More info on Voriconazole (Vfend, Pfizer)

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http://www.pharmacytimes.com/article.cfm?ID=424

Ali J. Olyaei, PharmD, BCPS

Introduction

Fungal infections have emerged as important causes of death among

immunocompromised patients. Asper-gillosis, in particular, is

associated with an increased risk of morbidity and mortality in

cancer, transplant, and AIDS patients. Approximately 14% of liver

transplant patients, 7% of bone marrow transplant patients, and 14% of

leukemia patients may develop invasive aspergillosis. Mortality rates

of 45% to 90% attributable to asper-gillosis have been reported in

clinical studies, with incidence rising to almost 100% when the

central nervous system (CNS) is involved. Amphotericin B has been the

cornerstone of treatment for systemic fungal infections. However, that

substance has a number of acute and chronic dose-limiting toxicities

in particular, nephrotoxicity. Other FDA-approved antifungal agents

(azoles) have a limited spectrum of antifungal activity. Voriconazole

(Vfend, Pfizer) was recently approved by the FDA for marketing in the

United States for the treatment of invasive aspergillosis and other

emerging fungal pathogens. In patients with suspected fungal

infections, voricona-zole should be instituted prior to receiving

culture results. Treatment should then be adjusted accordingly when

cultures are available.1,2

Pharmacology

Voriconazole, a second-generation triazole, was developed to expand

the antifungal spectrum of fluconazole. Voriconazole has

broad-spectrum coverage for molds, Candida albicans, and non-albicans

(glabrata, krusei, parapsilo-sis, and other Candida species). In

addition, voriconazole has an excellent efficacy profile for the

treatment of other emerging fungal pathogens (Scedosporium and

Fusarium). Voricon-azole is available as both intravenous and oral

preparations. These formulations allow treatment flexibility in

outpatients, improve quality of care, lower overall cost, and allow

for prolonged treatment frequently required in invasive fungal

infections to be given orally.

The pharmacokinetics of voricon-azole are characterized by high oral

bioavailability (96%), a large volume of distribution (4.5 L/kg), and

elimination through hepatic metabolism by cytochrome P-450 isozymes.

This high oral bioavailability allows for switching between

intravenous and oral administration. The large volume of distribution

of voriconazole indicates extensive tissue distribution with excellent

CNS penetration.2,3

Efficacy

The safety and efficacy of voricon-azole in the treatment of fungal

infections has been evaluated extensively in several clinical studies.

Approximately 2000 patients have been treated with voriconazole for

candidemia (albicans and non-albicans), invasive aspergillosis, and

neutropenic fever. The drug also has been used in critically ill

patients following solid organ transplantation or bone marrow

transplantation and in HIV-positive patients. In a comparative

clinical study, 392 patients with proven invasive asper-gillosis were

randomized to either voriconazole intravenous (IV)/oral or IV

amphotericin B. Voriconazole was administered with 2 loading doses of

6 mg/kg IV q 12 h followed by 4 mg/kg q 12 h for at least 7 days

followed by oral voriconazole 200 mg bid for up to 12 weeks.

Amphotericin B was administered at a dose of 1.0-1.5 mg/kg/day as a

slow IV infusion. Providers were allowed to switch amphotericin

patients to other licensed antifungal treatments if the initial drug

failed or if the patient became intolerant. The researchers found that

patients receiving voriconazole were more likely to continue

treatment. Significantly better response rates were noted in patients

receiving voriconazole, compared with those receiving amphotericin B

(53% vs 32%, P < .05). In addition, voriconazole therapy was

associated with significantly better survival rates, compared with

amphotericin B. This survival benefit has not been reported with any

other antifungal therapy, compared with amphotericin B.

In another study, significantly fewer cases of breakthrough invasive

fungal infections were experienced in vori-conazole-treated patients,

compared with liposomal amphotericin B treated patients (8 vs 21,

respectively), for empiric antifungal therapy in patients with

persistent fever and neutropenia.2-4

Safety

Available clinical evidence suggests that voriconazole-associated risk

includes mild and transient visual abnormalities, hepatic function

abnormalities, skin reactions, and potential for drug interactions.

Abnormal vision is dose related and was reported in approximately 30%

of patients However, altered vision tended to persist for only 30

minutes after the dose, with only 0.5% of patients requiring

voriconazole discontinuation.2,3,5

Outlook

Fungal infections occur in severely ill, immunocompromised patients

and are associated with high morbidity and mortality. Voriconazole is

an effective agent for the treatment of aspergillosis and Candida

infections. Voriconazole should be considered in immunocom-promised

patients when invasive fungal infection caused by aspergillosis,

candidiasis, Scedosporium, or Fusarium is suspected. It also should be

considered in documented fungal infections in patients with persistent

fever and neutropenia when a broader spectrum of coverage is required

than that which fluconazole provides.