What is the recommended dose of voriconazole (antifungal medication) in Intensive Care Unit (ICU) patients with impaired renal (kidney) function or hepatic (liver) impairment?

Voriconazole Dosing in ICU Patients

Standard Dosing for ICU Patients with Normal Organ Function

For ICU patients with normal renal and hepatic function, use a loading dose of 6 mg/kg IV every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg IV every 12 hours. 1

• The loading dose ensures rapid achievement of therapeutic concentrations, which is critical in critically ill patients with invasive fungal infections 1
• After stabilization, transition to oral voriconazole 200 mg every 12 hours is appropriate given the excellent oral bioavailability (>90%) 2

Dosing in Renal Impairment

In ICU patients with creatinine clearance <50 mL/min, avoid intravenous voriconazole and use oral formulation instead at standard doses without adjustment. 3, 4, 1

Why Avoid IV Formulation in Renal Dysfunction

• The IV formulation contains sulfobutylether-β-cyclodextrin (SBECD), a vehicle that accumulates in renal impairment and may cause nephrotoxicity 4
• Oral voriconazole requires NO dose adjustment for any degree of renal impairment: loading dose 400 mg (6 mg/kg) twice daily for 2 doses, then maintenance 200-300 mg (3-4 mg/kg) twice daily 3, 4, 2
• Retrospective data suggest IV voriconazole may be safer than previously thought in renal dysfunction, but guidelines still recommend avoiding it when creatinine clearance is <50 mL/min 3

Special Consideration: Continuous Renal Replacement Therapy

• For ICU patients on continuous venovenous hemodiafiltration (CVVHDF), standard IV dosing without adjustment is appropriate as voriconazole clearance via CVVHDF is minimal (1.1 L/h) compared to total clearance (12.9 L/h) 5
• The sieving coefficient is approximately 0.56, indicating moderate dialyzability, but this does not significantly impact overall drug exposure 5

Dosing in Hepatic Impairment

For ICU patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), reduce the maintenance dose by 50% while keeping the loading dose unchanged. 3, 2, 1

Specific Hepatic Dosing Recommendations

• Child-Pugh Class A/B: Loading dose 6 mg/kg IV every 12 hours for first 24 hours, then maintenance dose of 2 mg/kg IV every 12 hours (or 100 mg orally every 12 hours) 1, 6
• Child-Pugh Class C: Consider even more aggressive dose reduction—loading dose 5 mg/kg every 12 hours, maintenance 50 mg every 12 hours or 100 mg every 24 hours 6
• Voriconazole is the only triazole requiring dose reduction in hepatic impairment, making this adjustment critical 3, 2
• In one patient with liver cirrhosis on CVVHDF, elimination half-life increased dramatically to 52 hours (versus 14.7 hours in non-cirrhotic patients), supporting aggressive dose reduction 5

Critical Considerations for ICU Patients

Hypoalbuminemia

ICU patients with hypoalbuminemia (<35 g/L) have higher unbound voriconazole concentrations, increasing risk of toxicity even when total drug levels appear therapeutic. 7

• The relationship between protein binding and albumin is significant (P <0.001), with more pronounced effects when bilirubin is also elevated (P = 0.05) 7
• Consider therapeutic drug monitoring in hypoalbuminemic patients, targeting total trough concentrations of 2-6 mg/L but recognizing that unbound concentrations may be disproportionately elevated 6, 7
• Assuming 50% protein binding on average, the upper limit for unbound voriconazole is 2.75 mg/L when total concentration is 5.5 mg/L 7

Therapeutic Drug Monitoring

Strongly consider therapeutic drug monitoring in all ICU patients due to wide interpatient variability from CYP2C19 polymorphisms and critical illness-related pharmacokinetic changes. 4, 2

• Target trough concentrations of 2-6 mg/L for efficacy and safety 6
• For specific pathogens, ensure fAUC24/MIC ≥25 for optimal outcomes 6

Drug Interactions

Review all concomitant medications carefully as voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4. 4, 2

• Drug-drug interactions are extremely common and can significantly alter voriconazole levels 3, 2

Common Pitfalls to Avoid

• Never use IV voriconazole as first-line in patients with CrCl <50 mL/min when oral formulation is feasible 4
• Never fail to reduce maintenance dose by 50% in hepatic impairment (Child-Pugh A/B), as this is the only triazole requiring such adjustment 3, 4, 2
• Never assume standard dosing is adequate in hypoalbuminemic patients without monitoring, as unbound drug concentrations may be toxic despite "therapeutic" total levels 7
• Never use voriconazole for urinary candidiasis, as it does not accumulate in active form in urine 3, 2

Monitoring for Adverse Effects

• Visual disturbances occur in approximately 30% of patients and are dose-related but typically reversible 3, 8
• Monitor for hepatotoxicity, photosensitivity, periostitis, and CNS effects, which are more common with higher concentrations 3
• Voriconazole is generally better tolerated than amphotericin B, with significantly fewer treatment-related serious adverse events 8