VORANIGO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VORANIGO (VORANIGO).
VORANIGO (vorasidenib) is an oral, selective, brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes. It reduces the production of the oncometabolite D-2-hydroxyglutarate (2-HG), which drives tumorigenesis in IDH-mutant gliomas.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. |
| Excretion | Primarily hepatic metabolism with biliary excretion of metabolites. Renal excretion accounts for <1% of unchanged drug. Fecal excretion accounts for approximately 60% of the administered dose, mostly as metabolites. |
| Half-life | Terminal elimination half-life is approximately 14–20 hours, supporting once-daily dosing. Steady state is reached within 7–10 days. |
| Protein binding | Approximately 98% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 150–200 L (around 2.3 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 30–50% following oral administration (under fasting conditions). |
| Onset of Action | Oral administration: Clinical effect (antitumor activity) is typically observed after 2–4 weeks of continuous dosing. |
| Duration of Action | Duration of action is sustained with continuous daily dosing. No specific off-effect time; clinical effect persists as long as the drug is administered. |
| Molecular Weight | 484.61 |
100 mg orally once daily for 21 days of a 28-day cycle.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Data insufficient for GFR <30 mL/min or on dialysis; use with caution. |
| Liver impairment | Child-Pugh A: 100 mg once daily. Child-Pugh B: Reduce to 75 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustments recommended; monitor renal function due to age-related decline. |
| 1st trimester | Contraindicated due to teratogenicity based on animal studies and mechanism of action (inhibition of Hedgehog pathway critical for embryonic development). No adequate human data; high risk of severe birth defects. |
| 2nd trimester | Contraindicated; potential for fetal harm as Hedgehog pathway inhibition continues to affect fetal development. |
| 3rd trimester | Contraindicated; continued risk of fetal harm. Limited data, but advise avoidance. |
Clinical note
Comprehensive clinical and safety monograph for VORANIGO (VORANIGO).
| Placental transfer | Expected to cross placenta based on molecular weight (≤500 Da) and animal studies showing fetal malformations. |
| Breastfeeding | No data on presence in human milk; due to potential for serious adverse reactions (e.g., teratogenicity, growth retardation), breast-feeding is not recommended during treatment and for at least 12 months after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
PregnancyWomen of childbearing potential not using highly effective contraceptionHypersensitivity to the active substance or any excipientSevere hepatic impairment (Child-Pugh C)
| Precautions | Hepatotoxicity: Elevations of ALT, AST, and bilirubin; monitor liver function tests before and during treatment., QTc interval prolongation: Monitor ECG in patients at risk., Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception. |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit as they may increase vorasidenib exposure. No other specific food interactions known. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Voranicgo is contraindicated in pregnancy due to teratogenicity. In the first trimester, high risk of major congenital malformations and spontaneous abortion. Second and third trimesters may cause fetal growth restriction and oligohydramnios. Women of childbearing potential must use effective contraception during treatment and for at least 30 days after the last dose. |
| Fetal Monitoring | Monitor maternal liver function tests, thyroid function, and blood pressure monthly. Fetal ultrasound every 4 weeks to assess growth and amniotic fluid volume. Assess for fetal anomalies if exposure occurs. |
| Fertility Effects | Based on animal studies, voranicgo may impair female fertility (e.g., disrupted estrous cycles, reduced ovarian weight) and male fertility (e.g., impaired spermatogenesis, testicular atrophy). Reversibility unknown. |
| Clinical Pearls |
| VORANIGO (vorasidenib) is an IDH1/IDH2 inhibitor indicated for grade 2 IDH-mutant astrocytoma or oligodendroglioma. Monitor for liver enzyme elevations and hypertriglyceridemia. QT prolongation possible; obtain ECG at baseline and as clinically indicated. Avoid in severe hepatic impairment. Drug-drug interactions: avoid strong CYP2D6 substrates (e.g., thioridazine) due to increased toxicity. |
| Patient Advice | Take VORANIGO exactly as prescribed, once daily with or without food. · Do not crush, chew, or split tablets. · Report symptoms of liver problems (yellowing skin/eyes, dark urine, abdominal pain) or heart palpitations/syncope. · Avoid grapefruit, Seville oranges, and star fruit during treatment. · Use effective contraception during treatment and for 3 months after last dose; avoid breastfeeding. · Tell your doctor about all medications, including OTC and herbal products. |