What are the side effects of Voriconazole?

Voriconazole Side Effects

Voriconazole causes several unique and potentially serious adverse effects that require careful monitoring, including transient visual disturbances in approximately 30% of patients, hepatotoxicity, photosensitivity with increased risk of squamous cell carcinoma during prolonged therapy, cardiovascular complications including QT prolongation and arrhythmias, and periostitis from fluoride accumulation. 1, 2

Common Side Effects

Visual Disturbances

• Transient visual abnormalities occur in approximately 30% of patients, characterized primarily by photopsia (seeing flashes of light), blurred vision, changes in color perception, and photophobia 1, 3, 4
• These visual changes are typically non-sight-threatening and reversible 3
• Patients should not drive at night while taking voriconazole due to these vision changes 2

Gastrointestinal Effects

• Nausea, vomiting, and diarrhea are common 1, 2
• These effects are often associated with higher serum drug levels 5

Skin Reactions

• Skin rash occurs in approximately 20% of patients 3, 6
• Erythroderma and perioral excoriations may develop 1

Serious and Dose-Related Side Effects

Hepatotoxicity

• Hepatic injury manifests as elevated serum bilirubin, alkaline phosphatase, and hepatic aminotransferase enzyme levels and may be dose-limiting 1
• Symptoms include itchy skin, yellowing of eyes, severe fatigue, flu-like symptoms, and nausea/vomiting 2
• For mild to moderate liver enzyme elevations, continue voriconazole at current dose with increased monitoring frequency to twice weekly 7
• For significant elevations, consider dose reduction based on therapeutic drug monitoring with monitoring every 2-3 days 7
• For severe elevations or clinical hepatitis, discontinue voriconazole unless benefit clearly outweighs risk, and consider alternative therapy such as an echinocandin 7
• Voriconazole is the only triazole requiring dosage reduction for mild to moderate hepatic impairment 1

Cardiovascular Complications

• Tachyarrhythmias and QT interval prolongation on electrocardiography are well-documented 1
• Rare cases of ventricular arrhythmias including torsade de pointes, bradycardia, cardiac arrest, and sudden death have occurred 1
• These serious cardiac events typically occur in patients with multiple risk factors including history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant QT-prolonging medications 1
• Healthcare providers should obtain an EKG before starting voriconazole in patients with heart disease or abnormal heart rate/rhythm 2

Photosensitivity and Skin Cancer Risk

• Severe photosensitivity reactions can occur, making skin extremely sensitive to sunlight, sunlamps, and tanning beds 2, 5
• Prolonged voriconazole therapy significantly increases risk of cutaneous malignancies, primarily squamous cell carcinoma (SCC) 5
• This cancer risk is duration-dependent, and associated malignancies tend to be more aggressive and multifocal 5
• Patients must use sunscreen and wear protective clothing (hat and covering garments) when sun exposure is unavoidable 2

Neuropsychiatric Effects

• Visual and auditory hallucinations may occur 1, 2
• Encephalopathy and peripheral neuropathy have been reported, particularly with prolonged therapy 5
• Headache is common 2
• These neuropsychiatric toxicities are clearly associated with supratherapeutic serum voriconazole levels 5

Periostitis and Fluoride Toxicity

• Prolonged voriconazole therapy causes periostitis and bone pain due to fluoride excess, as voriconazole metabolism releases fluoride 8
• Patients receiving long-term therapy are at higher risk of fluoride toxicity 8
• This adverse effect has emerged as a concern with extended duration of therapy 5, 9

Renal Considerations

• Intravenous voriconazole is complexed to cyclodextrin, which accumulates in renal insufficiency and poses potential nephrotoxicity risk 1
• IV voriconazole is not currently recommended for patients with creatinine clearance <50 mL/minute 1, 6
• However, retrospective data have not identified toxic effects in patients with renal dysfunction below this cutoff, mitigating some concerns 1
• Oral voriconazole does not require dosage adjustment for renal insufficiency 1
• New or worsening kidney problems including kidney failure may occur 2

Additional Adverse Effects with Prolonged Use

• Alopecia (hair loss) 5, 9
• Nail changes 5
• Hyponatremia (low sodium) 5
• Serious skin reactions including rash, hives, mouth sores, blistering or peeling skin 2

Critical Monitoring Considerations

Therapeutic Drug Monitoring

• Measurement of serum voriconazole levels is useful in the majority of patients to evaluate for potential toxicity and document adequate drug exposure 1
• Toxicity is more common with higher drug levels, and careful monitoring is essential for safe drug use 1, 5
• Common polymorphisms in CYP2C19 result in wide variability of serum levels between patients 1, 9
• Some toxicities (neuropsychiatric and gastrointestinal including hepatic) are seen in clear association with supratherapeutic levels 5

Drug-Drug Interactions

• Drug interactions are common with voriconazole and must be considered when initiating and discontinuing treatment 1
• Voriconazole is both a substrate and inhibitor of CYP2C19 primarily, as well as CYP3A4 1
• The potential for drug-drug interactions is high and requires careful attention to dosage regimens and monitoring 3, 6, 9

Allergic Reactions

Symptoms requiring immediate medical attention include: 2

• Fever and sweating
• Rapid heartbeat (tachycardia)
• Chest tightness and trouble breathing
• Feeling faint
• Nausea, itching, and skin rash

Pediatric-Specific Side Effects

Common side effects in children include: 2

• Fever and rash
• Stomach pain and diarrhea
• Nosebleeds
• High blood pressure
• Low potassium, platelet, calcium, magnesium, and phosphate levels
• Cough and inflammation of mucous membranes
• Abnormal liver function tests