Side Effects of Voriconazole
Voriconazole has a wide range of potential side effects, with visual disturbances, hepatotoxicity, and photosensitivity reactions being the most common adverse events requiring monitoring and potential dose adjustments. 1, 2
Common Side Effects
Visual Disturbances
- Transient visual disturbances occur in approximately 30% of patients 1, 3
- Typically manifest as photopsia (seeing flashes of light), color vision changes, and photophobia 1
- Usually self-limited and reversible, not clearly associated with absolute drug levels 1
- Occur early in treatment and resolve after discontinuation 3
Hepatotoxicity
- Mild hepatotoxicity is common and related to drug concentration 1
- Manifests as elevated liver enzymes (ALT, AST), alkaline phosphatase, and bilirubin 1, 3
- Risk increases with voriconazole trough concentrations >3.61 mg/L 4
- Occurs in 66.7% of patients within 7 days and 94.4% within 15 days of starting therapy 4
- Severe hepatotoxicity is uncommon but requires careful monitoring 1
- Patients with pre-existing liver dysfunction are at higher risk 5
Dermatologic Reactions
- Photosensitivity reactions occur in approximately 20% of patients 6
- Skin rash, erythroderma, and perioral excoriations 1
- Long-term use associated with increased risk of squamous cell carcinoma and melanoma, especially in fair-skinned persons and immunosuppressed patients 1, 2, 7
- Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported 3
Neurological Side Effects
- Reversible central and peripheral neurologic symptoms 1
- Visual or auditory hallucinations (2.4% of patients) 1, 3
- Encephalopathy and peripheral neuropathy with prolonged use 7
- Neurological side effects correlate with higher drug concentrations 1, 4
Cardiovascular Side Effects
- QT interval prolongation on electrocardiography 1, 2
- Tachyarrhythmias 1
- Rare cases of ventricular arrhythmias (including torsade de pointes), bradycardia, cardiac arrest, and sudden death 1, 3
- Higher risk in patients with history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, or concomitant QT-prolonging medications 1
Gastrointestinal Side Effects
Long-Term Use Complications
- Periostitis with severe pain in bones or joints associated with elevated serum fluoride levels 1, 2, 7
- Squamous cell carcinoma and melanoma in sun-exposed areas 1, 2, 7
- Alopecia and nail changes 7
Monitoring Recommendations
Therapeutic Drug Monitoring
- Target trough concentrations: >1-1.5 μg/mL for efficacy and <5-6 μg/mL to minimize toxicity 1, 2
- Monitoring is essential due to:
Specific Monitoring
- Baseline and periodic liver function tests 2
- Regular skin examinations for patients on long-term therapy 2, 7
- ECG monitoring in patients with cardiac risk factors or on other QT-prolonging medications 2
- Visual symptom assessment 2
Risk Factors for Increased Toxicity
- Genetic polymorphisms in CYP2C19 (more common in non-Indian Asian populations) 1
- Concomitant medications that interact with CYP2C19 and CYP3A4 1, 2
- Pre-existing liver dysfunction 5
- Higher voriconazole trough concentrations 1, 4
- Loading doses >300 mg (4.5 mg/kg) in patients with severe liver dysfunction 5
Practical Considerations
- Consider oral formulation for patients with creatinine clearance <50 mL/min due to potential accumulation of cyclodextrin vehicle in IV formulation 1, 6
- Advise patients to avoid direct sunlight and use sun protection to minimize photosensitivity reactions 2
- Timely dose adjustments based on drug levels can prevent or mitigate hepatotoxicity 4
By understanding and monitoring for these side effects, clinicians can optimize the safety profile of voriconazole while maintaining its therapeutic efficacy in treating fungal infections.