Vorasidenib (Monograph)

Brand name: Voranigo
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Vorasidenib, an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, is an antineoplastic agent.

Uses for Vorasidenib

Vorasidenib has the following uses:

Vorasidenib is 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 following surgery including biopsy, sub-total resection, or gross total resection.

Vorasidenib Dosage and Administration

General

Vorasidenib is available in the following dosage form(s) and strength(s):

Tablets: 10 mg and 40 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage and Administration in Adults and Pediatric Patients ≥12 Years of Age

Before initiating vorasidenib, evaluate blood chemistry and liver laboratory tests.
Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment based on the presence of IDH1 or IDH2 mutations in tumor specimens.
Swallow tablets whole with water, with or without food.
Recommended dosage in adults: 40 mg orally once daily until disease progression or unacceptable toxicity.
Recommended dosage in pediatric patients ≥12 years of age who weigh ≥40 kg: 40 mg orally once daily until disease progression or unacceptable toxicity.
Recommended dosage in pediatric patients ≥12 years of age who weigh <40 kg: 20 mg orally once daily until disease progression or unacceptable toxicity.
See Full Prescribing Information for dosage modification recommendations for adverse reactions.

Cautions for Vorasidenib

Contraindications

None.

Warnings/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 and 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 >3 times the upper limit of normal (ULN) and total bilirubin >2 times the ULN; 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 times the human exposure based on the 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 vorasidenib and for 3 months after the last dose, since 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.

Specific Populations

Pregnancy

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 ≥8 times the human exposure based on the AUC at the highest recommended dose. 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.

Lactation

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.

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

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.

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.

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 12 years of age 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 of age and older is predicted to be within 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% (2 patients) were 65 years of age or older. Clinical studies of vorasidenib did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger subjects.

Renal Impairment

No dosage adjustment is recommended for patients with creatinine clearance (CL_cr) >40 mL/min.

The pharmacokinetics and safety of vorasidenib in patients with CL_cr≤40 mL/min or renal impairment requiring dialysis have not been studied. For patients with CL_cr≤40 mL/min 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.

Common Adverse Effects

The most common (≥15%) adverse reactions include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure.

Grade 3 or 4 (≥2%) laboratory abnormalities were increased ALT, increased AST, increased GGT, and decreased neutrophils.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

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.

Actions

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.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity to their healthcare provider.
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.
Advise males with female partners of reproductive potential to use effective contraception during treatment with vorasidenib and for 3 months after the last dose.
Advise women not to breastfeed during treatment with vorasidenib and for 2 months after the last dose.
Advise females and males of reproductive potential that vorasidenib may impair fertility.
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.
Advise patients to swallow tablets whole with a glass of water, with or without food, and to not split, crush or chew vorasidenib tablets.
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.
If a patient vomits a dose, instruct patients not to take another dose. Advise patients to take the next dose at the usual time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.