What are the considerations for using intravenous (IV) voriconazole in patients with impaired renal function, specifically those with an estimated glomerular filtration rate (eGFR) of less than 40?

IV Voriconazole in Patients with eGFR <40 mL/min

Avoid intravenous voriconazole in patients with eGFR <40 mL/min (or creatinine clearance <50 mL/min) and use oral voriconazole instead at standard doses without any adjustment. 1, 2, 3

Rationale for Avoiding IV Formulation

The intravenous formulation of voriconazole contains sulfobutylether-β-cyclodextrin (SBECD) as a solubilizing vehicle, which is exclusively cleared by the kidneys. 2 When creatinine clearance falls below 50 mL/min, SBECD accumulates to potentially toxic levels. 1, 2, 3

• The FDA drug label explicitly states that in patients with moderate or severe renal impairment (CrCl <50 mL/min), accumulation of SBECD occurs with IV administration. 3
• The IDSA guidelines note that while animal studies demonstrated renal toxicity from parenteral cyclodextrin, the theoretical risk in humans remains significant enough to warrant avoidance. 1, 2
• If IV voriconazole must be used despite renal impairment, serum creatinine should be closely monitored, and consideration should be given to switching to oral therapy if increases occur. 3

Recommended Alternative: Oral Voriconazole

Oral voriconazole formulations (tablets or suspension) do not contain SBECD and can be safely administered at standard doses without any adjustment in patients with any degree of renal impairment, including eGFR <40 mL/min. 2, 4, 3

Standard Oral Dosing

• Loading dose: 400 mg (6 mg/kg) orally twice daily for 2 doses on day 1. 2, 4, 5
• Maintenance dose: 200-300 mg (3-4 mg/kg) orally twice daily. 2, 4, 5
• No dose adjustment required for any degree of renal impairment when using oral formulation. 4, 3

Bioavailability Considerations

• Oral voriconazole has excellent bioavailability (>90%) and achieves therapeutic levels equivalent to IV administration. 2, 5
• Bioavailability decreases when administered with food; take at least 1 hour before or after meals for optimal absorption. 5
• If patients cannot swallow tablets, crushed tablets are bioequivalent to whole tablets. 6

Evidence Regarding Safety in Renal Impairment

While the FDA and IDSA guidelines recommend avoiding IV voriconazole in renal impairment, retrospective clinical data provide nuanced findings:

• A 2012 study of 58 candidemic patients with moderate-to-severe renal insufficiency found that IV voriconazole was associated with less acute renal toxicity than amphotericin B/fluconazole (39% vs 53% worsening renal function). 7
• A 2008 ICU study found no association between pretreatment impaired renal function and renal or liver damage from IV voriconazole. 8
• A 2012 study of 166 patients found that baseline renal function and voriconazole route of administration were not predictors of worsening renal dysfunction; rather, underlying disease, baseline liver impairment, and concomitant drugs (penicillins, immunosuppressants) were the strongest predictors. 9
• A 2015 systematic review concluded there is no strong evidence suggesting increased incidence of worsening renal function with IV voriconazole use. 10

Despite these retrospective findings, guideline recommendations and FDA labeling prioritize the theoretical risk and recommend oral formulation. 1, 2, 3

Critical Monitoring and Adjustments

Hepatic Function

• Voriconazole is the only triazole requiring dose reduction for hepatic impairment. 1, 5
• Reduce maintenance dose by 50% in patients with mild-to-moderate hepatic impairment (Child-Pugh Class A or B) while keeping loading dose unchanged. 1, 5, 3
• Use with extreme caution in severe hepatic impairment (Child-Pugh Class C); monitor closely for drug toxicity. 3

Drug Interactions

• Voriconazole is both substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, creating numerous interaction risks. 2, 4, 5
• Common polymorphisms in CYP2C19 result in wide variability of serum levels; therapeutic drug monitoring may be beneficial. 1, 5
• Reduce warfarin dose by 50% due to CYP2C9 inhibition. 5
• Significant dose reductions of immunosuppressants (cyclosporine, tacrolimus) are required when co-administered. 5

Hemodialysis Considerations

• Voriconazole is hemodialyzed with clearance of 121 mL/min, but a 4-hour hemodialysis session does not remove sufficient drug to warrant dose adjustment. 3
• SBECD is also hemodialyzed with clearance of 55 mL/min. 3

Common Pitfalls to Avoid

• Do not adjust oral voriconazole doses based on renal function, as this may lead to subtherapeutic levels. 4
• Do not use IV voriconazole as first-line in patients with CrCl <50 mL/min when oral formulation is feasible. 4
• Do not forget to reduce maintenance dose by 50% in hepatic impairment (Child-Pugh Class A or B), regardless of route of administration. 1, 5, 3
• Monitor for visual disturbances (occur in ~30% of patients), hepatotoxicity, photosensitivity, and QTc prolongation. 5
• Review all concomitant medications for potential CYP-mediated interactions before initiating therapy. 2, 4, 5