Voranigo (vorasidenib citrate)

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 Dosage Reductions for Adverse Reactions

Dosage Reduction Recommended Dosage Adults and pediatric patients >=12 20 mg once daily years of age and >=40 kg: First dosage reduction Adults and pediatric patients >=12 10 mg once daily Permanently years of age and >=40 kg: Second discontinue if unable to tolerate 10 dosage reduction mg once daily. Pediatric patients >=12 years of age 10 mg once daily Permanently and <40 kg: First dosage reduction discontinue if unable to tolerate 10 mg once daily.

Table 2. Recommended Vorasidenib Dosage Modifications and Management for Adverse Reactions

Adverse Reaction and Severity Management and Dosage Modifications Hepatotoxicity, Grade 1 (ALT or AST Continue vorasidenib at current increase >upper limit of normal dosage. Monitor liver function tests (ULN) to 3 times the ULN without weekly until recovery to Grade <1. total bilirubin >2 times the ULN) Hepatotoxicity, Grade 2 (ALT or AST First Occurrence: Withhold >3-5 times the ULN without total vorasidenib until recovery to Grade bilirubin >2 times the ULN) <=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 recover y to Grade <=1 or baseline, and resume at reduced dosage (see Table 1). Hepatotoxicity, Grade 3 (ALT or AST First Occurrence: Withhold >5-20 times the ULN without total vorasidenib until recovery to Grade bilirubin >2 times the ULN) <=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 discont inue vorasidenib. Hepatotoxicity, Grade 2 or 3 (Any First Occurrence: Withhold ALT or AST >3-20 times the ULN and vorasidenib until recovery to Grade total bilirubin >2 times the ULN) <=1 or baseline. Resume vorasidenib at reduced dosage (see Table 1). Recurrence: Permanently discontinue vorasidenib. Hepatotoxicity, Grade 4 (Any ALT or Permanently discontinue vorasidenib. AST >20 times the ULN) 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.

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

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

Store vorasidenib tablets at room temperature (20-25degreesC; excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Vorasidenib/Hormonal Contraceptives

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Vorasidenib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) Hormonal contraceptives may inhibit the CYP1A2-mediated metabolism of vorasidenib.(1,2)

CLINICAL EFFECTS: Concurrent use of vorasidenib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Concurrent use of moderate CYP1A2 inhibitors such as hormonal contraceptives may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of vorasidenib states that concurrent use of moderate CYP1A2 inhibitors should be avoided. If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1) Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 3 months after vorasidenib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: Vorasidenib is an inducer of CYP3A4 in vitro. Concomitant use of multiple doses of vorasidenib is predicted to decrease the concentration of CYP3A4 substrates, including hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Vorasidenib is primarily metabolized by CYP1A2. In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1)

Vorasidenib/Moderate Cyp1a2 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate CYP1A2 inducers may increase the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of vorasidenib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of vorasidenib states concurrent use with moderate CYP1A2 inducers should be avoided.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib with phenytoin or rifampin (moderate CYP1A2 inducers) is predicted to decrease vorasidenib concentration maximum (Cmax) by 30% and area-under-curve (AUC) by 40%.(1) Moderate CYP1A2 inducers linked to this monograph include: fosphenytoin, leflunomide, nelfinavir, phenytoin, rifampin, ritonavir, and teriflunomide.(2)

Vorasidenib/Moderate Cyp1a2 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with moderate CYP1A2 inhibitors should be avoided.(1) If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, ciprofloxacin, dipyrone, fexinidazole, genistein, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)

Vorasidenib/Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with strong CYP1A2 inhibitors should be avoided.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*None.

• Lactation

• Pregnancy

There are no moderate contraindications for this drug.

The most common (>=15%) adverse reactions reported with vorasidenib in clinical studies include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure.

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

More Frequent

• Abnormal hepatic function tests
• Hepatic failure
• Increased alanine transaminase
• Increased aspartate transaminase
• Neutropenic disorder
• Seizure disorder

Rare or Very Rare

• Drug-induced hepatitis

More Frequent

• Diarrhea
• Fatigue
• Headache disorder
• Musculoskeletal pain
• Nausea
• Viral infection

Less Frequent

• Acute abdominal pain
• Anorexia
• Constipation

No enhanced messaging available.

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. Its safety and effectiveness have not been established in patients <12 years of age.

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

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.

No specific dosage adjustment recommended.

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.