Why should caution be exercised when prescribing voriconazole?

Caution When Prescribing Voriconazole

Caution must be exercised when prescribing voriconazole due to its significant potential for hepatotoxicity, QT interval prolongation, severe drug-drug interactions, neurologic toxicities, and photosensitivity reactions that can lead to cutaneous malignancies with long-term use. 1, 2

Major Safety Concerns

Hepatotoxicity

• Monitor hepatic function in all patients:
  • Measure serum transaminase levels and bilirubin at initiation of therapy
  • Monitor weekly for the first month of treatment
  • Reduce to monthly monitoring if no significant changes occur 2
• Discontinue voriconazole if liver function tests become markedly elevated compared to baseline
• Higher frequency of liver enzyme elevations observed in pediatric populations 2
• Cases of serious hepatic reactions including clinical hepatitis, cholestasis, and fulminant hepatic failure (some fatal) have been reported 2

Cardiac Effects

• QT interval prolongation can occur, especially when combined with:
  • Other QT-prolonging medications (fluoroquinolones, macrolides, ondansetron)
  • Certain chemotherapies (nilotinib, panobinostat) 1
• Rare cases of arrhythmias (including torsade de pointes), cardiac arrests, and sudden deaths have occurred 2
• Use with caution in patients with:
  • Congenital or acquired QT prolongation
  • Cardiomyopathy (particularly with heart failure)
  • Sinus bradycardia
  • Existing symptomatic arrhythmias 2
• Correct electrolyte abnormalities (potassium, magnesium, calcium) before and during therapy 2

Drug-Drug Interactions

• Voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4 1
• Significant interactions with multiple medications due to inhibition of cytochrome P450 enzymes 1
• Contraindicated with several medications including:
  • Cisapride, pimozide, quinidine (risk of QT prolongation)
  • Sirolimus (significantly increased concentrations)
  • Rifampin, carbamazepine, long-acting barbiturates (decrease voriconazole levels)
  • Ergot alkaloids (risk of ergotism)
  • St. John's Wort (decreases voriconazole concentration) 2
• High interpatient variability of genetic CYP2C19 polymorphisms affecting dosing 1

Visual Disturbances

• Transient visual disturbances (photopsia) occur in approximately 30% of patients 1, 3
• Monitor visual function if treatment continues beyond 28 days
• Post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema 2

Photosensitivity and Skin Reactions

• Severe photosensitivity reactions require strict sun avoidance
• Long-term use associated with:
  • Squamous cell carcinoma of the skin
  • Melanoma
  • Severe photosensitivity
  • Periostitis with elevated serum fluoride levels 1
• Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS can occur 2

Renal Concerns

• IV formulation contains cyclodextrin vehicle that accumulates in renal insufficiency
• Consider oral formulation for patients with creatinine clearance <50 mL/min 1

Therapeutic Drug Monitoring (TDM)

• Recommended due to nonlinear pharmacokinetics and high interpatient variability 1, 4
• Target trough concentrations:

  • 1-1.5 μg/mL for efficacy

  • <5-6 μg/mL to minimize toxicity, especially CNS toxicity 1
• Factors affecting voriconazole levels:
  • Age
  • Liver function
  • Drug-drug interactions
  • Genetic polymorphisms in CYP2C19 1, 5

Special Populations

Pediatric Patients

• Higher doses may be required due to accelerated metabolic clearance 1
• Higher frequency of liver enzyme elevations 2
• Higher frequency of photosensitivity reactions 2

Patients with Hepatic Impairment

• Dose reduction recommended in mild to moderate hepatic dysfunction (Child-Pugh class A or B) 6

Practical Recommendations

1. Perform baseline liver function tests before initiating therapy
2. Screen for potential drug interactions before prescribing
3. Implement therapeutic drug monitoring, especially in high-risk patients
4. Advise patients to avoid direct sunlight and use sun protection
5. Monitor for visual disturbances and discontinue if severe
6. Consider oral formulation in patients with renal impairment
7. Consult with infectious disease specialists when incorporating voriconazole into treatment regimens 1

The unique toxicity profile and complex pharmacokinetics of voriconazole require careful patient selection, monitoring, and dose adjustment to maximize efficacy while minimizing potentially serious adverse effects.