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New antifungal approved for aspergillosis

More patients are undergoing procedures such as aggressive chemotherapy for cancer or organ transplants. As such, they are at risk for serious fungal infections. In these immunosuppressed patients, such infections have a high morbidity and mortality rate.

Thus, it's good to hear that Pfizer has received marketing approval from the Food & Drug Administration for voriconazole (Vfend tablets) and voriconazole for injection (Vfend I.V.) for use in the treatment of invasive aspergillosis and the treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp in patients intolerant of, or refractory to, other therapy.

According to John Papadopoulos, Pharm.D., assistant professor of pharmacy practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn, N.Y., voriconazole appears to have similar efficacy to amphotericin B. "In a few published articles, amphotericin B seemed superior in some areas, and voriconazole appeared superior in other areas. In general, though, in the data that I have had the opportunity to evaluate, voriconazole is similar in efficacy to amphotericin B," he said.

A triazole antifungal compound, voriconazole impairs the production of ergosterol, a vital component of the fungal cell membrane. "After several cell divisions, fungi produce porous cell walls, which leads to leakage of the intracellular contents, and the subsequent death of the fungus," explained Papadopoulos, also critical care pharmacist, New York University Medical Center.

The following regimen is recommended for adults with aspergillosis and infection with S. apiospermum and Fusarium spp:

• A loading dose of voriconazole I.V. of 6 mg/kg q12h for two doses can be followed by a maintenance dose of 4 mg/kg q12h

• Once the patient can tolerate oral therapy, an oral maintenance dose can be given of 200 mg q12h for patients who weigh more than 40 kg, and 100 mg q12h for those who weigh less than 40 kg.

In clinical trials, one of the more commonly reported side effects was visual disturbance. According to Papadopoulos, it usually occurred within 30 minutes after the first dose and may last for approximately 30 minutes. This adverse effect usually improves as the patient continues taking the compound. "To my knowledge, no long-term visual sequelae are associated with the chronic use of voriconazole," he said.

Laboratory monitoring of hepatic function (particularly liver function tests and bilirubin) should be done regularly during treatment with voriconazole, based on clinical judgment. Renal monitoring (particularly serum creatinine) should also be done in those with renal impairment who are being given the IV formulation of voriconazole, said Papadopoulos, because the solubilizer used is excreted renally.

According to the proposed package insert posted on the FDA Web site, voriconazole is contraindicated in those taking the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, and quinidine, because they can cause QT prolongation and, on rare occasions, torsade de pointes. Coadministration with sirolimus is also contraindicated, because voriconazole increases the sirolimus concentrations in healthy subjects.

Rifampin, carbamazepine, and long-acting barbiturates may decrease plasma concentrations of voriconazole, so coadministration with voriconazole is contraindicated. Coadministration of rifabutin with voriconazole is contraindicated because voriconazole increases plasma concentrations of rifabutin and rifabutin decreases plasma concentrations of voriconazole. Voriconazole may increase the concentration of ergot alkaloids, which may lead to ergotism, so voriconazole should not be coadministered with ergot alkaloids.

Voriconazole is expected to be available in hospitals this summer.

Charlotte LoBuono

TIPS TO REMEMBER: Vfend

• In addition to visual disturbance, other adverse events of Vfend may include skin rashes and elevations in liver function enzymes.

• Vfend is classified as pregnancy category D. Pregnant women or women who become pregnant while taking Vfend should be warned of the potential risk to the fetus. Those who are breast-feeding should not take Vfend.

 

Charlotte LoBuono. New antifungal approved for aspergillosis. Drug Topics 2002;12:14.