Vorasidenib is a small molecule antineoplastic agent that inhibits isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2).1, 2, 3
Vorasidenib is used for the 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 that includes biopsy, sub-total resection, or gross total resection.1, 2, 3 An FDA approved test ([Web]) should be used to determine IDH1 or IDH2 mutations.1 Vorasidenib has been designated an orphan drug by FDA for the treatment of glioma.4
The safety and efficacy of vorasidenib were established in a multicenter, randomized, double-blind, placebo-controlled trial (INDIGO) that included 331 patients ≥12 years of age with IDH1- or IDH2-mutant grade 2 astrocytoma or oligodendroglioma who had undergone prior surgery including biopsy, sub-total resection, or gross total resection.1, 2, 3 Eligible patients were also required to have measurable nonenhancing glioma (≥1 lesion ≥1 cm × 1 cm).1, 3 Patients who received prior chemotherapy or radiation for glioma were excluded.1, 3 Disease progression was assessed by a blinded independent review committee (BIRC) using modified Response Assessment in Neuro-Oncology for Low-Grade Glioma (RANO-LGG) criteria, which assessed radiographic tumor growth, or death from any cause, whichever occurred earlier.1, 2, 3
Patients were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo in 28-day cycles.1, 2, 3 At baseline, the median age of patients was 40 years (range, 16-71 years); 57% were male; 78% were white, 4% Asian, 1% Black or African American, and 16% did not report race.1, 2 There was only one patient <18 years of age enrolled in the study who was assigned to the placebo arm.2 Patients had either oligodendroglioma (52%) or astrocytoma (48%).1, 2 Most (83-84%) had tumors ≥2 cm in diameter, all had non-enhancing measurable disease on magnetic resonance imaging (MRI), and the median time from last surgery was 2.4-2.6 years.2, 3 The majority (87%) of IDH1 mutations were R132H.1 All patients had a Karnofsky performance status ≥80.1
The primary efficacy outcome, median time to progression-free survival, was significantly longer with vorasidenib than with placebo (27.7 versus 11.1 months, respectively).2, 3 Additionally, the median time to the next anticancer intervention was significantly longer with vorasidenib than with placebo, not reached versus 17.8 months, respectively.1, 2, 3 No deaths occurred at the time of analysis.1 Imaging-based progression occurred significantly less in patients receiving vorasidenib (28%) than placebo (54%).1, 3
WHO grade 2 oligodendrogliomas and astrocytomas are slow-growing, infiltrative brain tumors with low proliferative potential, but ultimately undergo malignant transformation into high-grade gliomas.2 Oligodendroglioma tumors contain an IDH1 or IDH2 mutation and a 1p/19q codeletion (caused by an unbalanced translocation between chromosomes 1 and 19), while astrocytoma tumors contain an IDH1 or IDH2 mutation and no 1p/19q codeletion.3, 5
The 2025 American Society of Clinical Oncology and the Society for Neuro-Oncology (ASCO-SNO) guideline recommends a risk-adapted approach for treating WHO grade 2 diffuse astrocytoma and oligodendrogliomas.5 For patients with oligodendroglioma, IDH-mutant, 1p19q codeleted, CNS WHO grade 2, standard therapy is radiation followed by PCV (procarbazine, lomustine, and vincristine), with temozolomide as a reasonable alternative when toxicity is a concern.2, 5 Observation may be appropriate in select low-risk patients after complete resection.2, 5 For astrocytoma, radiation followed by temozolomide is typically recommended.2, 5 Treatment decisions are guided by molecular features of the cancer, patient age, extent of resection, and clinical risk.5
According to the ASCO-SNO 2025 guideline, 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.5 The panel emphasizes shared decision-making given the evolving role of targeted therapies in this setting.5
Administer vorasidenib orally with or without food.1 Swallow tablets whole; do not split, crush, or chew the tablets.1
Take vorasidenib at the same time each day.1 If a dose is missed, take the missed dose as soon as possible within 6 hours.1 If a dose is missed by >6 hours, skip the dose and take the next dose at the scheduled time.1 If vomiting occurs after taking vorasidenib, do not retake the dose; take the next dose as scheduled the following day.1
Store vorasidenib tablets at room temperature (20-25°C; excursions permitted between 15-30°C).1
The recommended dosage of vorasidenib for the treatment of grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation in adults and pediatric patients ≥12 years of age who are ≥40 kg is 40 mg orally once daily.1 The recommended dosage for patients ≥12 years of age who are <40 kg is 20 mg orally once daily.1
Continue therapy until disease progression or unacceptable toxicity.1
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.1
The manufacturer's recommended dosage reduction schedule and dosing modifications for adverse reactions are provided in Tables 1 and 2.1
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. |
Adverse Reaction and Severity | Management and Dosage Modifications |
|---|---|
Hepatotoxicity, Grade 1 (ALT or AST increase >upper limit of normal (ULN) to 3 times the ULN without 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 dosa 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. |
No dosage adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).1 Monitor patients with severe hepatic impairment (Child-Pugh Class C) for adverse reactions and modify the dosage as recommended.1
No dosage adjustment is recommended for patients with creatinine clearance (Clcr) >40 mL/minute.1 Patients with Clcr≤40 mL/minute or requiring dialysis have not been studied; monitor such patients closely for adverse reactions and adjust the dosage as needed.1
No specific dosage adjustment recommended.1
Vorasidenib can cause elevations in liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase, which may lead to serious hepatic events such as hepatic failure or autoimmune hepatitis.1
In the pooled safety population, 58% of patients receiving vorasidenib had ALT elevations and 44% had AST elevations, with grade 3 or 4 increases in 9% and 4.8%, respectively; 4.1% had concurrent grade 3-4 ALT or AST elevations.1 An increase in GGT occurred in 34% of patients with grade 3-4 elevations in 2.2%; bilirubin increased in 4.8% of patients, with grade 3-4 elevations in 0.4%; alkaline phosphatase increased in 9% of patients, with grade 3-4 elevations in 0.9%.1
Two patients met Hy's Law criteria with ALT or AST >3 times the ULN and bilirubin >2 times the ULN, associated with autoimmune hepatitis and hepatic failure.1 The median time to first ALT or AST elevation was 57 days (range: 1-1049).1
Vorasidenib was permanently discontinued in 2.9% of patients due to ALT elevations, 1.6% of patients due to AST elevations, and 0.4% of patients due to GGT elevations.1 Dosage reductions were required in 7% of patients due to elevated ALT, 1.2% of patients due to elevated AST, and 0.4% of patients due to elevated GGT.1 Dosage interruptions occurred in 14% of patients due to ALT elevations, 6% of patients due to AST elevations, and 1.6% due to GGT elevations.1
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, with more frequent testing if transaminase elevations occur.1
Reduce the dose, withhold, or permanently discontinue vorasidenib based on severity.1
Fetal/Neonatal Morbidity and Mortality
Vorasidenib may cause fetal harm based on animal studies showing embryo-fetal toxicity at exposures ≥45 times the human exposure in rats and ≥8 times the human exposure in rabbits.1 Advise pregnant women and females of reproductive potential of this risk.1
Females of reproductive potential should use effective nonhormonal contraception during treatment and for 3 months after the last dose because vorasidenib may reduce hormonal contraceptive effectiveness.1 Males with female partners of reproductive potential should also use effective contraception during vorasidenib treatment and for 3 months after the last dose.1
Based on animal studies and its mechanism of action, vorasidenib may cause fetal harm when given during pregnancy.1 No human data are available, but embryo-fetal toxicity was observed in rats and rabbits at doses ≥8 times the human exposure based on the AUC at the highest recommended vorasidenib dosage.1 Advise pregnant women of the potential fetal risk.1
There are no data on vorasidenib in human milk or its effects on the infant or milk production.1 Advise women not to breastfeed during treatment and for 2 months after the last dose.1
Females and Males of Reproductive Potential
Vorasidenib may cause fetal harm based on animal studies; verify pregnancy status before starting treatment.1 Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 3 months after the last dose, as vorasidenib may reduce hormonal contraceptive effectiveness.1 Males with female partners of reproductive potential should also use contraception during and for 3 months after treatment.1 Vorasidenib may impair fertility in both sexes, with non-reversible effects observed in rats.1
Vorasidenib is approved for pediatric patients ≥12 years of age with grade 2 IDH1- or IDH2-mutant astrocytoma or oligodendroglioma, based on clinical trial data and pharmacokinetic analyses demonstrating comparable exposure and disease similarity to adults.1 Its safety and effectiveness have not been established in patients <12 years of age.1
In the principal efficacy trial, only 1.2% of patients treated with vorasidenib were ≥65 years of age, limiting conclusions about differences in response by age.1
No dosage adjustment of vorasidenib is needed for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).1 Vorasidenib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); monitor for adverse reactions and adjust the dosage if needed in such patients.1
No dosage adjustment of vorasidenib is needed for patients with creatinine clearance (Clcr) >40 mL/min.1 Patients with Clcr≤40 mL/min or on dialysis were not studied; monitor for adverse reactions and adjust the dosage as needed in such patients.1
The most common (≥15%) adverse reactions reported with vorasidenib in clinical studies include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure.1
Grade 3 or 4 (≥2%) laboratory abnormalities include increased ALT, increased AST, increased GGT, and decreased neutrophils.1
Vorasidenib is primarily metabolized by cytochrome P-450 (CYP) 1A2 with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A.1
In vitro studies show that vorasidenib is an inducer of several enzymes, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, and uridine diphosphate-glucuronosyltransferase (UGT) 1A4.1
Vorasidenib is not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or the hepatic transporters organic anion transporting polypeptides (OATP) 1B1 and OATP1B3.1
Vorasidenib acts as an inhibitor of BCRP but does not inhibit P-gp or OATP1B1.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of vorasidenib with strong or moderate CYP1A2 inhibitors may increase vorasidenib plasma concentrations and the risk of adverse reactions; avoid coadministration or monitor closely for increased adverse reactions if use cannot be avoided.1 Concomitant use of ciprofloxacin, a moderate CYP1A2 inhibitor, increased vorasidenib plasma exposure by 1.3-fold and AUC by 2.5-fold.1 Concomitant use with fluvoxamine, a strong CYP1A2 inhibitor, is predicted to increase vorasidenib exposure by ≥5-fold.1
Concomitant use of vorasidenib with moderate CYP1A2 inducers, including tobacco smoke, may decrease vorasidenib plasma concentrations and reduce efficacy; avoid use during treatment.1 Concomitant use with phenytoin or rifampicin, moderate CYP1A2 inducers, is predicted to decrease vorasidenib exposure by 30-40%.1
Concomitant use of vorasidenib may decrease plasma concentrations of CYP3A4 substrates.1 Avoid using vorasidenib with CYP3A4 substrates that require consistent drug levels, as even small decreases in concentration may reduce therapeutic effect.1
Concomitant use of vorasidenib may decrease concentrations of hormonal contraceptives.1 If use cannot be avoided, recommend a nonhormonal method of contraception during treatment.1
Concomitant use of omeprazole, an acid-reducing agent, did not result in a clinically significant change in vorasidenib pharmacokinetics.1
Vorasidenib is a small molecule inhibitor of isocitrate dehydrogenase enzymes (IDH) 1 and IDH2.1 In vitro, vorasidenib inhibits both wild-type and mutant forms of IDH1 and IDH2, including common mutations such as IDH1 R132H.1 In cell-based and animal tumor models with IDH1 or IDH2 mutations, vorasidenib reduces production of the oncometabolite 2-hydroxyglutarate (2-HG) and partially restores cellular differentiation.1 In patients with IDH-mutant glioma, vorasidenib lowered tumor 2-HG levels by a median of 64-93% compared to untreated tumors, with reductions observed at drug exposures ranging from 0.3-0.8 times the highest recommended dose.1 The relationship between exposure, response, and time course of effect has not been fully established.1
Vorasidenib demonstrates dose proportional increases in peak plasma concentrations and systemic exposure.1 Steady state is achieved within 28 days of once daily dosage.1 The mean absolute bioavailability is 34%, and median time to peak plasma concentrations at steady state is 2 hours with a range of 0.5-4 hours.1 High-fat, high-calorie meals (total calories 800-1,000 of which 500-600 are from fat) increases peak plasma concentration 3.1-fold and AUC 1.4-fold compared to fasting, while a low-fat, low-calorie meal (total calories 400-500 with 100-125 from fat) increases peak plasma concentration by 2.3-fold and AUC by 1.4-fold compared to fasting.1 Vorasidenib is 97% protein-bound (independent of drug concentration in vitro) and has a brain tumor-to-plasma ratio of 1.6.1 The mean terminal half-life is 10 days.1 Vorasidenib is mainly metabolized by cytochrome P-450 (CYP) 1A2, with minor roles from several other CYP enzymes and non-CYP pathways.1 Elimination is primarily fecal at 85%, which includes 56% as unchanged drug; 4.5% is excreted in urine.1 No clinically significant pharmacokinetic differences were observed based on age, sex, race, weight, mild/moderate hepatic impairment, or mild renal impairment.1
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 10 mg | Voranigo® | Servier Pharmaceuticals |
40 mg | Voranigo® | Servier Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Servier Pharmaceuticals LLC. VORANIGO® (vorasidenib) ORAL prescribing information. 2025 Apr. [Web]
2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 218784Orig1s000: Multidisciplinary review. [Web]
3. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023;389(7):589-601.
4. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2025 May 31. [Web]
5. Blakeley J, Mohile NA, Messersmith H, Lassman AB, Schiff D; Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults Guideline Expert Panel. Therapy for diffuse astrocytic and oligodendroglial tumors in adults: ASCO-SNO guideline rapid recommendation update. J Clin Oncol. Published online April 29, 2025.