Voriconazole (Vfend)
voriconazole
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Invasive aspergillosis | Adults and pediatrics ≥2 years | First-line | FDA Approved |
| Candidemia in non-neutropenic patients and other deep tissue Candida infections | Adults and pediatrics ≥2 years | Monotherapy | FDA Approved |
| Esophageal candidiasis | Adults and pediatrics ≥2 years | Monotherapy | FDA Approved |
| Serious infections caused by Scedosporium apiospermum and Fusarium spp. | Adults and pediatrics ≥2 years | Monotherapy | FDA Approved |
Voriconazole is the first-line agent for invasive aspergillosis per IDSA guidelines and represents a major advance over older azoles due to its broader spectrum, including activity against fluconazole-resistant Candida species (C. krusei, C. glabrata), Scedosporium, and Fusarium. Unlike itraconazole, voriconazole achieves meaningful CSF concentrations (~50% of plasma), making it useful for CNS infections. Its high oral bioavailability (~96%) allows seamless IV-to-oral step-down. However, voriconazole has no activity against Mucorales (Rhizopus, Mucor), which is a critical clinical distinction when Aspergillus and mucormycosis are in the differential.
Fluconazole-resistant invasive candidiasis — particularly C. krusei and C. glabrata infections. Evidence quality: High
CNS aspergillosis / fungal meningitis — preferred azole given CSF penetration. Evidence quality: Moderate
Prophylaxis in HSCT recipients — allogeneic stem cell transplant patients at high risk for invasive fungal infection. Evidence quality: High
Coccidioidomycosis (non-meningeal) — alternative to fluconazole or itraconazole. Evidence quality: Moderate
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Invasive aspergillosis / Scedosporium / Fusarium infections | IV: 6 mg/kg q12h × 2 doses (Day 1) | IV: 4 mg/kg q12h; Oral: 200 mg q12h (≥40 kg) or 100 mg q12h (<40 kg) | IV: 4 mg/kg q12h; Oral: 300 mg q12h | IV for ≥7 days before oral step-down; median IV duration 10 days in IA trials Oral 200 mg ≈ IV 3 mg/kg; Oral 300 mg ≈ IV 4 mg/kg exposure |
| Candidemia (non-neutropenic) — primary therapy | IV: 6 mg/kg q12h × 2 doses (Day 1) | IV: 3 mg/kg q12h; Oral: 200 mg q12h | IV: 4 mg/kg q12h | Treat ≥14 days after resolution of symptoms or last positive culture, whichever is longer |
| Other deep tissue Candida infections — salvage | IV: 6 mg/kg q12h × 2 doses (Day 1) | IV: 4 mg/kg q12h; Oral: 200 mg q12h | IV: 4 mg/kg q12h | Minimum 14 days and ≥7 days after resolution of signs and symptoms |
| Esophageal candidiasis | Oral: 200 mg q12h | 200 mg q12h | 300 mg q12h | Minimum 14 days and ≥7 days after symptom resolution; max 42 days Patients <40 kg: 100 mg q12h |
Pediatric Dosing (2 to <12 years; 12–14 years <50 kg)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| All approved indications | IV: 9 mg/kg q12h × 2 doses (Day 1) | IV: 8 mg/kg q12h; Oral: 9 mg/kg q12h (max 350 mg) | IV: 8 mg/kg q12h | Initiate with IV; switch to oral only after clinical improvement Pediatric 12–14 y ≥50 kg and ≥15 y: use adult dosing |
Dose Adjustments
| Situation | Adjustment | Notes |
|---|---|---|
| Hepatic impairment (Child-Pugh A/B) | Standard loading dose; halve maintenance dose | No data for Child-Pugh C; use only if benefit outweighs risk with close monitoring |
| Renal impairment (CrCl <50 mL/min) | Use oral voriconazole (no dose adjustment needed) | IV vehicle (SBECD) accumulates; avoid IV unless benefit outweighs risk; monitor serum creatinine |
| Co-administration with phenytoin | Increase voriconazole maintenance to 5 mg/kg IV q12h or 400 mg PO q12h | Phenytoin induces voriconazole metabolism and voriconazole increases phenytoin levels (reduce phenytoin dose) |
| Co-administration with efavirenz | Voriconazole 400 mg PO q12h + efavirenz 300 mg daily | Standard doses contraindicated due to bidirectional interaction; only use adjusted doses |
| Inadequate response at standard dose | Increase IV to 4 mg/kg q12h (if on 3 mg/kg); increase oral to 300 mg q12h | Check trough level before escalating; target trough ≥1 mcg/mL |
| If unable to tolerate 4 mg/kg IV | Reduce to 3 mg/kg IV q12h | Minimum effective IV dose |
Voriconazole has ~96% oral bioavailability, making IV-to-oral conversion straightforward. The oral dose of 200 mg q12h achieves exposure equivalent to 3 mg/kg IV q12h, and 300 mg q12h matches 4 mg/kg IV q12h. Tablets should be taken at least 1 hour before or 1 hour after meals, as food reduces absorption. Switch to oral once the patient is clinically improving and can tolerate oral medications. In patients with renal impairment (CrCl <50), oral administration is preferred to avoid accumulation of the IV vehicle (SBECD).
TDM is strongly recommended for all patients receiving voriconazole for invasive infections. Measure trough concentration at steady state (Day 5–7 on maintenance dose, or 24 hours after loading). Widely accepted target trough: 1–5.5 mcg/mL. Troughs <1 mcg/mL are associated with treatment failure; troughs >5.5 mcg/mL are associated with increased toxicity (hepatic, visual, neurological). CYP2C19 poor metabolizers (more common in Asian populations, 12–23%) have approximately 3-fold higher exposure and may need dose reduction. Ultrarapid metabolizers (CYP2C19*17) may have sub-therapeutic levels at standard doses.
Pharmacology
Mechanism of Action
Voriconazole is a second-generation triazole that inhibits fungal lanosterol 14α-demethylase (CYP51), disrupting ergosterol biosynthesis and destabilizing fungal cell membranes. Compared with first-generation triazoles, voriconazole has enhanced affinity for the target enzyme across a broader range of fungal species, including Aspergillus, fluconazole-resistant Candida (C. krusei, C. glabrata), Scedosporium, and Fusarium. Its activity is concentration-independent, with the AUC/MIC ratio being the key pharmacodynamic predictor of efficacy. The drug exhibits non-linear pharmacokinetics due to saturable hepatic metabolism, meaning disproportionate increases in exposure occur with dose escalation. This, combined with significant CYP2C19 genetic polymorphism, produces wide inter-individual variability in plasma levels and necessitates therapeutic drug monitoring.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | ~96% oral bioavailability (fasted); Tmax 1–2 h; food reduces Cmax by 34% and AUC by 24% | Take tablets ≥1 h before or after meals; high bioavailability permits seamless IV-to-oral switch at equivalent doses; oral suspension taken ≥1 h before or ≥2 h after meals |
| Distribution | Vd ~4.6 L/kg; protein binding ~58% (dose-independent); penetrates into brain, CSF, lung, liver, kidney, heart, skin | Excellent tissue penetration including CNS (~50% CSF:plasma ratio); suitable for CNS fungal infections unlike itraconazole |
| Metabolism | Extensive hepatic via CYP2C19 (primary), CYP2C9, CYP3A4; major metabolite voriconazole N-oxide (72% of circulating metabolites, minimal antifungal activity); <2% excreted unchanged in urine | Non-linear (saturable) metabolism — superproportional AUC increase with dose; CYP2C19 polymorphism causes 3-fold exposure variation between poor and extensive metabolizers; strong inhibitor of CYP2C19, CYP2C9, CYP3A4 |
| Elimination | ~80–83% recovered in urine as metabolites within 96 h; terminal t½ dose-dependent (not useful for predicting accumulation); not removed by dialysis | Steady state in ~5 days without loading; within 24 h with loading dose regimen; SBECD (IV vehicle) accumulates in renal impairment — prefer oral route if CrCl <50 |
Side Effects
Adverse event data below are derived from 1655 patients across nine therapeutic studies (FDA PI). Visual disturbances are the hallmark adverse effect of voriconazole and a key differentiator from other azoles.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Visual disturbances (blurred vision, photophobia, color vision change) | 18.7% (up to 21% including all visual impairments) | Transient, fully reversible in most cases; spontaneously resolve within 1 hour; rarely require discontinuation; associated with higher plasma concentrations; ERG changes documented but no long-term sequelae in 28-day studies |
| Transaminase elevations (>3× ULN) | 17.7% (ALT >3×: 11.2%; AST >3×: 19.5%) | Majority resolve during treatment or after dose adjustment; associated with higher plasma concentrations; ~1% require discontinuation due to ALT elevations |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fever | 5.7% | Distinguish from underlying infection or infusion-related reaction |
| Nausea | 5.4% | GI effects generally mild; take tablets on empty stomach as directed |
| Rash | 5.3% | Photosensitivity-related rash common; advise sun avoidance and sunscreen |
| Vomiting | 4.4% | May require antiemetic support |
| Chills | 3.7% | May occur with infusion-related reactions |
| Headache | 3.0% | Generally mild and self-limiting |
| LFT increased | 2.7% | Includes clinical hepatic adverse events (distinct from lab elevations listed in Tier 1) |
| Tachycardia | 2.4% | May be related to infusion reaction or underlying condition |
| Hallucinations | 2.4% | Associated with higher trough concentrations (>5.5 mcg/mL); usually resolve with dose reduction |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (hepatitis, cholestasis, hepatic failure including fatal cases) | Uncommon; 0.9% hepatic failure in clinical trials | Days to weeks | Monitor LFTs at baseline and during therapy; discontinue if clinical hepatitis or significant enzyme elevations develop |
| QT prolongation / Torsades de pointes | Rare | Any time during therapy | Correct electrolytes (K+, Mg2+, Ca2+) before and during therapy; avoid concurrent QT-prolonging drugs; contraindicated with pimozide, quinidine |
| Photosensitivity / Phototoxicity / Squamous cell carcinoma | Photosensitivity: common (~10%); SCC: rare, long-term use | Photosensitivity: days; SCC: months to years | Strict sun avoidance and protective clothing; dermatologic surveillance for long-term (>28 days) therapy; discontinue if premalignant lesions develop |
| Periostitis / Skeletal fluorosis | Rare; associated with prolonged use and elevated fluoride levels | Months of therapy | Assess for bone pain; check serum fluoride if available; discontinue if periostitis confirmed |
| Adrenal insufficiency / Cushing syndrome | Rare; especially with concurrent corticosteroids | Weeks to months | Voriconazole inhibits corticosteroid metabolism; monitor for cushingoid features or adrenal crisis on withdrawal; adjust corticosteroid doses |
| Stevens-Johnson syndrome / Toxic epidermal necrolysis | Very rare | 1–4 weeks | Immediate discontinuation; dermatology consultation |
| Optic neuritis / Papilledema | Rare (post-marketing) | Variable; reported with treatment >28 days | Assess visual acuity, visual field, and color perception if treatment exceeds 28 days; discontinue if optic neuropathy suspected |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Elevated liver function tests | Most common lab reason | Associated with higher plasma concentrations; majority resolve after dose reduction or discontinuation |
| Rash / Photosensitivity | Common clinical reason | Distinguish phototoxic rash from drug allergy; phototoxic rash improves with sun avoidance |
| Visual disturbances | Rarely led to discontinuation | Despite high incidence (21%), visual effects are transient and well-tolerated; rarely a sole reason for stopping |
Visual disturbances are the signature adverse effect of voriconazole, affecting approximately 21% of patients. These typically include blurred vision, altered color perception (objects appearing brighter or with a yellow-green tinge), and photophobia. Importantly, these effects are transient, usually occur within 30 minutes of dosing, resolve within 60 minutes, and attenuate with repeated doses. They are not associated with permanent visual damage in standard treatment courses. However, for treatment beyond 28 days, the FDA PI recommends monitoring visual acuity, visual fields, and color perception, as post-marketing reports have described optic neuritis and papilledema. Patients should be warned to avoid driving at night during the early days of treatment.
Drug Interactions
Voriconazole is both a substrate and a potent inhibitor of CYP2C19, CYP2C9, and CYP3A4. This creates bidirectional interaction potential: enzyme inducers can reduce voriconazole to sub-therapeutic levels, while voriconazole can markedly raise levels of co-administered CYP substrates. The interaction profile is among the most complex of all antifungals.
Monitoring
- Voriconazole Trough LevelDay 5–7 of therapy; repeat after dose changes
RoutineTarget: 1–5.5 mcg/mL. Sub-therapeutic levels (<1) associated with treatment failure; supra-therapeutic (>5.5) associated with neurotoxicity, visual and hepatic adverse effects. CYP2C19 genotyping may guide initial dosing. - Hepatic Function (LFTs)Baseline, weekly for first month, then monthly
RoutineTransaminase elevations occur in 11–19% of patients. Discontinue if clinical signs of liver disease develop. Higher incidence of hepatic adverse events in pediatric patients (28.6% vs 24.1% in adults). - Renal FunctionBaseline; periodically during IV therapy
RoutineMonitor serum creatinine especially during IV administration (SBECD vehicle accumulation if CrCl <50). Switch to oral formulation if creatinine increases. - Visual FunctionBaseline; if treatment >28 days
Trigger-basedAssess visual acuity, visual field, and color perception for courses exceeding 28 days. Post-marketing reports of optic neuritis and papilledema exist. - Electrolytes (K+, Mg2+, Ca2+)Baseline and during therapy
RoutineCorrect disturbances before and during therapy to reduce QT prolongation risk. Hypokalemia occurs in 1–10% of patients. - Dermatologic SurveillanceOngoing for long-term therapy
RoutinePhotosensitivity and phototoxic reactions are common. Long-term voriconazole has been associated with squamous cell carcinoma of the skin. Advise strict sun avoidance and refer to dermatology if suspicious lesions develop. - Adrenal FunctionAs needed if on concurrent corticosteroids
Trigger-basedCYP3A4 inhibition of corticosteroid metabolism can cause Cushing syndrome or adrenal insufficiency. Monitor cortisol if symptoms develop.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to voriconazole or excipients
- Coadministration with sirolimus — significantly increased sirolimus concentrations
- Coadministration with rifampin, carbamazepine, or long-acting barbiturates — reduce voriconazole to sub-therapeutic levels
- Coadministration with pimozide, quinidine, or ivabradine — risk of QT prolongation and fatal arrhythmias
- Coadministration with ergot alkaloids — risk of ergotism
- Coadministration with efavirenz at standard doses (400 mg/day) — bidirectional interaction renders both drugs ineffective/toxic
- Coadministration with high-dose ritonavir (400 mg q12h) — significantly reduces voriconazole
Relative Contraindications (Specialist Input Recommended)
- Pregnancy — Category D; teratogenic in animals; use only if life-threatening infection with no alternative
- Severe hepatic impairment (Child-Pugh C) — no PK data available; use with extreme caution and close monitoring
- Galactose intolerance — tablets contain lactose
Use with Caution
- Renal impairment (CrCl <50 mL/min) — IV vehicle SBECD accumulates; use oral formulation when possible
- Proarrhythmic conditions — electrolyte imbalances, concurrent QTc-prolonging drugs, cardiomyopathy
- Concurrent corticosteroid therapy — risk of Cushing syndrome or adrenal insufficiency
- CYP2C19 poor metabolizers — ~3-fold higher exposure; consider lower starting dose and early TDM
- Long-term therapy (>28 days) — increased risk of photosensitivity, skin cancer, periostitis, and prolonged visual adverse events
Serious hepatic reactions including clinical hepatitis, cholestasis, and fulminant hepatic failure (including fatalities) have been reported. LFTs should be monitored at initiation and during treatment. Visual disturbances are common (~21%) and usually transient, but prolonged visual adverse events including optic neuritis have been reported post-marketing. For treatment exceeding 28 days, comprehensive visual assessment is recommended. Voriconazole causes photosensitivity and has been associated with accelerated photoaging and squamous cell carcinoma of the skin during long-term use. Patients must avoid direct sunlight exposure and use protective measures.
Patient Counselling
Purpose of Therapy
Voriconazole is a powerful antifungal medication used to treat serious fungal infections, most commonly Aspergillus infections of the lungs and other organs. Treatment typically begins with the medication given through an IV, then transitions to tablets once improvement is seen. The tablets work just as well as the IV form. Treatment duration depends on the type and severity of infection and may last weeks to months.
How to Take
Tablets should be taken at least 1 hour before or 1 hour after meals, as food significantly reduces absorption. The oral suspension should be taken at least 1 hour before or 2 hours after meals. Shake the suspension well before each dose. Do not take the tablets with food, even though this is opposite to many other medications. Maintain consistent timing of doses approximately 12 hours apart.
Sources
- Pfizer Inc. VFEND (voriconazole) Prescribing Information (revised 2019). U.S. Food and Drug Administration. accessdata.fda.govPrimary source for all FDA-approved indications, dosing (including loading dose regimens), adverse reactions (1655-patient dataset), drug interactions, hepatic/renal adjustment, and pediatric dosing.
- Pfizer Inc. VFEND (voriconazole) Clinical Pharmacology. pfizermedical.comPfizer clinical pharmacology resource detailing CYP interaction studies, non-linear pharmacokinetics, and specific drug interaction magnitude data (rifampin, tacrolimus, warfarin).
- Pfizer Inc. VFEND (voriconazole) Adverse Reactions. pfizermedical.comDetailed adverse event tables from therapeutic studies including visual disturbance rates (18.7%), transaminase elevations (17.7%), and discontinuation data by study.
- Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415. doi:10.1056/NEJMoa020191Landmark RCT establishing voriconazole superiority over amphotericin B as first-line therapy for invasive aspergillosis, with improved survival and fewer adverse events.
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326IDSA guideline recommending voriconazole as first-line therapy for invasive aspergillosis and providing TDM guidance.
- Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201-211. doi:10.1086/524669Key TDM study establishing the relationship between voriconazole trough concentrations, clinical outcomes, and toxicity, supporting the 1–5.5 mcg/mL target range.
- Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31(5):540-547. doi:10.1124/dmd.31.5.540In vitro study demonstrating CYP2C19 as the primary metabolizing enzyme for voriconazole, with contributions from CYP2C9 and CYP3A4.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Voriconazole. National Institute of Diabetes and Digestive and Kidney Diseases. ncbi.nlm.nih.govNIH resource detailing voriconazole-induced hepatotoxicity: transaminase elevations in 11–19%, ALT-related discontinuation in ~1%, and hepatic failure in 0.9% of clinical trial patients.
- Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45(7):649-663. doi:10.2165/00003088-200645070-00002Comprehensive PK/PD review establishing Vd 2–4.6 L/kg, protein binding ~60%, non-linear pharmacokinetics, and tissue penetration including CSF.
- Scholz I, Oberwittler H, Riedel KD, et al. Pharmacokinetics, metabolism and bioavailability of voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68(6):906-915. doi:10.1111/j.1365-2125.2009.03534.xCrossover PK study measuring oral bioavailability of 82.6% overall (94.4% in CYP2C19 poor metabolizers vs 75.2% in extensive metabolizers), demonstrating the clinical impact of CYP2C19 polymorphism.
- Zonios DI, Gea-Banacloche J, Childs R, Bennett JE. Voriconazole metabolism, toxicity, and the effect of CYP2C19 genotype. J Infect Dis. 2014;209(12):1941-1948. doi:10.1093/infdis/jiu017Prospective study of 95 patients documenting hallucinations in 16.8%, visual changes in 17.9%, photosensitivity in 10.5%, and hepatotoxicity in 6.3%, with correlation between higher trough levels and hallucinations.
- Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48(6):2166-2172. doi:10.1128/AAC.48.6.2166-2172.2004Pediatric PK study demonstrating linear pharmacokinetics in children <12 years with higher clearance relative to body weight, supporting the higher mg/kg pediatric dosing.
- Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother. 2002;46(8):2546-2553. doi:10.1128/AAC.46.8.2546-2553.2002Dose escalation study characterizing non-linear pharmacokinetics, oral bioavailability >90%, and establishing the equivalence of IV-to-oral conversion at recommended doses.