What is the recommended oral dosage of voriconazole (Vfend) for a patient with cerebral aspergillosis?

Oral Voriconazole Dosing for Cerebral Aspergillosis

For cerebral aspergillosis, initiate voriconazole with a loading dose of 400 mg (6 mg/kg) orally every 12 hours for 2 doses on day 1, followed by a maintenance dose of 200 mg orally every 12 hours, with the option to increase to 300 mg every 12 hours if response is inadequate. 1, 2

Loading Dose Regimen

• Day 1: Administer 400 mg (or 6 mg/kg) orally every 12 hours for 2 doses 1, 2, 3
• This loading regimen is critical for rapidly achieving therapeutic drug levels 4
• The loading dose should not be reduced even in patients with hepatic impairment 2

Maintenance Dose Regimen

• Standard maintenance: 200 mg orally every 12 hours starting on day 2 1, 2
• If inadequate response: Increase to 300 mg orally every 12 hours 1, 2, 3
• If intolerance occurs: Reduce by 50 mg increments to a minimum of 200 mg every 12 hours 3

Duration of Therapy

• Treat for a minimum of 6-12 weeks and continue throughout the period of immunosuppression until lesions resolve 5, 4
• CNS aspergillosis is associated with the highest mortality among all patterns of invasive aspergillosis, necessitating prolonged therapy 1
• Reversal of immunosuppression is critical for favorable outcomes 5

Critical Considerations for CNS Aspergillosis

• CNS penetration: Voriconazole achieves excellent CSF concentrations (>50% of serum concentration), making it the preferred agent for cerebral aspergillosis 2
• Drug interactions: Exercise particular caution with anticonvulsants, as significant bidirectional interactions occur with voriconazole 5
• Voriconazole inhibits CYP2C19, CYP2C9, and CYP3A4, requiring careful review of all concurrent medications 1, 4

Dosing Adjustments

Hepatic Impairment

• Mild to moderate hepatic impairment (Child-Pugh Class A or B): Reduce maintenance dose by 50% while keeping the loading dose unchanged 2, 4, 3
• Voriconazole is the only triazole requiring dose reduction in hepatic impairment 2, 4

Renal Impairment

• No dose adjustment required for oral voriconazole regardless of renal function 2, 4, 3
• Oral formulation is strongly preferred over IV in patients with creatinine clearance <50 mL/min due to cyclodextrin vehicle accumulation with IV formulation 1, 2, 4

Body Weight <40 kg

• Reduce maintenance dose to 100 mg every 12 hours, with option to increase to 150 mg every 12 hours if needed 3

Therapeutic Drug Monitoring

• Strongly recommended due to high interpatient variability in voriconazole exposure 2, 4
• CYP2C19 polymorphisms cause wide variability in serum levels, with higher frequencies of slow metabolizers in non-Indian Asian populations 1, 4
• Target trough concentrations: 1-4 mg/L (measured by HPLC) 5
• Monitoring is particularly important with oral therapy to evaluate for potential toxicity or document adequate drug exposure in progressive infection 1

Administration Considerations

• Take on empty stomach: Bioavailability decreases when administered with food; take at least 1 hour before or after meals 2
• Oral bioavailability is excellent (>90%), allowing easy transition between IV and oral formulations 2

Common Pitfalls to Avoid

• Never skip the loading dose: Steady-state levels may take up to a week without loading, which is unacceptable in life-threatening CNS infection 1
• Monitor anticonvulsant levels closely: Bidirectional interactions can result in subtherapeutic voriconazole levels or anticonvulsant toxicity 5
• Do not use IV formulation if creatinine clearance <50 mL/min: The cyclodextrin vehicle accumulates and has uncertain toxicity 1, 2, 4
• Check baseline liver function: Voriconazole causes hepatotoxicity; monitor ALT, AST, and alkaline phosphatase regularly 2, 3

Adverse Effects Monitoring

• Visual disturbances: Occur in approximately 30% of patients, are dose-related but typically reversible 2, 6
• Hepatotoxicity: Monitor liver function tests regularly for elevations 2, 3
• Other common effects: Photosensitivity, periostitis, and CNS effects are more common with higher concentrations 2
• Voriconazole is generally well tolerated, with fewer treatment-related adverse events compared to amphotericin B 6, 7

Evidence for Efficacy

• Voriconazole demonstrated superior outcomes versus amphotericin B in invasive aspergillosis, with 53% versus 32% successful response and 71% versus 58% survival at 12 weeks 4, 6, 7
• This establishes voriconazole as first-line therapy for all forms of invasive aspergillosis, including CNS disease 1, 5