Voriconazole is a broad-spectrum triazole antifungal agent, a second-generation synthetic derivative of fluconazole. It is a first-line treatment for invasive aspergillosis and other serious fungal infections. It works by inhibiting the fungal cytochrome P450-mediated 14α-lanosterol demethylation, a vital step in ergosterol biosynthesis, leading to depletion of ergosterol and accumulation of toxic sterol precursors in the fungal cell membrane, causing cell death.
Adult: **Loading Dose:** 400 mg every 12 hours for the first 24 hours (oral). **Maintenance Dose:** 200 mg every 12 hours (oral). Dose may be increased to 300 mg every 12 hours if inadequate response and tolerated. For patients weighing <40 kg, maintenance dose is 100 mg every 12 hours.
Note: Tablets should be taken at least one hour before or one hour after a meal for optimal absorption. Swallow whole with a full glass of water. For patients with difficulty swallowing, tablets can be dissolved in a glass of water. Do not crush or chew.
Voriconazole selectively inhibits the fungal cytochrome P450-dependent enzyme lanosterol 14α-demethylase. This inhibition disrupts the conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. The resultant depletion of ergosterol and accumulation of methylated sterol precursors compromises membrane integrity, fluidity, and the function of membrane-associated enzymes, leading to inhibition of fungal cell growth and eventual cell death.
Pregnancy: Pregnancy Category D (US FDA). There is positive evidence of human fetal risk based on animal studies (teratogenic, embryotoxic) and adverse human pregnancy outcomes. Use only if the potential benefit justifies the potential risk to the fetus. Effective contraception is required in women of childbearing potential.
Driving: Voriconazole may cause transient and reversible visual disturbances (blurred vision, photophobia) and dizziness. Patients should be cautioned about driving at night, operating machinery, or performing hazardous tasks, especially during the first week of therapy.
| Rifampin | Markedly decreases voriconazole plasma concentrations; concomitant use is contraindicated. | Contraindicated |
| Phenytoin | Phenytoin decreases voriconazole levels; voriconazole increases phenytoin levels. Increase voriconazole maintenance dose to 400 mg every 12 hrs; monitor phenytoin levels closely. | Major |
| Omeprazole / Other CYP2C19 inhibitors | Increase voriconazole plasma concentrations. May require dose reduction of voriconazole. | Moderate |
| Warfarin | Voriconazole increases S-warfarin levels, significantly increasing prothrombin time (PT/INR). Monitor INR closely. | Major |
| Sirolimus | Voriconazole dramatically increases sirolimus levels; concomitant use is contraindicated. | Contraindicated |
| Cyclosporine, Tacrolimus | Voriconazole increases levels of these calcineurin inhibitors. Reduce cyclosporine/tacrolimus dose by 50% and monitor levels frequently. | Major |
| Sulfonylureas (e.g., Glimepiride) | Increased risk of hypoglycemia. Monitor blood glucose. | Moderate |
| Statins (Metabolized by CYP3A4) | Increased risk of myopathy/rhabdomyolysis. Consider using a non-CYP3A4 metabolized statin (e.g., pravastatin). | Moderate |
| Efavirenz | Complex bidirectional interaction. Efavirenz decreases voriconazole levels, voriconazole increases efavirenz levels. Adjust doses: Voriconazole maintenance to 400 mg q12h, Efavirenz to 300 mg once daily. Monitor for toxicity. | Major |
| Ritonavir (low dose) | Decreases voriconazole levels. Avoid concomitant use unless benefit outweighs risk. | Major |
| QT-prolonging drugs (e.g., Amiodarone, Fluoroquinolones) | Additive risk of QT prolongation and arrhythmias. Monitor ECG and electrolytes. | Major |