What is the treatment regimen for Voriconazole (antifungal medication)?

Voriconazole Treatment Regimen

For invasive aspergillosis and serious fungal infections, voriconazole should be initiated with 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 for at least 7 days, then transition to 200 mg oral twice daily once the patient is clinically stable. 1

Loading and Maintenance Dosing

Invasive Aspergillosis and Serious Mold Infections

• Loading dose: 6 mg/kg IV every 12 hours on Day 1 1
• IV maintenance: 4 mg/kg IV every 12 hours for minimum 7 days 1
• Oral maintenance: 200 mg orally every 12 hours after clinical improvement 1
• Duration: Median IV therapy is 10 days (range 2-85 days); median oral therapy is 76 days (range 2-232 days) 1

Candidemia and Deep Tissue Candida Infections

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 1
• IV maintenance: 3-4 mg/kg IV every 12 hours depending on severity 1
• Oral maintenance: 200 mg orally every 12 hours 1
• Duration: Minimum 14 days after documented clearance from bloodstream and symptom resolution 2, 1

Important caveat: Voriconazole is primarily recommended as step-down oral therapy for C. krusei or voriconazole-susceptible C. glabrata infections, not as first-line therapy for most candidemia cases 2. Echinocandins or fluconazole are preferred initial agents for candidemia 2.

Esophageal Candidiasis

• Oral dosing: 200 mg orally every 12 hours 1
• Duration: Minimum 14 days and at least 7 days after symptom resolution 1

CNS Fungal Infections

• Voriconazole achieves excellent CNS penetration with CSF concentrations >50% of serum levels 2
• Dosing: Standard loading and maintenance regimen as above 2
• Particularly useful for CNS aspergillosis and candidiasis where additional mold coverage is needed 2

Dose Adjustments

For Inadequate Response

• Increase oral dose from 200 mg every 12 hours to 300 mg every 12 hours 1
• For patients <40 kg: Increase from 100 mg every 12 hours to 150 mg every 12 hours 1

For Intolerance

• Reduce oral dose by 50 mg increments to minimum of 200 mg every 12 hours (or 100 mg every 12 hours if <40 kg) 1
• Reduce IV dose from 4 mg/kg to 3 mg/kg every 12 hours 1

Hepatic Impairment

• Voriconazole is the only triazole requiring dose reduction for mild to moderate hepatic impairment 2
• Use standard loading dose, then reduce maintenance dose by 50% 2

Renal Impairment

• IV formulation: Not recommended if creatinine clearance <50 mL/min due to cyclodextrin accumulation risk 2, 1
• Oral formulation: No dose adjustment needed for renal insufficiency 2
• Critical consideration: Retrospective data suggest IV use may be safer than initially thought in renal dysfunction, but oral formulation is preferred when feasible 2

Administration Requirements

IV Administration

• Must reconstitute to 10 mg/mL, then dilute to ≤5 mg/mL 1
• Infusion rate: Maximum 3 mg/kg/hour over 1-2 hours 1
• Never administer as IV bolus 1
• Separate line required for blood products, concentrated electrolytes, and TPN 1

Oral Administration

• Excellent bioavailability >90% allows seamless IV-to-oral switching 2, 1
• 200 mg oral dose achieves exposure similar to 3 mg/kg IV 1
• 300 mg oral dose achieves exposure similar to 4 mg/kg IV 1
• Absorption decreases with food; administer on empty stomach when possible 2

Critical Drug Interactions

Dose Increases Required

• Phenytoin co-administration: Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV (or 200 mg to 400 mg orally) 1
• Efavirenz co-administration: Same dose increase as phenytoin 1

Monitoring Requirements

• Therapeutic drug monitoring strongly recommended due to wide pharmacokinetic variability from CYP2C19 polymorphisms 2, 3
• Target trough concentrations: 1-5.5 mcg/mL for efficacy while minimizing toxicity 3
• Steady-state reached in 5-7 days without loading dose, within 24 hours with loading dose 4

Common Adverse Effects

Visual Disturbances

• Occur in approximately 30-45% of patients 5, 6
• Typically transient and reversible 5
• More common with voriconazole than amphotericin B 5

Other Significant Effects

• Hepatotoxicity: Monitor liver enzymes regularly 2, 7
• Skin reactions: Rashes occur in ~6% of patients 5
• Photosensitivity: Unique to voriconazole among triazoles 2
• CNS effects and periostitis: More common with higher concentrations 2

Clinical Efficacy Data

Voriconazole demonstrates superior outcomes compared to amphotericin B for invasive aspergillosis: 52.8% successful response rate versus 31.6% with amphotericin B at 12 weeks, with improved survival (70.8% vs 57.9%) and fewer severe adverse events 6. This landmark trial established voriconazole as the preferred agent for invasive aspergillosis 2, 6.

Common Pitfalls to Avoid

• Do not use for urinary candidiasis: Voriconazole does not accumulate in active form in urine 2
• Do not use as first-line for most candidemia: Echinocandins or fluconazole are preferred unless treating C. krusei or resistant C. glabrata 2
• Do not ignore drug interactions: Extensive hepatic metabolism via CYP2C19, CYP2C9, and CYP3A4 creates high interaction potential 2, 7
• Do not use IV formulation in severe renal dysfunction without considering alternatives: Switch to oral formulation when possible 2
• Do not skip loading dose: Critical for achieving therapeutic levels rapidly in critically ill patients 1, 4