Pharm

Voriconazole

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Voriconazole, Vfend

  • See also
  1. Antifungal Medication
  2. Topical Antifungal
  3. Fluconazole
  4. Isavuconazole
  5. Itraconazole
  6. Posaconazole
  • Indications
  1. Conditions
    1. Invasive Aspergillosis
    2. Invasive Scedospiosis
    3. Invasive fusariosis
    4. Systemic Candidiasis
    5. Esophageal Candidiasis
  2. Activity (broader activity than Fluconazole)
    1. Aspergillus species
    2. Blastomyces dermatitidis
    3. Candida (most species, including C. glabrata and C. Krusei)
    4. Cryptococcus neoformans
    5. Fusarium species
    6. Histoplasma capsulatum
    7. Scedosporium Species
  • Contraindications
  1. Intravenous formulation in GFR <50 ml/min (relative contraindication)
    1. Voriconazole is removed with Hemodialysis
    2. Voriconazole does not worsen Renal Function
  2. Age <2 years
  3. Resistant organisms
    1. Mucorales or Zygomycetes (e.g. Mucor species, Rhizopus species)
  • Mechanism
  1. Azole Antifungal (triazole)
  2. Inhibits fungal CYP450 enzymes
  3. Inhibits fungal sterol demethylation (selectively at 14-alpha-lanosterol)
    1. Blocks the synthesis of plasma membrane steroids (conversion from lanosterol to ergosterol)
    2. Results in plasma membrane damage
  • Medications
  1. Oral Voriconazole
    1. Tablets: 50 mg, 200 mg
    2. Suspension: 40 ml/ml
      1. Stable at room Temperature for 14 days
  2. Intravenous Voriconazole
    1. Avoid in GFR <50 ml/min (risk of accumulation)
    2. Dilute Voriconazole for IV infusion to <=5 mg/ml
    3. Limit infusion to 3 mg/kg/hour over 1 to 2 hours
    4. Do NOT infuse Voriconazole IV at the same time as Blood Products or concentrated Electrolytes
      1. Avoid even if via separate IV lines
      2. Parenteral nutrition may be infused at same time, but different IV line
  • Dosing
  1. General
    1. Follow therapeutic drug levels
    2. Take oral preparation on an empty Stomach (no food within one hour of dose)
    3. Hepatic dosing (mild to moderate Cirrhosis)
      1. Give standard loading dose, but decrease maintenance doses to 50%
  2. Invasive Aspergillosis, Scedospiosis, fusariosis and Systemic Candidiasis
    1. Treatment duration at least 14 days after symptoms resolve and last positive Blood Culture
    2. Adult (or child age >15 years, or weight >50 kg)
      1. Load: 6 mg/kg IV (3 mg/kg/hour over 1 to 2 hours) every 12 hours for 2 doses
      2. Next: 4 mg/kg IV every 12 hours until significant clinical improvement
      3. Next: 200 mg orally twice daily on an empty Stomach
        1. If weight <40 kg, decrease dose to 100 mg orally every 12 hours
    3. Child (age 2 to 15 years and weight <50 kg)
      1. Load: 9 mg/kg IV (3 mg/kg/hour over 1 to 2 hours) every 12 hours for 2 doses
      2. Next: 8 mg/kg IV every 12 hours until significant clinical improvement
      3. Next: 9 mg/kg (up to 350 mg) orally every 12 hours on an empty Stomach
      4. Adjust dose in 1 mg/kg increments (up if lack of response, or down if poorly tolerated)
  3. Esophageal Candidiasis
    1. Treatment duration at least 14 days, and 7 days after symptoms resolve
    2. Adult (or child age >15 years, or weight >50 kg)
      1. Take 200 mg orally every 12 hours on an empty Stomach
      2. Decrease dose if weight <40 kg: 100 mg orally every 12 hours
    3. Child (age 2 to 15 years and weight <50 kg)
      1. Infuse 4 mg/kg IV at (3 mg/kg/hour over 1 to 2 hours) every 12 hours OR
      2. Give 9 mg/kg (up to 350 mg) orally every 12 hours on an empty Stomach
  • Adverse Effects
  1. Transient visual disturbance (20-30% of patients)
    1. Occurs within 30 minutes of oral or IV dose
    2. Avoid night driving
    3. Blurred Vision
    4. Photophobia
    5. Altered color Perception
  2. Other adverse effects
    1. Fever
    2. Nausea
    3. Photosensitivity
  3. Serious adverse effects
    1. Stevens Johnson Syndrome
    2. Hepatotoxicity
      1. Increased serum transaminases
      2. Fulminant hepatic failure has occurred in rare cases
    3. Anaphylactoid Transfusion Reactions
    4. Neurologic Effects
      1. Hallucinations
      2. Confusion
    5. Acute Pancreatitis
      1. Increased risk in patients on Chemotherapy or following Stem Cell Transplant
  4. Longterm administration effects
    1. Long bone painful periostitis
    2. Premature aging
    3. Increased Skin Cancer risk in sun exposed areas
      1. Squamous Cell Carcinoma
      2. Melanoma
  • Safety
  1. Unknown safety in Lactation
  2. Pregnancy Category D
    1. Avoid in first trimester (and unknown safety in later trimesters)
  • Pharmacokinetics
  1. Oral Bioavailability: 96%
    1. Serum levels peak within 2 hours of oral dose
    2. Food interferes with absorption (avoid food within one hour of oral dose)
    3. Decreased oral Bioavailability in children age 2 to 12 years with low body weight or malabsorption
    4. Serum concentrations vary significantly between patients on the same dose (monitor levels)
  2. Terminal half life varies widely: 6 to 24 hours
  3. Narrow therapeutic window
    1. Ineffective at serum concentrations <1 mcg/ml
    2. Neurotoxicity at serum concentrations >5.5 mcg/ml
  • Drug Interactions
  1. General
    1. Numerous Drug Interactions that require dosing adjustments or medication discontinuation
    2. CYP2C9 Substrate and CYP2C9 Inhibitor
    3. CYP3A4 Substrate and CYP3A4 Inhibitor
    4. CYP2C19 Substrate and CYP2C19 Inhibitor
      1. Risk of toxic levels (2-4 fold higher) in CYP2C19 deficiency
      2. CYP2C19 deficiency occurs in 15-20% of asians, 3-5% of caucasian and black patients
  2. Agents that prolong QTc Interval (risk of Torsades de Pointes)
    1. See Prolonged QT Interval due to Medication
    2. Avoid these agents in combination
  3. Agents that significantly decrease Voriconazole plasma levels (as much as 50%)
    1. Carbamazepine
    2. Rifampin
    3. Rifabutin
    4. Phenobarbital
    5. Phenytoin
  4. Agents that may significantly increase Voriconazole levels
    1. Ergot alkaloids
    2. Everolimus
    3. Fluconazole
    4. Lopinavir-Ritonavir
    5. Pimozide
    6. Quinidine
    7. Sirolimus
    8. St. Johns Wort
  5. Agents that require adjustments (numerous)
    1. Opioids and Benzodiazepines may require adjustment
  6. Efavirenz requires dosing adjustment of Voriconazole
    1. See other resources for recommended adjustments
    2. Avoid Efavirenz at doses >400 mg/day
  • Monitoring
  1. Voriconazole levels
  2. Liver Function Tests
    1. Obtain at baseline, weekly for 1 month, then monthly
  3. Vision
    1. If continuous use >28 days
  • Resources
  1. Voriconazole Tablet (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=67c174da-41b8-4738-8a22-dd814b8e96b8
  2. Voriconazole powder for injection (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=dac26bcd-7a59-401f-9f66-a0649767cece
  • References
  1. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  2. (2012) Med Lett Drugs Ther 10(120): 61-8 [PubMed]
  3. (2002) Med Lett Drugs Ther 44(W1135A): 63-5 [PubMed]