Precautions of Vorasidenib

1. Hepatotoxicity

Vorasidenib can cause elevations in liver transaminases, which may lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis.

In the pooled safety population, 58% of patients treated with vorasidenib developed ALT elevation and 44% developed AST elevation. Grade 3 or 4 ALT or AST elevation occurred in 9% and 4.8% of patients, respectively. Among these patients, 4.1% had concurrent Grade 3 to 4 ALT or AST elevation. Overall, 34% of patients treated with vorasidenib developed gamma-glutamyl transferase (GGT) elevation, of which 2.2% were Grade 3 or 4. Bilirubin elevation occurred in 4.8% of patients treated with vorasidenib, of which 0.4% were Grade 3 or 4. Alkaline phosphatase elevation occurred in 9% of patients treated with vorasidenib, of which 0.9% were Grade 3 or 4.

Two patients met the laboratory criteria of Hy's law, with concurrent ALT or AST >3 times ULN and total bilirubin >2 times ULN; these events were associated with cases of autoimmune hepatitis and hepatic failure. The median time to first onset of ALT or AST elevation was 57 days (range: 1 to 1049 days).

Permanent discontinuation of vorasidenib was required due to ALT elevation in 2.9% of patients, AST elevation in 1.6%, and GGT elevation in 0.4%. Dose reduction of vorasidenib was required due to ALT elevation in 7% of patients, AST elevation in 1.2%, and GGT elevation in 0.4%. Interruption of vorasidenib dosing was required due to ALT elevation in 14% of patients, AST elevation in 6%, and GGT elevation in 1.6%.

Monitor liver laboratory tests (AST, ALT, GGT, total bilirubin, and alkaline phosphatase) before initiating vorasidenib treatment, every 2 weeks during the first 2 months of treatment, monthly for the first 2 years of treatment, and as clinically indicated; increase testing frequency in patients who develop transaminase elevations.

Reduce the dose, withhold dosing, or permanently discontinue vorasidenib based on severity.

2. Embryo-Fetal Toxicity

Based on animal study findings, vorasidenib can cause fetal harm when administered to pregnant women. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats during organogenesis caused embryo-fetal toxicity at doses ≥45 times the human exposure based on area under the curve (AUC) at the maximum recommended dose. Oral administration of vorasidenib to pregnant rabbits during organogenesis caused embryo-fetal toxicity at doses ≥8 times the human exposure based on AUC at the maximum recommended dose.

Inform pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during vorasidenib treatment and for 3 months after the last dose, because vorasidenib may render certain hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during vorasidenib treatment and for 3 months after the last dose.