Voranigo
(vorasidenib)Dosage & Administration
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Voranigo Prescribing Information
VORANIGO is indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection [see Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)].
Recommended Evaluation Before Initiating VORANIGO
Before initiating VORANIGO, evaluate blood chemistry and liver laboratory tests [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Patient Selection
Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment with VORANIGO based on the presence of IDH1 or IDH2 mutations in tumor specimens [see Clinical Studies (14)].
Information on FDA-approved tests for detection of IDH1 or IDH2 mutations in Grade 2 astrocytoma or oligodendroglioma for selecting patients for treatment with VORANIGO is available at: https://www.fda.gov/CompanionDiagnostics.
Recommended Dosage and Administration
Recommended Dosage
Adult Patients
The recommended dosage of VORANIGO in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity.
Pediatric Patients 12 Years and Older
The recommended dosage of VORANIGO in pediatric patients 12 years and older is based on body weight:
- Patients weighing ≥40 kg: 40 mg orally once daily
- Patients weighing <40 kg: 20 mg orally once daily
Continue treatment with VORANIGO until disease progression or unacceptable toxicity.
Administration
Swallow VORANIGO tablets whole with water with or without food [see Clinical Pharmacology (12.3)]. Do not split, crush or chew tablets.
Missed Dose
Take VORANIGO tablets at about 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 more than 6 hours, skip the missed dose and take the next dose at the scheduled time.
Vomiting
If vomiting occurs after taking a dose, do not take a replacement dose, and take the next dose at the scheduled time on the following day.
Dosage Modifications, Management and Monitoring for Adverse Reactions
The recommended VORANIGO dosage reductions for adverse reactions are provided in Table 1.
| Dosage Reduction | Recommended Dose and Schedule |
|---|---|
| Adult patients and Pediatric patients 12 years and older weighing at least 40 kg | |
| First | 20 mg once daily |
| Second | 10 mg once daily |
| Pediatric patients 12 years and older weighing less than 40 kg | |
| First | 10 mg once daily |
| Permanently discontinue VORANIGO in patients unable to tolerate 10 mg once daily. | |
The recommended management for adverse reactions and VORANIGO dosage modifications for adverse reactions are provided in Table 2.
| Adverse Reaction | Severity * | Management and Dosage Modifications |
|---|---|---|
| Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal | ||
| ||
| Hepatotoxicity (Elevation of ALT or AST) [see Warnings and Precautions (5.1)] | Grade 1 ALT or AST increase >ULN to 3 × ULN without concurrent total bilirubin >2 × ULN | Continue VORANIGO at current dose. Monitor liver laboratory tests weekly until recovery to <Grade 1. |
| Grade 2 ALT or AST >3 to 5 × ULN without concurrent total bilirubin >2 × ULN | First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline.
| |
| Grade 3 ALT or AST >5 to 20 × ULN without concurrent total bilirubin >2 × ULN | First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline.
| |
| Grade 2 or 3 Any ALT or AST >3 to 20 × ULN with concurrent total bilirubin >2 × ULN | First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline.
| |
| Grade 4 Any ALT or AST >20 × ULN | Permanently discontinue VORANIGO. | |
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 | First Occurrence: Withhold VORANIGO until recovery to ≤Grade 1 or baseline.
|
| Grade 4 | Permanently discontinue VORANIGO. | |
Tablets:
- 10 mg: White to off-white, round film-coated tablet imprinted with "10" in black ink on one side and plain on the other side. Each tablet contains 10 mg of vorasidenib.
- 40 mg: White to off-white, oblong film-coated tablet imprinted with "40" in black ink on one side and plain on the other side. Each tablet contains 40 mg of vorasidenib.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], VORANIGO can cause fetal harm when administered to a pregnant woman. There are no available data on VORANIGO use in pregnant women to inform a drug-associated risk. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity at ≥8 times the human exposure based on the AUC at the highest recommended dose (see Data). Advise pregnant women of the potential risk to the fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study, vorasidenib was administered to pregnant rats via oral gavage at dose levels of 10, 25, and 75 mg/kg/day during the period of organogenesis (gestation days 6 to 17). Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose). Malformation of heart occurred in a rat at a dose of 25 mg/kg (approximately 97 times the human exposure based on the AUC at the highest recommended dose). Dose-related delayed ossification of bones and short ribs associated with decreased fetal body weights was observed at 10 and 25 mg/kg/day in the absence of maternal toxicity and at 75 mg/kg/day. The dose of 10 mg/kg/day is ≥45 times the human exposure based on the AUC at the highest recommended dose.
In an embryo-fetal development study, oral administration of vorasidenib to pregnant rabbits at dose levels of 2, 6, and 18 mg/kg/day during the period of organogenesis (gestation days 6 to 19) resulted in maternal toxicity at all doses (≥1.5 times the human exposure based on the AUC at the highest recommended dose) and caused higher incidence of late resorptions at 18 mg/kg/day as well as decreased fetal weights and delayed ossification at doses ≥6 mg/kg/day (≥8 times the human exposure based on the AUC at the highest recommended dose).
Lactation
Risk Summary
There are no data on the presence of vorasidenib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Because of the potential for adverse reactions in breastfed children from VORANIGO, advise women not to breastfeed during treatment with VORANIGO and for 2 months after the last dose.
Females and Males of Reproductive Potential
Based on animal embryo-fetal toxicity studies, VORANIGO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to starting VORANIGO [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for 3 months after the last dose. VORANIGO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)].
Males
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.
Infertility
Based on findings in animals, VORANIGO may impair fertility in females and males of reproductive potential. The effects on female and male fertility were not reversible in rats [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of VORANIGO have been established in pediatric patients aged 12 years and older for the treatment of Grade 2 IDH1- or IDH2-mutant astrocytoma or oligodendroglioma. Use of VORANIGO for this indication in this age group is supported by evidence from an adequate and well-controlled study of VORANIGO in adult and pediatric patients with additional population pharmacokinetic data demonstrating that age had no clinically meaningful effect on the pharmacokinetics of vorasidenib. In addition, the course of IDH1- or IDH2-mutant astrocytoma or oligodendroglioma is sufficiently similar between adults and pediatric patients to allow extrapolation of pharmacokinetic data in adults to pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].
The exposure of vorasidenib in pediatric patients 12 years and older is predicted to be within range of exposure observed in adults at the recommended dosages [see Clinical Pharmacology (12.3)].
The safety and effectiveness of VORANIGO have not been established in pediatric patients younger than 12 years of age for any indication.
Geriatric Use
Of the 167 patients who were randomized and received VORANIGO 40 mg once daily in the INDIGO trial, 1.2% (2 patients) were 65 years or older. Clinical studies of VORANIGO did not include sufficient numbers of patients aged ≥65 to determine whether they respond differently from younger subjects.
Renal Impairment
No dosage adjustment is recommended for patients with creatinine clearance (CLcr) >40 mL/min.
The pharmacokinetics and safety of vorasidenib in patients with CLcr ≤40 mL/min or renal impairment requiring dialysis have not been studied [see Clinical Pharmacology (12.3)]. For patients with CLcr ≤40 mL/min or who require dialysis, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment is recommended for patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment [see Clinical Pharmacology (12.3)].
The pharmacokinetics and safety of vorasidenib in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. For patients with severe hepatic impairment, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
None.
Hepatotoxicity
VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis.
In the pooled safety population [see Adverse Reactions (6.1)], 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)].
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 [see Drug Interactions (7.2)]. 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 [see Use in Specific Populations (8.1, 8.3)].