P&T Portfolio-VFEND

September 16, 2002

Voriconazole (VFEND) - Broad-spectrum triazole anti-fungal agent.

 

HEALTH-SYSTEM EDITION
P&T PORTFOLIO

Generic name

Voriconazole

Proprietary name/manufacturer

Vfend/Pfizer

FDA-approved indication

Treatment of invasive aspergillosis; treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani in patients intolerant of, or refractory to, other therapy

Pharmacology

Voriconazole is a broad-spectrum triazole antifungal agent. Its primary mechanism of action is the inhibition of fungal cytochrome P450-dependent ergosterol synthesis mediated via 14-alpha-sterol demethylase. The accumulation of 14-alpha-methyl sterols correlates with the subsequent reduction of normal ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole.

Efficacy

A limited number of clinical trials and case reports demonstrated that voriconazole is effective for the primary therapy of invasive aspergillosis and for the treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy. Voriconazole appears to be more effective than conventional amphotericin B in the treatment of acute invasive aspergillosis, but comparative studies with other antifungal agents are not available. Pooled analyses of patient study data also indicate that voriconazole is effective against additional fungal pathogens, including Scedosporium apiospermum and Fusarium spp., with response rates of 63% (15/24) and 43% (9/21), respectively.

Pharmacokinetics

Oral bioavailability96%
Protein binding58%
Volume of distribution4.6 L/kg
MetabolismExtensive in liver via cytochrome P450 enzymes, CYP2C19, CYP2C9, and CYP3A4 to inactive metabolites
ExcretionUrine (80%-83%) Bile

 

Contraindications

• Hypersensitivity to voriconazole or its excipients

• Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, or quinidine, which can lead to QT prolongation and rare occurrences of torsade de pointes

• Coadministration with sirolimus, which can cause a significant increase in sirolimus concentrations

• Coadministration with rifampin, carbamazepine, and long-acting barbiturates, which can significantly decrease plasma voriconazole concentrations

• Coadministration with rifabutin, which can significantly increase rifabutin plasma concentrations and significantly decrease voriconazole plasma concentrations

• Coadministration with ergot alkaloids (ergotamine and dihydroergotamine), which can lead to ergotism

Warnings

• Accumulation of the intravenous vehicle, SBECD, may occur in patients with renal dysfunction; oral voriconazole is preferred.

• Dosage adjustment is required in patients with hepatic insufficiency. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored.

• There have been uncommon cases of serious hepatic reactions during treatment with voriconazole. Liver function tests should be evaluated at the start of and during the course of therapy.

• Voriconazole can cause fetal harm when administered to pregnant women.

• Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

• Hypersensitivity to other antifungals.

Adverse effects

The most common adverse events (5%-20%) were:

• Abnormal vision

• Fever

• Nausea

• Rash

• Vomiting

Less common adverse events (2%-5%) were:

• Chills

• Alkaline phosphatase increased

• Headache

• Liver function tests abnormal

• Hallucinations

• Photophobia

• Tachycardia

• SGPT increased

• Hypertension

Drug interactions

• Astemizole

• Barbiturates, long-acting

• Carbamazepine

• Cisapride

• Ergot alkaloids

• Pimozide

• Quinidine

• Rifabutin

• Rifampin

• Sirolimus

• Terfenadine

Dose

Intravenous: loading dose: 6 mg/kg IV every 12 hours for 2 doses; maintenance dose: 4 mg/kg IV every 12 hours

Oral: patients > 40 kg: 200 mg every 12 hours; patients < 40 kg: 100 mg every 12 hours

Dosage adjustment: inadequate response, coadministration with phenytoin, hepatic insufficiency, intolerance to treatment

Conclusion/comments

Voriconazole is a triazole antifungal agent that has shown efficacy in the treatment of invasive aspergillosis and of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. including Fusarium solani in patients intolerant of, or refractory to, other therapy. It appears to be more effective than conventional amphotericin B in the primary therapy of acute invasive aspergillosis, but comparisons to other antifungal agents are not available. The manufacturer of voriconazole is also seeking approval for the treatment of other serious fungal infections and for empiric antifungal therapy of febrile neutropenia.

Published August 2002. Content based on medical literature and product information available at that time.

 

 

P&T Portfolio-VFEND. Drug Topics 2002;18:HSE23.