Voriconazole (Vfend ®)

Mechanism of Action
Voriconazole is a triazole antifungal 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.

Activity In Vitro
Voriconazole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.

Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In clinical studies, the voriconazole MIC90 was 4 µg/mL) [1*]
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum

The following data are available, but their clinical significance is unknown.

Voriconazole exhibits in vitro minimal inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of voriconazole in treating clinical infections due to these Candida species have not been established in adequate and well-controlled clinical trials:

Candida lusitaniae
Candida guilliermondii

*1. In clinical studies, voriconazole MIC90 for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 µg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC90 was 1 µg/mL

VFEND is indicated for use in the treatment of the following fungal infections:

Invasive aspergillosis. In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus.

Candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds.

Esophageal candidiasis.

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.

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Administration

VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, 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 1–2 hours (see Intravenous Administration).

NOT FOR IV BOLUS INJECTION

Use of VFEND I.V. with other Parenteral Drug Products

Blood products and concentrated electrolytes
VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of VFEND therapy (see PRECAUTIONS).

Intravenous solutions containing (non-concentrated) electrolytes
VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN)
VFEND I.V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V.

Use in Adults
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Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum

For the treatment of adults with invasive aspergillosis and infections due to Fusarium spp. and Scedosporium apiospermum, therapy must be initiated with the specified loading dose regimen of intravenous VFEND to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of high oral bioavailability, switching between intravenous and oral administration is appropriate when clinically indicated (see package insert for CLINICAL PHARMACOLOGY). Once the patient can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized. (See Table below.)

Candidemia in nonneutropenic 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

Infection	Loading dose	Maintenance Dose
	IV	IV	Oral*
Invasive Aspergillosis	6 mg/kg q12h for the first 24 hours	4 mg/kg q12h	200 mg q12h
Candidemia in nonneutropenic patients and other deep tissue Candida infections	6 mg/kg q12h for the first 24 hours	3–4 mg/kg q12h †	200 mg q12h
Esophageal Candidiasis	‡	‡	200 mg q12h
Scedosporiosis and Fusariosis	6 mg/kg q12h for the first 24 hours	4 mg/kg q12h	200 mg q12h
*Patients who weigh 40 kg or more should receive an oral maintenance dose of 200 mg VFEND every 12 hours. Adult patients who weigh less than 40 kg should receive an oral maintenance dose of 100 mg every 12 hours. † In clinical trials, patients with candidemia received 3 mg/kg q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. ‡ Not evaluated in patients with esophageal candidiasis.

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Dosage Adjustment
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If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patients are unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

If patients are unable to tolerate 4 mg/kg IV, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

Phenytoin may be coadministered with VFEND if the intravenous maintenance dose of VFEND is increased to 5 mg/kg every 12 hours, or the oral maintenance dose is increased from 200 mg to 400 mg every 12 hours (100 mg to 200 mg every 12 hours in adult patients weighing less than 40 kg) (see package insert: CLINICAL PHARMACOLOGY, PRECAUTIONS - Drug Interactions).

When voriconazole is coadministered with efavirenz, the voriconazole maintenance dose should be increased to 400 mg Q12h and the efavirenz dose should be decreased to 300 mg Q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see package insert: CLINICAL PHARMACOLOGY and PRECAUTIONS – Drug Interactions).

Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

Use in Geriatric Patients
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No dose adjustment is necessary for geriatric patients.

Use in Patients with Hepatic Insufficiency
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In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended.

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B).

VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

Use in Patients with Renal Insufficiency
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The pharmacokinetics of orally administered VFEND are not significantly affected by renal insufficiency. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment (see package insert: CLINICAL PHARMACOLOGY - Special Populations).

In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see DOSAGE and ADMINISTRATION).

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.