General Information

Vfend (voriconazole) is an azole antifungal.

Vfend is indicated for the treatment of adults and pediatric patients 2 years of age and older with:

• Invasive aspergillosis 

• Candidemia in non-neutropenics and other deep tissue Candida infections 

• Esophageal candidiasis

• Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy

Vfend is supplied as tablets, oral suspension and intravenous injection. The recommended dosing is as follows:

Administer Vfend Tablets or Oral Suspension at least one hour before or after a meal.

Vfend I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

Administer diluted Vfend I.V. by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.

Recommended Dosing Regimen in Adults

Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum. See drug prescription label for specific dosing recommendations and modifications.

• See table below. Therapy must be initiated with the specified loading dose regimen of intravenous Vfend on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of Vfend may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults 

Candidemia in non-neutropenic patients and other deep tissue Candida infections

• See table below. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

• See table below. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Recommended Dosing Regimen in Pediatric Patients

The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in the table below. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of Vfend.

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The oral dose recommendation for children is based on studies in which Vfend was administered as the powder for oral suspension formulation. Bioequivalence between the Vfend powder for oral suspension and Vfend tablets has not been investigated in a pediatric population.

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous Vfend administration is recommended.

Mechanism of Action

Voriconazole is a triazole anti-fungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. 

Side Effects

Adverse events (regardless of cause) reported in clinical testing include the following:

• Visual disturbances
• Fever
• Rash
• Vomiting
• Nausea
• Diarrhea
• Headache
• Sepsis
• Peripheral edema
• Abdominal pain
• Respiratory disorder

Elevated liver function tests, rash and visual disturbances were the treatment-related adverse events that most often led to discontinuation of Vfend therapy.

Clinical Trial Results

Vfend has been evaluated as primary or salvage therapy in 520 subjects (12 years of age and older) with infections caused by Aspergillus spp., Fusarium spp. and Scedosporium spp.

Invasive Aspergillosis

The effectiveness of Vfend as a primary therapy for invasive aspergillosis was evaluated in a randomized and controlled trial (Study 307/602). The 277-subject trial was designed to compare treatment with amphotericin B, an approved anti-fungal medication, to treatment with Vfend. The trial included subjects with solid organ transplantation, solid tumors and AIDS.

Study results demonstrated that at 12 weeks, a satisfactory global response was observed in 53% of Vfend-treated subjects, compared to 32% of amphotericin B-treated subjects. Additionally, the survival rate for Vfend treatment at Day 84 was 71%, compared to 58% for amphotericin B .

Other Disease-Causing Agents

In pooled analyses of subjects, Vfend was shown to be effective against both Scedosporium apiospermum and Fusarium spp. For Scedosporium apiospermum, a successful response to Vfend was reported in 15 of 24 subjects (63%). In those with Fusarium spp., nine of 21 (43%) were successfully treated with Vfend.

Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.