What is the recommended dosage and treatment duration for Voriconazole (Voriconazole) in adults with serious fungal infections?

Voriconazole Dosing and Treatment Duration for Serious Fungal Infections in Adults

For invasive aspergillosis and serious fungal infections, initiate voriconazole with a loading dose of 6 mg/kg IV every 12 hours on Day 1, followed by a maintenance dose of 4 mg/kg IV every 12 hours (or 200 mg PO every 12 hours after at least 7 days of IV therapy), continuing treatment until complete resolution or stabilization of all clinical and radiographic manifestations. 1, 2

Loading Dose Regimen (Day 1)

• All serious fungal infections require a loading dose of 6 mg/kg IV every 12 hours for the first 24 hours to rapidly achieve therapeutic concentrations 1
• This loading dose applies to invasive aspergillosis, candidemia, scedosporiosis, and fusariosis 1
• Administer oral tablets at least one hour before or after meals to optimize absorption 1

Maintenance Dosing by Indication

Invasive Aspergillosis

• Maintenance: 4 mg/kg IV every 12 hours or 200 mg PO every 12 hours 1
• Continue IV therapy for at least 7 days before considering switch to oral formulation 1
• Treatment duration: Continue until resolution or stabilization of all clinical and radiographic manifestations 2
• In clinical trials, median IV duration was 10 days (range 2-85 days) and median oral duration was 76 days (range 2-232 days) 1
• Voriconazole is preferred for CNS aspergillosis due to excellent CNS penetration 2

Candidemia in Non-Neutropenic Patients

• Maintenance: 3-4 mg/kg IV every 12 hours or 200 mg PO every 12 hours 1
• The 3 mg/kg dose is used for primary therapy; 4 mg/kg for salvage therapy based on infection severity 1
• Treatment duration: At least 14 days following resolution of symptoms OR following last positive culture, whichever is longer 1, 2
• Obtain follow-up blood cultures for all patients to ensure clearance 2

Esophageal Candidiasis

• Oral therapy only: 200 mg PO every 12 hours 1
• Treatment duration: Minimum 14 days AND at least 7 days following resolution of symptoms 1
• Guidelines suggest 14-21 days until clinical improvement 3

Scedosporiosis and Fusariosis

• Maintenance: 4 mg/kg IV every 12 hours or 200 mg PO every 12 hours 1
• These rare mold infections require the same aggressive dosing as invasive aspergillosis 1

Dose Adjustments for Inadequate Response

If clinical response is inadequate, escalate the oral maintenance dose from 200 mg to 300 mg every 12 hours (equivalent to increasing from 3 mg/kg to 4 mg/kg IV) 1

• For patients weighing <40 kg, increase from 100 mg to 150 mg every 12 hours 1
• If unable to tolerate 300 mg PO every 12 hours, reduce by 50 mg increments to minimum of 200 mg every 12 hours 1
• If unable to tolerate 4 mg/kg IV, reduce to 3 mg/kg IV every 12 hours 1

Special Populations and Considerations

Patients <40 kg Body Weight

• Administer half of the standard oral maintenance dose (100 mg every 12 hours instead of 200 mg) 1
• Loading dose remains 6 mg/kg IV every 12 hours 1

CNS Infections

• Voriconazole is preferred for CNS candidiasis and aspergillosis due to superior CNS penetration 2
• Monitor for drug interactions with anticonvulsants, which commonly reduce voriconazole levels 2
• Continue treatment until all signs, symptoms, CSF abnormalities, and radiologic findings resolve 3

Hepatic Impairment

• Reduce maintenance dose in patients with hepatic dysfunction 1
• Voriconazole concentrations are significantly elevated in hepatic impairment due to reduced CYP-mediated clearance 4

Switching from IV to Oral Therapy

Switch to oral voriconazole once the patient has clinically improved and can tolerate oral medication 1

• The 200 mg oral dose achieves exposure similar to 3 mg/kg IV 1
• The 300 mg oral dose achieves exposure similar to 4 mg/kg IV 1
• High oral bioavailability (>90%) ensures therapeutic concentrations are maintained during the switch 5
• Continue IV therapy for at least 7 days before switching 1

Drug Interactions Requiring Dose Modification

Increase voriconazole maintenance dose when co-administered with phenytoin or efavirenz due to CYP450 enzyme induction 1

• Voriconazole inhibits CYP2C9, CYP2C19, and CYP3A4, creating multiple potential drug interactions 6
• CYP2C19 genetic polymorphism significantly affects voriconazole exposure, with poor metabolizers having 4-fold higher concentrations 4

Therapeutic Drug Monitoring

Consider selective therapeutic drug monitoring in cases of treatment failure, suspected toxicity, or significant drug interactions 4

• Suggested target trough concentrations: 0.25-2 mg/L (lower threshold) and 4-6 mg/L (upper threshold) 4
• Routine monitoring is not recommended for all patients 4
• Time to steady state varies from 5-7 days due to nonlinear pharmacokinetics 7
• For Aspergillus infections, doses of 300-600 mg may be needed to maximize net benefit (51-66.7%) depending on CYP2C19 status 7

Common Pitfalls to Avoid

• Do not skip the loading dose – therapeutic concentrations require 5-7 days to reach steady state without loading 7
• Do not administer oral tablets with food – give at least 1 hour before or after meals 1
• Do not use IV formulation in severe renal dysfunction (CrCl <50 mL/min) due to cyclodextrin vehicle accumulation; switch to oral formulation 5
• Do not assume bioequivalence issues with crushed tablets – crushed voriconazole tablets are bioequivalent to whole tablets 8
• Do not discontinue therapy prematurely – invasive fungal infections require prolonged treatment until radiographic resolution 2