voriconazole
Brand: Vfend
TDM Required Prototype Drug
Drug Class: triazole antifungal
Drug Family: antifungal
Subclass: second-generation triazole (anti-Aspergillus, anti-Candida)
Organ Systems: infectious-disease
Mechanism of Action
Inhibits fungal CYP51 with greater potency and broader spectrum than fluconazole; drug of choice for invasive aspergillosis; also inhibits human CYP2C19, CYP2C9, and CYP3A4 as a substrate and inhibitor.
fungal CYP51 (14-alpha-demethylase)
Indications
- invasive aspergillosis (first-line)
- candidemia/invasive candidiasis (alternative)
- esophageal candidiasis
- scedosporiosis, fusariosis (salvage therapy)
- antifungal prophylaxis in HSCT recipients
Contraindications
- voriconazole hypersensitivity
- concurrent use of drugs metabolized by CYP2C19/2C9/3A4 with narrow TI (pimozide, quinidine, ergotamine, sirolimus)
- concurrent rifampin, carbamazepine, phenobarbital (CYP inducers)
Adverse Effects
Common
- visual disturbances (photopsia/altered color perception — very common, usually transient)
- photosensitivity
- nausea
- hepatotoxicity
Serious
- hepatotoxicity
- QTc prolongation
- visual/optic neuritis (with long-term use)
- squamous cell carcinoma (photosensitivity-mediated — rare but reported with prolonged therapy)
- periostitis/fluorosis (long-term use in children)
- adrenal insufficiency (rare)
Pharmacokinetics (ADME)
| Absorption | 96% oral bioavailability (fasting); food reduces by 24% — administer fasting |
| Distribution | widely distributed; Vd 4.6 L/kg; CSF penetration |
| Metabolism | extensive CYP2C19 (primary), CYP2C9, CYP3A4; CYP2C19 polymorphism causes 4-fold AUC differences; ALSO inhibits all three CYP enzymes |
| Excretion | renal (<2% unchanged); primarily as metabolites |
| Half-life | 6 hours (variable due to CYP2C19 polymorphism) |
| Onset | 1–2 hours |
| Peak | 1–2 hours |
| Duration | 12 hours |
| Protein Binding | 58% |
| Vd | large (4.6 L/kg) |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| sirolimus | CYP3A4 inhibition raises sirolimus levels >10-fold; contraindicated combination | major |
| tacrolimus/cyclosporine | CYP3A4 inhibition increases levels; reduce dose by 1/3 (tacrolimus) or 50% (cyclosporine) | major |
| rifampin | potent CYP inducer reduces voriconazole AUC by 96%; contraindicated | major |
| opioids (fentanyl, oxycodone) | CYP3A4 inhibition increases opioid exposure; risk of respiratory depression | major |
Nursing Considerations
- Administer oral voriconazole on an empty stomach (at least 1 hour before or 2 hours after a meal).
- Visual disturbances (blurred vision, altered color vision, photopsia) are extremely common — warn patients before initiating and assess at each visit; these usually resolve spontaneously.
- Strictly avoid direct sunlight and UV exposure; use high-SPF sunscreen daily — photosensitivity and risk of squamous cell carcinoma with prolonged therapy.
- Monitor LFTs at baseline and monthly; also monitor for fluoride toxicity (periostitis) with long-term use in children — bone pain is a red flag.
Clinical Pearls
- Voriconazole is the first-line treatment for invasive aspergillosis per IDSA guidelines, reducing mortality compared to amphotericin B, but it requires TDM in complex patients due to CYP2C19 polymorphism causing wide inter-individual AUC variability.
- Therapeutic drug monitoring of voriconazole (target trough 1–5.5 mg/L) is recommended, especially in poor metabolizers (CYP2C19 *2/*2), patients on interacting drugs, and those with variable absorption.
Safety Profile
Pregnancy contraindicated
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Required
Concordance Terms
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