II. Indications
- Conditions
- Invasive Aspergillosis
- Invasive Scedospiosis
- Invasive fusariosis
- Systemic Candidiasis
- Esophageal Candidiasis
- Activity (broader activity than Fluconazole)
- Aspergillus species
- Blastomyces dermatitidis
- Candida (most species, including C. glabrata and C. Krusei)
- Cryptococcus neoformans
- Fusarium species
- Histoplasma capsulatum
- Scedosporium Species
III. Contraindications
- Intravenous formulation in GFR <50 ml/min (relative contraindication)
- Voriconazole is removed with Hemodialysis
- Voriconazole does not worsen Renal Function
- Age <2 years
- Resistant organisms
- Mucorales or Zygomycetes (e.g. Mucor species, Rhizopus species)
IV. Mechanism
- Azole Antifungal (triazole)
- Inhibits fungal CYP450 enzymes
- Inhibits fungal sterol demethylation (selectively at 14-alpha-lanosterol)
- Blocks the synthesis of plasma membrane steroids (conversion from lanosterol to ergosterol)
- Results in plasma membrane damage
V. Medications
- Oral Voriconazole
- Tablets: 50 mg, 200 mg
- Suspension: 40 ml/ml
- Stable at room Temperature for 14 days
- Intravenous Voriconazole
- Avoid in GFR <50 ml/min (risk of accumulation)
- Dilute Voriconazole for IV infusion to <=5 mg/ml
- Limit infusion to 3 mg/kg/hour over 1 to 2 hours
- Do NOT infuse Voriconazole IV at the same time as Blood Products or concentrated Electrolytes
- Avoid even if via separate IV lines
- Parenteral nutrition may be infused at same time, but different IV line
VI. Dosing
- General
- Invasive Aspergillosis, Scedospiosis, fusariosis and Systemic Candidiasis
- Treatment duration at least 14 days after symptoms resolve and last positive Blood Culture
- Adult (or child age >15 years, or weight >50 kg)
- Load: 6 mg/kg IV (3 mg/kg/hour over 1 to 2 hours) every 12 hours for 2 doses
- Next: 4 mg/kg IV every 12 hours until significant clinical improvement
- Next: 200 mg orally twice daily on an empty Stomach
- If weight <40 kg, decrease dose to 100 mg orally every 12 hours
- Child (age 2 to 15 years and weight <50 kg)
- Load: 9 mg/kg IV (3 mg/kg/hour over 1 to 2 hours) every 12 hours for 2 doses
- Next: 8 mg/kg IV every 12 hours until significant clinical improvement
- Next: 9 mg/kg (up to 350 mg) orally every 12 hours on an empty Stomach
- Adjust dose in 1 mg/kg increments (up if lack of response, or down if poorly tolerated)
-
Esophageal Candidiasis
- Treatment duration at least 14 days, and 7 days after symptoms resolve
- Adult (or child age >15 years, or weight >50 kg)
- Take 200 mg orally every 12 hours on an empty Stomach
- Decrease dose if weight <40 kg: 100 mg orally every 12 hours
- Child (age 2 to 15 years and weight <50 kg)
- Infuse 4 mg/kg IV at (3 mg/kg/hour over 1 to 2 hours) every 12 hours OR
- Give 9 mg/kg (up to 350 mg) orally every 12 hours on an empty Stomach
VII. Adverse Effects
- Transient visual disturbance (20-30% of patients)
- Occurs within 30 minutes of oral or IV dose
- Avoid night driving
- Blurred Vision
- Photophobia
- Altered color Perception
- Other adverse effects
- Serious adverse effects
- Stevens Johnson Syndrome
- Hepatotoxicity
- Increased serum transaminases
- Fulminant hepatic failure has occurred in rare cases
- Anaphylactoid Transfusion Reactions
- Neurologic Effects
- Hallucinations
- Confusion
- Acute Pancreatitis
- Increased risk in patients on Chemotherapy or following Stem Cell Transplant
- Longterm administration effects
- Long bone painful periostitis
- Premature aging
- Increased Skin Cancer risk in sun exposed areas
VIII. Safety
- Unknown safety in Lactation
- Pregnancy Category D
- Avoid in first trimester (and unknown safety in later trimesters)
IX. Pharmacokinetics
- Oral Bioavailability: 96%
- Serum levels peak within 2 hours of oral dose
- Food interferes with absorption (avoid food within one hour of oral dose)
- Decreased oral Bioavailability in children age 2 to 12 years with low body weight or malabsorption
- Serum concentrations vary significantly between patients on the same dose (monitor levels)
- Terminal half life varies widely: 6 to 24 hours
- Narrow therapeutic window
- Ineffective at serum concentrations <1 mcg/ml
- Neurotoxicity at serum concentrations >5.5 mcg/ml
X. Drug Interactions
-
General
- Numerous Drug Interactions that require dosing adjustments or medication discontinuation
- CYP2C9 Substrate and CYP2C9 Inhibitor
- CYP3A4 Substrate and CYP3A4 Inhibitor
- CYP2C19 Substrate and CYP2C19 Inhibitor
- Agents that prolong QTc Interval (risk of Torsades de Pointes)
- See Prolonged QT Interval due to Medication
- Avoid these agents in combination
- Agents that significantly decrease Voriconazole plasma levels (as much as 50%)
- Agents that may significantly increase Voriconazole levels
- Agents that require adjustments (numerous)
- Opioids and Benzodiazepines may require adjustment
-
Efavirenz requires dosing adjustment of Voriconazole
- See other resources for recommended adjustments
- Avoid Efavirenz at doses >400 mg/day
XI. Monitoring
- Voriconazole levels
-
Liver Function Tests
- Obtain at baseline, weekly for 1 month, then monthly
-
Vision
- If continuous use >28 days
XII. Resources
- Voriconazole Tablet (DailyMed)
- Voriconazole powder for injection (DailyMed)
XIII. References
- Hamilton (2020) Tarascon Pocket Pharmacopoeia
- (2012) Med Lett Drugs Ther 10(120): 61-8 [PubMed]
- (2002) Med Lett Drugs Ther 44(W1135A): 63-5 [PubMed]
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