What is the recommended dosage and indications for Voriconazole (Voriconazole) in treating fungal infections, specifically invasive aspergillosis and candidiasis?

Voriconazole Indications and Dosage in Fungal Infections

Voriconazole is the first-line agent for invasive aspergillosis and is indicated for serious fungal infections including candidemia, esophageal candidiasis, scedosporiosis, and fusariosis, with specific dosing regimens that require loading doses followed by maintenance therapy. 1

Primary Indications

Invasive Aspergillosis

• Voriconazole is the drug of choice for all forms of invasive aspergillosis, including pulmonary, CNS, sinus, endocarditis, osteomyelitis, and skin/soft tissue infections 2
• It should be favored when radiological presentations are consistent with invasive aspergillosis, particularly with positive galactomannan antigen 2
• For CNS aspergillosis, voriconazole is the preferred first-line agent, with surgical resection recommended when feasible 2, 3

Candidiasis

• For esophageal candidiasis: Voriconazole is listed as an alternative agent when fluconazole or itraconazole cannot be used 2
• For candidemia in non-neutropenic patients: Voriconazole can be used as salvage therapy 1
• For CNS candidiasis: Voriconazole is an option as step-down therapy in stable patients 2
• For Candida endophthalmitis: Voriconazole is among the recommended agents, with treatment duration of at least 4-6 weeks 2

Rare Fungal Infections

• Scedosporiosis and fusariosis: Voriconazole is indicated for patients refractory to or intolerant of other antifungal therapy 1, 4, 5

Chronic Pulmonary Aspergillosis

• For chronic cavitary pulmonary aspergillosis, itraconazole is preferred, but voriconazole is an acceptable alternative for oral therapy 2

Dosing Regimens

Adult Dosing (≥40 kg body weight)

Loading Dose (Day 1):

• 6 mg/kg IV every 12 hours for the first 24 hours for invasive aspergillosis, candidemia, scedosporiosis, and fusariosis 1

Maintenance Dose:

• Invasive aspergillosis, scedosporiosis, fusariosis: 4 mg/kg IV every 12 hours OR 200 mg PO every 12 hours 1
• Candidemia in non-neutropenic patients: 3-4 mg/kg IV every 12 hours OR 200 mg PO every 12 hours (dose based on severity) 1
• Esophageal candidiasis: 200 mg PO every 12 hours (no IV loading dose evaluated) 1

Dose Adjustments:

• If response is inadequate, increase oral dose from 200 mg to 300 mg every 12 hours 1
• If unable to tolerate 300 mg orally, reduce by 50 mg steps to minimum of 200 mg every 12 hours 1
• If unable to tolerate 4 mg/kg IV, reduce to 3 mg/kg every 12 hours 1

Adult Dosing (<40 kg body weight)

• Maintenance dose should be halved: 100 mg PO every 12 hours (can increase to 150 mg every 12 hours if inadequate response) 1

Pediatric Dosing

• For patients 12-14 years with weight ≥50 kg and those ≥15 years regardless of weight: Use adult dosing regimen 1
• Initiate with IV therapy; consider oral only after significant clinical improvement 1

Hepatic Impairment

• For mild to moderate hepatic impairment (Child-Pugh Class A and B): Use standard loading dose, but reduce maintenance dose by 50% 1, 4
• For severe hepatic impairment (Child-Pugh Class C): No dosing recommendations available due to lack of pharmacokinetic data 1

Administration Guidelines

Route and Timing

• Oral tablets must be administered at least 1 hour before or after meals 1
• IV treatment should continue for at least 7 days before switching to oral 1
• Switching between IV and oral is appropriate due to high oral bioavailability in adults 1

Duration of Therapy

• Invasive aspergillosis: Treat until resolution or stabilization of all clinical and radiographic manifestations; median duration in clinical trials was 10 days IV followed by 76 days oral 2, 1
• Candidemia: At least 14 days following resolution of symptoms or last positive culture, whichever is longer 1
• Esophageal candidiasis: Minimum 14 days and at least 7 days following resolution of symptoms 1
• Skull base osteomyelitis: Prolonged therapy (3-6 months or longer) until complete resolution 3

Critical Drug Interactions and Monitoring

Drug Interactions

• Beware of interactions with anticonvulsants, particularly phenytoin and efavirenz, which require dose increases 2, 1
• Voriconazole undergoes extensive hepatic metabolism via CYP2C19, CYP3A4, and CYP2C9, creating high potential for drug interactions 4, 6
• Dose reduction recommended when co-administered with medications that inhibit these enzymes 4

Therapeutic Drug Monitoring

• Therapeutic drug monitoring is recommended due to non-linear pharmacokinetics and narrow therapeutic window 6
• Significant interpatient variability occurs with the same dose 6
• Risk of toxicity increases at serum levels 3-5 times higher than minimal efficacy threshold 6

Common Adverse Effects

• Visual disturbances occur in approximately 30% of patients but are typically transient 4, 7
• Skin reactions occur in approximately 20% of patients 4
• Hepatic enzyme elevations occur in ≤20% of patients 4
• Voriconazole is generally better tolerated than amphotericin B with fewer serious adverse events 7

Critical Pitfalls to Avoid

Renal Considerations

• Prefer oral voriconazole in patients with creatinine clearance <50 mL/min due to potential accumulation of the solubilizing excipient in IV formulation 4

Contraindications

• Do NOT use voriconazole for invasive zygomycosis (mucormycosis) - amphotericin B formulations are mandatory 2
• Favor amphotericin B for patients at risk of invasive zygomycosis 2

Monitoring Requirements

• Monitor liver function tests regularly, especially in patients with baseline elevations up to 5 times ULN 1
• Regular monitoring of clinical response and radiographic findings is essential 3

Surgical Considerations

• Surgical intervention should be pursued when feasible for pulmonary lesions near great vessels, chest wall invasion, CNS infections, sinus infections, and skull base osteomyelitis 2, 3