vFEND

	Loading Dose		Maintenance
	>40KG	<40KG	>40KG	<40KG
Aspergillosis	400mg q12h	200mg q12h	200mg BID	100mg BID
Candidemia/Candidiasis	As above	As above	As above	As above

Treatment duration depends upon the patient's clinical and mycological response. Patients with candidemia should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

 

Administration

·        VFEND (voriconazole) Tablets should be taken at least one hour before, or two hours following, a meal.

Absorption

·        Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing.

 

Mechanism of Action

·        VFEND (voriconazole) is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in ergosterol biosynthesis. The subsequent loss of normal sterols correlates with the accumulation of 14α-methyl sterols in fungi and may be responsible for its fungistatic/fungicidal activity.

 

QT Interval Prolongation

VFEND (voriconazole) has been associated with prolongation of the QT interval of the electrocardiogram in some patients. Prolongation of QT interval may increase the risk of arrhythmia, cardiac arrests and sudden deaths.

·        Due to limited clinical experience, voriconazole should be administered with caution to patients with potentially proarrhythmic conditions such as hypokalemia, clinically significant bradycardia, acute myocardial ischemia, congestive heart failure or congenital prolongation of QT.

·        Caution should be exercised if voriconazole is used in patients taking other drugs that may prolong the QT interval, such as antipsychotics, tricyclic antidepressants, erythromycin, Class IA (e.g. procainamide, quinidine) Class III (e.g. amiodarone, sotalol) antiarrythmic agents.

·        Drugs metabolized by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4 may also affect, or be affected by, voriconazole levels, with possible resulting QT effects. Such drugs include tacrolimus, HIV protease inhibitors, and macrolide antibiotics.

 

Ophthalmologic

·        Voriconazole may cause visual symptoms including photophobia altered/enhanced visual perception, blurred vision and/or color vision change. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. The effect of VFEND (voriconazole) on visual function is not known if treatment continues beyond 28 days. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored.

 

Effects on Ability to Drive and Operating Machines

·        Voriconazole may cause visual symptoms including blurring and/or photophobia. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes.

 

Hepatic

·        In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (including clinical hepatitis, cholestasis, and fulminant hepatic failure, including fatalities).. Liver dysfunction has usually been reversible on discontinuation of therapy.

Renal

·        Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.

 

 

Skin

There have been cases of exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole. Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia). Patients should be closely monitored at the first appearance of a skin rash and voriconazole should be discontinued if lesions progress. Photosensitivity reactions have been observed. It is recommended that patients avoid strong sunlight.

 

Adverse Drug Reaction Overview

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances.

 

Visual Disturbances

·        Voriconazole treatment related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced altered/enhanced visual perception, blurred vision, color vision change and/or photophobia. The visual disturbances were generally mild and rarely resulted in discontinuation. Visual disturbances may be associated with higher plasma concentrations and/or doses.

·        The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes.

 

Dermatological Reactions

·        Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. In clinical trials, rashes considered related to therapy were reported by 7% (110/1655) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long term treatment. Patients have developed serious cutaneous reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole. Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia).

·        Patients should be closely monitored at the first appearance of a skin rash and voriconazole should be discontinued if lesions progress. It is recommended that patients avoid strong, direct sunlight during voriconazole therapy.