg tablets with desiccant canister(s) and child-resistant cap (NDC 72694-728-40)

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).

Patient counseling information

Advise the patient to read the FDA-approved patient labeling.

Hepatotoxicity. Inform patients of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity to their healthcare provider.

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.

Advise females of reproductive potential to use effective nonhormonal contraception during treatment with vorasidenib and for 3 months after the last dose because vorasidenib can render some hormonal contraceptives ineffective.

Advise males with female partners of reproductive potential to use effective contraception during treatment with vorasidenib and for 3 months after the last dose.

Lactation. Advise women not to breastfeed during treatment with vorasidenib and for 2 months after the last dose.

Infertility. Advise females and males of reproductive potential that vorasidenib may impair fertility.

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.

Advise patients and caregivers to inform their healthcare provider if they currently smoke tobacco, as it may affect how well vorasidenib works.

Instructions for taking vorasidenib. Advise patients to swallow tablets whole with a glass of water, with or without food, and not to split, crush, or chew vorasidenib tablets.

If a patient misses a dose by less than 6 hours, instruct the patient 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.

If a patient vomits a dose, instruct patients not to take another dose. Advise patients to take the next dose at the usual time.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.