Fungal Infections

Voriconazole

Voriconazole (Vfend) (Pfizer) was approved in 2002 for the treatment of invasive aspergillosis, Fusarium and Scedosporium infections as well as the treatment of resistant candidiasis. It is referred to as a second generation triazole. Structurally it has some resemblance to fluconazole its activity but its handling by the body and antifungal spectrum is completely different. It interferes with fungal biosynthesis of ergosterol like all azoles, by interfering with the activity of 14alpha demethylase.

Dose & Delivery          

Oral, intravenous and ocular preparations of voriconazole are available. For intravenous usage a loading dose of 6mg/Kg twice at 12 hour intervals is recommended for life threatening infections in adults, followed by 4mg/Kg twice daily. The dose in children should be 7mg/Kg twice daily intravenously although very young children may require proportionately larger doses, because of rapid clearance. If drug-monitoring facilities are available the dose can be altered on the basis of blood levels. Bioavailability is nearly 100% so oral dosing can be relied upon, which is usually 200mg twice daily. Lower treatment doses should be given to adults weighing less than 40Kg, elderly people and any with prior liver disease to minimise the chance of high levels and toxicity. Dose increases result in disproportionate increase in drug exposure in adults, but not children, because the pharmacokinetics of voriconazole is not linear in adults.

Fungi the drug is active against

Voriconazole has a broad spectrum of activity. It is active against the vast majority of Candida spp., Cryptococcus spp., all Aspergillus species, Scedosporium apiospermum, some isolates of Fusarium many rather rare pathogens. It is not active against Mucorales species such as Mucor spp., Rhizopus spp., Rhizomucor spp., and others.

Typical regimens          

Invasive aspergillosis – 6mg/Kg twice (loading) followed by 3-4 mg/Kg twice daily followed by 200mg twice daily orally, in adults; proportionally larger doses in children.

Metabolism and excretion        

Voriconazole is metabolised by the liver. The most important enzymes involved in this metabolism are CYP 2C19, CYP 3A4 and CYP 2C9. Genetic variation between different individuals, particularly with CYP 2C19, partially affects the rate at which the drug is metabolised. Slow metabolisers are found in about 3% of Caucasians and in approximately 20% of patients from Japan and other parts of Asia. These patients may accumulate drug and sometimes very high concentrations are found in the blood. Elderly people and those with moderate or severe liver disease are also slow metabolisers.

Young children appear to metabolise the drug very fast and older children and teenagers quite fast. It is necessary to increase the dose in children.

Drug/Drug interactions 

As with most azoles there are a substantial number of drug drug interactions with voriconazole. Drugs, which reduce the effective exposure of voriconazole, include rifampicin, refabutin (less marked), phenytoin and carbamazapine. Interactions with other drugs result in increased exposure to those drugs including some antihistamines (terfenadine and astemizole), prednisolone, sirolimus, cyclosporin (halve the dose), tacrolimus (reduce dose to one third), ergotamine, warfarin, sulphonylureas, statins, midazolam and other benzodiazepines, vincristine and some HIV drugs. A few drugs reduce the metabolism of voriconazole, including omeprazole and probably other proton pump inhibitors. View drug interactions database.

Side effects      

Perhaps the most common side effect associated with voriconazole is visual side effects. Patients describe wavy lines, mild blurred vision or bright lights in the first few days after taking voriconazole, which typically lasts a few minutes. Extensive investigations have not unearthed the precise mechanism but the side effect wears off over time and only rarely has their been any long term damage to the eye.

Some patients develop abnormal liver function tests with voriconazole and if these are remarkably elevated then the drug should be stopped.

High concentrations result in reduced concentration, and sensation of a ‘muzzy head’, and sometimes hallucinations and frank confusion. Peripheral neuropathy also occurs after some months of therapy in a small minority of patients.

Occasional serious side effects have occurred in patients with very high concentrations of voriconazole. The long term usage of voriconazole may lead to reddening of exposed skin, especially the face, dry eyes and dryness of the lips, in those with white skin. Sunscreen (SPF 50) is advised for all white patients as well as avoidance of sunny environments such as conservatories. UV protective film can be used on car windows. View video "Antifungal skin reactions" and video "Neurological toxicity"

Other information         

Detailed information is available in the treatment section of the Aspergillus website.


Structure of voriconazole

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