Vonazol

• Treatment of invasive aspergillosis
• Treatment of candidemia (bloodstream infections caused by Candida species)
• Treatment of esophageal candidiasis
• Treatment of serious invasive infections caused by Scedosporium apiospermum and Fusarium species
• Prophylaxis of invasive fungal infections in high-risk immunocompromised patients, such as those undergoing hematopoietic stem cell transplantation
• Other serious fungal infections caused by susceptible organisms when alternative treatments are ineffective or contraindicated

Adults:

• Loading dose: 6 mg/kg intravenously every 12 hours for two doses (12 hours apart)
• Maintenance dose: 4 mg/kg intravenously every 12 hours or 200 mg orally every 12 hours
• Transition from IV to oral therapy may be done when clinically appropriate

Pediatrics (2 to 12 years):

• Loading dose: 9 mg/kg IV every 12 hours for two doses (maximum 350 mg per dose)
• Maintenance dose: 8 mg/kg IV every 12 hours or 9 mg/kg orally every 12 hours (maximum 350 mg per dose)

Elderly:

• No specific dose adjustment; monitor closely for adverse effects

Renal Impairment:

• Oral administration preferred in renal impairment due to accumulation of IV vehicle (cyclodextrin) in renal dysfunction
• No dose adjustment recommended but caution advised if creatinine clearance <50 mL/min

Hepatic Impairment:

• In moderate hepatic impairment (Child-Pugh class B), reduce maintenance dose by 50%
• Use with caution in severe hepatic impairment (Child-Pugh class C); insufficient data for dosing recommendations

Administration:

• IV infusion over 1 to 2 hours
• Oral tablets or suspension can be taken with or without food
• Complete full course as prescribed to prevent fungal resistance

Voriconazole is a triazole antifungal agent that inhibits fungal cytochrome P450-dependent 14-alpha-sterol demethylase. This enzyme is critical for the conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. Inhibition disrupts ergosterol synthesis, impairing cell membrane integrity and function, leading to increased membrane permeability and fungal cell death or growth arrest. Voriconazole is active against a broad spectrum of fungi, including Aspergillus, Candida, Scedosporium, and Fusarium species.

• Absorption: Voriconazole has excellent oral bioavailability (~96%) with peak plasma concentrations occurring 1 to 2 hours after dosing.
• Distribution: Widely distributed, including penetration into cerebrospinal fluid; volume of distribution approximately 4.6 L/kg.
• Metabolism: Extensively metabolized in the liver primarily by CYP2C19, with contributions from CYP2C9 and CYP3A4. Genetic polymorphisms in CYP2C19 significantly affect metabolism rates.
• Half-life: Approximately 6 hours in adults; varies based on metabolism phenotype.
• Excretion: Less than 2% excreted unchanged in urine; primarily eliminated as metabolites via renal and fecal routes.

• Pregnancy: Voriconazole is classified as FDA Pregnancy Category D. Animal studies have shown evidence of embryotoxicity and teratogenicity. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Lactation: It is unknown whether voriconazole is excreted in human breast milk. Due to potential adverse effects on the nursing infant, breastfeeding is generally not recommended during treatment.

• Triazole antifungal agent

• Known hypersensitivity to voriconazole or any component of the formulation
• Concurrent use with drugs contraindicated due to CYP3A4 interactions (e.g., rifampin, carbamazepine, sirolimus)
• Patients with known QT prolongation or a history of ventricular arrhythmias should avoid use unless benefits outweigh risks

• Hepatotoxicity: Monitor liver function tests prior to and periodically during treatment; discontinue if clinically significant liver injury occurs.
• Visual disturbances: Common and usually transient (e.g., blurred vision, altered color perception). Patients should be cautioned about potential effects on vision.
• QT interval prolongation: Use with caution in patients at risk; monitor ECG as appropriate.
• Photosensitivity and increased risk of skin cancer: Patients on prolonged therapy should avoid excessive sunlight and UV exposure.
• Neurological adverse effects: Hallucinations and encephalopathy reported; monitor mental status.
• Renal impairment: Avoid intravenous formulation in patients with severe renal impairment due to accumulation of the cyclodextrin vehicle.
• Therapeutic drug monitoring is recommended to optimize dosing and minimize toxicity.

• Common: Visual disturbances (up to 30%), rash, fever, nausea, vomiting, diarrhea, headache, elevated liver enzymes
• Serious but rare: Hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, QT prolongation, cardiac arrhythmias, hallucinations, severe hypersensitivity reactions including anaphylaxis

• Voriconazole is both a substrate and a potent inhibitor of CYP2C19, CYP2C9, and CYP3A4 enzymes, resulting in numerous drug interactions.
• Increases plasma concentrations of cyclosporine, tacrolimus, sirolimus, phenytoin, warfarin, and certain statins, increasing the risk of toxicity.
• Contraindicated with strong CYP450 inducers such as rifampin, carbamazepine, and St. John's Wort, which markedly reduce voriconazole levels.
• Concomitant use with other QT-prolonging drugs increases the risk of arrhythmias.
• Alcohol consumption may increase the risk of hepatotoxicity and should be avoided.

• Voriconazole remains the first-line therapy for invasive aspergillosis according to Infectious Diseases Society of America (IDSA) and European guidelines.
• Therapeutic drug monitoring has been increasingly recommended to tailor therapy, improve efficacy, and reduce adverse effects.
• Recent safety updates emphasize phototoxicity risk and the potential for skin cancer with long-term use.
• Dose adjustments based on hepatic function and CYP2C19 metabolism phenotype are highlighted in current prescribing information.

• Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Oral suspension should be refrigerated at 2°C to 8°C (36°F to 46°F) and must not be frozen
• Intravenous formulation should be stored refrigerated and used promptly after preparation
• Keep all formulations out of reach of children