1. Clinical Overview
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.
| Onset | Duration | Bioavailability |
|---|---|---|
| Steady-state plasma concentrations are typically achieved after the first 24 hours of dosing with the intravenous formulation. Oral absorption is rapid. | Dose-dependent; requires twice-daily dosing to maintain therapeutic plasma concentrations. | Approximately 96% for the oral tablet, indicating excellent absorption. |
2. Mechanism of Action
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.
3. Indications & Uses
- Invasive Aspergillosis (first-line treatment)
- Candidemia in non-neutropenic patients
- Esophageal Candidiasis
- Serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. (including Fusarium solani) in patients refractory to, or intolerant of, other antifungal therapy
4. Dosage & Administration
Adult Dosage: **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.
Administration: 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.
5. Side Effects
Common side effects may include:
- Visual disturbances (photopsia, blurred vision, color vision change, photophobia) - usually transient and reversible
- Gastrointestinal disturbances (nausea, vomiting, diarrhea, abdominal pain)
- Skin rash (often maculopapular)
- Headache
- Peripheral edema
- Fever
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| 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 |
7. Patient Counselling
- DO take the tablet at least 1 hour before or 1 hour after meals.
- DO swallow the tablet whole with water. It can be dissolved in water if you cannot swallow it whole.
- DO inform all your doctors and pharmacists that you are taking voriconazole.
- DO use effective contraception during treatment if you are a woman of childbearing potential.
- DONT drive or operate machinery if you experience blurred vision or dizziness, especially at night.
- DONT take with rifampin, phenytoin, certain HIV medications, or St. John's Wort without consulting your doctor.
- DONT crush or chew the tablets.
8. Toxicology & Storage
Overdose: In cases of overdose, exaggerated adverse effects may be seen, including pronounced visual disturbances, hallucinations, confusion, nausea, vomiting, and hepatic enzyme elevations. QT prolongation is also a concern.
Storage: Store at room temperature (15°C to 30°C). Protect from light and moisture. Keep in the original blister pack or container. Keep out of reach of children. Do not use after the expiry date printed on the pack.