Voriconazole

Voriconazole is a triazole medicine used to treat fungal infections. It is effective against a broad spectrum of fungi and is usually reserved for the treatment of serious Candida and mould infections. It is indicated for the treatment of the following infections:

• Fluconazole-resistant serious invasive Candida infections (including C. krusei)
• Oesophageal candidiasis
• Invasive aspergillosis
• Serious fungal infections caused by Scedosporium spp. and Fusarium spp.
• Other serious fungal infections, in patients intolerant of, or unresponsive to, other therapy

In New Zealand, voriconazole is available as 50 mg and 200 mg tablets, 45 g bottle of powder to make a 40 mg/ml oral suspension, and as 200 mg lyophilised powder for intravenous injection. The trade name for voriconazole is VFEND® and is only available with a doctor’s prescription.

Voriconazole binds to the fungal p450 enzymes and stops the cells making ergosterol, the main component of the cell wall.

Pharmacokinetics of voriconazole

Voriconazole is rapidly and almost completely absorbed following oral administration. It is widely distributed in body tissues. The terminal half-life (for half of the medication to be cleared from the bloodstream) of voriconazole is dose-dependent and is approximately 6 hours for a 200 mg oral dose. Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of accumulation or elimination of voriconazole. Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

Dose regime for voriconazole

Intravenous or oral administration can be given to treat fluconazole-resistant serious invasive Candida infections, invasive aspergillosis, Scedosporium and Fusarium infections and other serious fungal infections. The recommended adult dose is:

• IV – 6 mg/kg every 12 hr (for first 24 hr) followed by 4mg/kg every 12 hr
• Oral
  • patients > 40 kg – 400 mg every 12 hr (for first 24 hr) followed by 200mg twice daily
  • patients < 40 kg – 200mg every 12 hr (for first 24 hr) followed by 100 mg twice daily

Oesophageal candidiasis is normally treated with oral voriconazole using the same oral doses as for other infections above.

If clinical response is inadequate, the oral maintenance dose may be increased to 300 mg twice daily in patients > 40 kg and 150 mg twice daily in patients < 40 kg.

The dosage for children aged 2 to < 12 years is 6 mg/kg every 12 hr (for first 24 hr) followed by 4 mg/kg every 12 hr administered either intravenously or orally.

How to take voriconazole

• Voriconazole should be taken at least one hour before or one hour after a meal.
• Tablets should be swallowed whole with a full glass of water.
• Voriconazole should be taken regularly at about the same time each day.
• Voriconazole should be continued for the full course, even if symptoms improve, as this can occur before the infection is completely cleared.
• The suspension must be shaken before measuring the dose. Do not refrigerate or freeze suspension and discard any unused suspension after 14 days.

What are the side effects of voriconazole?

The more common side effects of voriconazole are usually mild and short-lived. These include:

• Nausea and vomiting
• Headache
• Stomach pain, indigestion, diarrhoea
• Swelling or water retention of the arms or legs
• Blurred vision, increased eye sensitivity to light
• Soreness at the injection site
• Photosensitivity resulting in unexpected sunburn on exposed skin

An increased risk of squamous cell carcinoma has been reported in patients taking voriconazole long term. This is of particular concern in patients at high risk of squamous cell carcinoma, such as elderly white-skinned persons that are immune suppressed (eg, organ transplant recipients).

If any of the following serious side effects occur, voriconazole should be stopped and emergency medical attention sought immediately:

• An allergic reaction (swelling of the face, lips or tongue, hives, difficulty breathing)
• Sudden or severe itching, skin rash, hives or blisters, flaking of the skin
• Asthma, wheezing, shortness of breath
• Fainting, seizures or fits.

Voriconazole should not be taken in pregnancy except in patients with severe or potentially life-threatening fungal infections and the benefit to the mother clearly outweighs the potential risk to the fetus. Use during breast-feeding is not generally recommended, as it is not known whether voriconazole is excreted in breast milk.

What are the drug interactions with voriconazole?

Voriconazole is known to interact with many other medications. Voriconazole is metabolised by cytochrome P450 isoenzymes, hence inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole also inhibits cytochrome P450 isoenzyme activity and has the potential to increase the plasma level of drugs also metabolised by these isoenzymes.

Contraindications (do not take with voriconazole)

• Rifampicin
• Sirolimus
• Long-acting barbiturates 
• Carbamazepine 
• Astemizole 
• Cisapride 
• Terfenadine 
• Pimozide 
• Quinidine 
• Ergot alkaloids 
• Ritonavir 
• Efavirenz

Adjust dose of voriconazole

• Phenytoin 
• Rifabutin

Adjust the dose of voriconazole and/or monitor other drugs

• Ciclosporin
• Tacrolimus
• Omeprazole 
• Warfarin 
• Phenytoin 
• Sulphonylureas 
• Rifabutin 
• Statins 
• Benzodiazepines 
• Vinca alkaloids 
• Nevirapine 
• HIV protease inhibitors (excluding indinavir and ritonavir)

No dose adjustment of voriconazole or other drug required

• Indinavir 
• Mycophenolate mofetil
• Cimetidine 
• Ranitidine 
• Macrolides eg erythromycin
• Prednis(ol)one
• Digoxin

Antifungal drug resistance

In recent years, both topical and oral allylamine and triazole antifungal drug resistance has become a problem, particularly in the Indian subcontinent.

Extensive therapy-resistant dermatophyte infection should prompt this as a possible problem. Where available, fungal culture and estimation of drug minimum inhibitory concentration determined to guide appropriate medication

For more information, see antifungal drug resistance.