VORASIDENIB Drug Interactions: What You Need to Know

INTERACTIONS CYP1A2 Inhibitors : Avoid concomitant use of strong and moderate CYP1A2 inhibitors. ( 7.1 ) CYP1A2 Inducers : Avoid concomitant use of moderate CYP1A2 inducers and smoking tobacco. ( 7.1 ) Certain CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where a minimal concentration change can reduce efficacy. ( 7.2 )

Hormonal

Contraception : If concomitant use cannot be avoided, use with nonhormonal contraception methods. ( 7.2 )

7.1 Effect of Other Drugs on VORANIGO Table 5: Effect of Other Drugs on VORANIGO Strong and Moderate CYP1A2 Inhibitors Clinical Impact Concomitant use of VORANIGO with a strong or moderate CYP1A2 inhibitor may increase vorasidenib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of adverse reactions. Prevention or Management Avoid concomitant use of VORANIGO with strong and moderate CYP1A2 inhibitors. If concomitant use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Moderate CYP1A2 Inducers Clinical Impact Concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco may decrease vorasidenib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may reduce the anti-tumor activity of VORANIGO. Prevention or Management Avoid concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco.

7.2 Effect of VORANIGO on Other Drugs Table 6: Effect of VORANIGO on Other Drugs Certain CYP3A Substrates Clinical Impact Concomitant use of VORANIGO with CYP3A substrates may decrease plasma concentrations of CYP3A substrates. Prevention or Management Avoid concomitant use of VORANIGO with CYP3A substrates, where a minimal concentration change may lead to reduced therapeutic effect.

Hormonal Contraception Clinical Impact

Concomitant use of VORANIGO may decrease the concentrations of hormonal contraceptives, which may lead to contraception failure and/or an increase in breakthrough bleeding. Prevention or Management If concomitant use cannot be avoided, use with nonhormonal contraception methods.

None. None. ( 4 )

AND PRECAUTIONS Hepatotoxicity : Monitor liver function tests every 2 weeks during the first 2 months of treatment, then monthly for the first 2 years of treatment, and as clinically indicated. Withhold, reduce the dose or discontinue VORANIGO based on severity. ( 2.3 , 5.1 ) Embryo-Fetal Toxicity : VORANIGO can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective nonhormonal contraception. ( 5.2 , 8.1 , 8.3 )

5.1 Hepatotoxicity VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 58% of patients treated with VORANIGO 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 VORANIGO 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 VORANIGO, with 0.4% Grade 3 or 4. Nine percent of patients treated with VORANIGO 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 and total bilirubin >2 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 VORANIGO was required for 2.9% of patients with ALT elevations, 1.6% of AST elevations, and 0.4% of GGT elevations. Dosage reductions of VORANIGO 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 VORANIGO, 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 VORANIGO based on severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ].

5.2 Embryo-Fetal Toxicity Based on findings from animal studies, VORANIGO 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 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 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 VORANIGO and for 3 months after the last dose, since VORANIGO can render some hormonal contraceptives ineffective <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .