Vorasidenib (Monograph)

Brand name: Voranigo
Drug class: Antineoplastic Agents

Introduction

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) inhibitor; antineoplastic agent.

Uses for Vorasidenib

Brain Tumors

Treatment of adults and pediatric patients ≥12 years of age with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection. To determine IDH mutations, use an FDA approved test ([Web]).

Designated an orphan drug by FDA for the treatment of glioma.

The 2025 American Society of Clinical Oncology and the Society for Neuro-Oncology (ASCO-SNO) guideline recommends a risk-adapted approach for treatment of WHO grade 2 astrocytoma and oligodendroglioma. According to ASCO-SNO, vorasidenib may be offered to adults with IDH-mutant, WHO grade 2 astrocytoma or oligodendroglioma when further treatment with radiation and chemotherapy has been or can be deferred, particularly in patients with favorable prognostic features or when avoiding immediate chemoradiation is clinically appropriate.

Vorasidenib Dosage and Administration

General

Pretreatment Screening

Confirm presence of IDH1 or IDH2 mutations in tumor specimens using an approved FDA test ([Web]).
Assess blood chemistry and liver function tests (ALT, AST, gamma-glutamyl transferase [GGT], total bilirubin, and alkaline phosphatase).
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor liver function tests (ALT, AST, GGT, total bilirubin and alkaline phosphatase) every 2 weeks for the first 2 months of treatment, once monthly for the first 2 years, and as clinically indicated, thereafter.

Administration

Administer orally with or without food. Swallow tablets whole; do not split, crush, or chew.

Take vorasidenib at the same time each day.

If a dose is missed, take missed dose as soon as possible within 6 hours. If dose is missed by >6 hours, skip dose and take next dose at scheduled time. If vomiting occurs, do not retake the dose; take next dose as scheduled the following day.

Dosage

Pediatric Patients

Brain Tumors (Grade 2 Astrocytoma or Oligodendroglioma)

Oral

≥12 years of age and ≥40 kg: 40 mg once daily.

≥12 years of age and <40 kg: 20 mg once daily.

Continue therapy until disease progression or unacceptable toxicity.

Adults

Brain Tumors (Grade 2 Astrocytoma or Oligodendroglioma)

Oral

40 mg once daily.

Continue therapy until disease progression or unacceptable toxicity.

Dosage Adjustment for Adverse Reactions

If an adverse reaction occurs, treatment interruption, dosage reduction, and/or discontinuation of therapy may be necessary based on severity of the adverse event.

The manufacturer's recommended dosage reduction schedule and dosing modifications for adverse reactions are provided in Tables 1 and 2.

Table 1. Recommended Vorasidenib Dosage Reductions for Adverse Reactions1
Dosage Reduction	Recommended Dosage
Adults and pediatric patients ≥12 years of age and ≥40 kg: First dosage reduction	20 mg once daily
Adults and pediatric patients ≥12 years of age and ≥40 kg: Second dosage reduction	10 mg once daily Permanently discontinue if unable to tolerate 10 mg once daily.
Pediatric patients ≥12 years of age and <40 kg: First dosage reduction	10 mg once daily Permanently discontinue if unable to tolerate 10 mg once daily.

Table 2. Recommended Vorasidenib Dosage Modifications and Management for Adverse Reactions1
Adverse Reaction and Severity	Management and Dosage Modifications
Hepatotoxicity, Grade 1 (ALT or AST increase >ULN to 3 times ULN with total bilirubin >2 times the ULN)	Continue vorasidenib at current dosage. Monitor liver function tests weekly until recovery to Grade <1.
Hepatotoxicity, Grade 2 (ALT or AST >3-5 times the ULN without total bilirubin >2 times the ULN)	First Occurrence: Withhold vorasidenib until recovery to Grade ≤1 or baseline. For recovery in ≤28 days, resume vorasidenib at the same dosage; for recovery in >28 days, resume at reduced dosage (see Table 1). Recurrence: Withhold vorasidenib until recovery to Grade ≤1 or baseline, and resume at reduced dosage (see Table 1).
Hepatotoxicity, Grade 3 (ALT or AST >5-20 times the ULN without total bilirubin >2 times the ULN)	First Occurrence: Withhold vorasidenib until recovery to ≤Grade 1 or baseline. For recovery in ≤28 days, resume vorasidenib at reduced dosage (see Table 1); if not recovered in ≤28 days, permanently discontinue vorasidenib. Recurrence: Permanently discontinue vorasidenib.
Hepatotoxicity, Grade 2 or 3 (Any ALT or AST >3-20 times the ULN and total bilirubin >2 times the ULN)	First Occurrence: Withhold vorasidenib until recovery to Grade ≤1 or baseline. Resume vorasidenib at reduced dosage (see Table 1). Recurrence: Permanently discontinue vorasidenib.
Hepatotoxicity, Grade 4 (Any ALT or AST >20 times the ULN)	Permanently discontinue vorasidenib.
Other Adverse Reactions, Grade 3	First Occurrence: Withhold vorasidenib until recovery to Grade ≤1 or baseline. Resume vorasidenib at reduced dosage (see Table 1). Recurrence: Permanently discontinue vorasidenib.
Other Adverse Reactions, Grade 4	Permanently discontinue vorasidenib.

Special Populations

Hepatic Impairment

No dosage adjustment needed for mild or moderate hepatic impairment (Child-Pugh Class A or B). Monitor patients with severe hepatic impairment (Child-Pugh Class C) for adverse reactions and modify dosage as recommended.

Renal Impairment

No dosage adjustment needed for Cl_cr>40 mL/minute. In patients with Cl_cr ≤40 mL/minute or requiring dialysis, monitor closely for adverse reactions and adjust dosage as needed.

Geriatric Patients

No specific dosage adjustment recommended.

Cautions for Vorasidenib

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Possible elevations in liver enzymes, which may lead to serious hepatic events such as hepatic failure or autoimmune hepatitis.

Monitor liver function tests (AST, ALT, GGT, total bilirubin, and alkaline phosphatase) before starting vorasidenib, every 2 weeks for the first 2 months, then monthly for 2 years, and as clinically indicated; monitor more frequently if transaminase elevations occur.

Reduce dosage, withhold, or permanently discontinue vorasidenib based on severity.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal studies.

Females of reproductive potential should use effective nonhormonal contraception during treatment and for 3 months after the last dose, as vorasidenib may reduce hormonal contraceptive effectiveness. Males with female partners of reproductive potential should also use effective contraception during this period.

Specific Populations

Pregnancy

Based on animal studies and its mechanism of action, vorasidenib may cause fetal harm when given during pregnancy. Advise pregnant women of the potential fetal risk.

Lactation

There are no data on vorasidenib in human milk or its effects on the infant or milk production. Advise women not to breastfeed during treatment and for 2 months after the last dose.

Females and Males of Reproductive Potential

Confirm pregnancy status before starting vorasidenib, which may cause fetal harm and impair fertility in both sexes. Use effective nonhormonal contraception during treatment and for 3 months after, as vorasidenib may reduce hormonal contraceptive efficacy. Males with female partners of reproductive potential should also use contraception during this period.

Pediatric Use

Vorasidenib approved in pediatric patients ≥12 years of age with grade 2 IDH1- or IDH2-mutant astrocytoma or oligodendroglioma based on similar exposure and disease profile to adults. Safety and effectiveness in patients <12 years of age have not been studied.

Geriatric Use

In the principal efficacy trial, only 1.2% of patients treated were ≥65 years of age, limiting conclusions about differences in response by age.

Hepatic Impairment

No dosage adjustment needed for mild or moderate hepatic impairment (Child-Pugh Class A or B). Not studied in severe impairment (Child-Pugh Class C); monitor for adverse reactions and adjust dosage if needed.

Renal Impairment

No dosage adjustment needed for Cl_cr>40 mL/min. For those with Cl_cr ≤40 mL/min or on dialysis, populations not studied, monitor for adverse reactions and adjust dosage as needed.

Common Adverse Effects

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

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

Drug Interactions

Metabolized by CYP1A2 with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Induces CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, and uridine diphosphate-glucuronosyltransferase (UGT) 1A4.

Inhibits breast cancer resistance protein (BCRP), but does not inhibit P-glycoprotein (P-gp) or organic anion transporting polypeptides (OATP) 1B1.

Not a substrate of P-gp, BCRP, or OATP1B1 and OATP1B3.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong or moderate CYP1A2 inhibitors: may increase vorasidenib exposure; avoid coadministration or monitor closely for toxicity when use concomitantly.

Moderate CYP1A2 inducers: may reduce vorasidenib exposure; avoid concomitant use.

CYP3A4 substrates: vorasidenib may reduce CYP3A4 substrate exposure. Avoid concomitant use of CYP3A4 substrates that require consistent drug levels.

Specific Drugs

Drug	Interaction	Recommendation
Ciprofloxacin	Increased vorasidenib exposure by 1.3-2.5 fold	Avoid use
Fluvoxamine	Predicted to increase vorasidenib exposure by ≥5-fold	Avoid use
Hormonal contraceptives	Vorasidenib may decrease hormonal contraceptive exposure	Avoid use; may consider nonhormonal contraceptive use
Omeprazole	No clinically significant difference in vorasidenib exposure
Phenytoin	Predicted to decrease vorasidenib exposure by 30-40%	Avoid use
Rifampin	Predicted to decrease vorasidenib exposure by 30-40%	Avoid use
Tobacco smoke	May lower vorasidenib exposure	Avoid use

Vorasidenib Pharmacokinetics

Absorption

Bioavailability

Demonstrates dose proportional increases in peak plasma concentrations and AUC.

Mean absolute bioavailability is 34%.

Plasma Concentrations

Median time to peak plasma concentrations at steady state is 2 hours (range 0.5 to 4 hours).

Steady-state achieved within 28 days with once daily dosing.

Food

High-fat, high-calorie meal (total calories 800–1000 with 500–600 from fat) increases peak plasma concentration by 3.1-fold and AUC by 1.4-fold compared to fasting conditions.

Low-fat, low-calorie meal (total calories 400–500 with 100–125 from fat) increases peak plasma concentrations by 2.3-fold and AUC by 1.4-fold compared to fasting conditions.

Special Populations

No clinically significant pharmacokinetic differences observed based on age, sex, race, weight, mild/moderate hepatic impairment, or mild renal impairment.

Distribution

Extent

Brain tumor-to-plasma ratio of 1.6

Plasma Protein Binding

97% independent of drug concentration in vitro.

Elimination

Metabolism

Primarily metabolized by CYP1A2, with minor roles from several other CYP enzymes and non-CYP pathways.

Elimination Route

Fecal: 85% with 56% as unchanged drug.

Urine: 4.5%.

Half-life

Mean terminal half-life: 10 days.

Stability

Storage

Oral

Tablets

Store at room temperature (20-25°C; excursions permitted between 15–30°C).

Actions

Small molecule inhibitor of isocitrate dehydrogenase enzymes (IDH) 1 and IDH2.
Inhibits both wild-type and mutant forms of IDH1 and IDH2, including common mutations such as IDH1 R132H.
Reduces oncometabolite 2-hydroxyglutarate (2-HG) production and partially restores cellular differentiation.

Advice to Patients

Advise patients 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 patients 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, and males with female partners of reproductive potential, to use effective nonhormonal contraception during treatment with vorasidenib and for 3 months after the last dose.
Advise patients not to breastfeed during treatment with vorasidenib and for 2 months after the last dose.
Advise patients to inform their healthcare provider if they currently smoke tobacco as it may affect how well vorasidenib works.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Vorasidenib is available through designated specialty pharmacies. Contact the manufacturer or consult the Voranigo web site ([Web]) for specific availability information.