Indication
Voriconazole is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows:
Treatment of invasive aspergillosis.
Treatment of candidaemia in non-neutropenic patients.
Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).
Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.
Voriconazole should be administered primarily to patients with progressive, possibly life-threatening infections. Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.
Pharmacology
The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-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 membrane 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.
Dosage
Oral-Therapy must be initiated with the specified loading dose regimen of either intravenous or oral voriconazole to achieve plasma concentrations on day 1 that are close to steady state. On the basis of the high oral bioavailability (96%), switching between intravenous and oral administration is appropriate when clinically indicated. Detailed information on dosage recommendations is provided in the following table:Loading dose regimen (first 24 hours)-
Patients 40 kg and above: 400 mg every 12 hours.
Patients less than 40 kg: 200 mg every 12 hours.
Maintenance dose (after first 24 hours)-
Patients 40 kg and above: 200 mg twice daily.
Patients less than 40 kg: 100 mg twice daily.
Injection-Invasive Aspergillosisd :
Loading dose: 6 mg/kg 12 hourly for the first 24 hours.
Maintenance Dose: 4 mg/kg 12 hourly.
Candidemia in nonneutropenic patients and other deep tissue Candida infections:
Loading dose: 6 mg/kg 12 hourly for the first 24 hours.
Maintenance Dose: 3-4 mg/kg 12 hourly.
Scedosporiosis and Fusariosis:
Loading dose: 6 mg/kg 12 hourly for the first 24 hours.
Maintenance Dose: 4 mg/kg 12 hourly.
Interaction
CYP3A4, CYP2C9 and CYP2C19 inhibitors and inducers: Adjust Voriconazole dosage and monitor for adverse reactions or lack of efficacy.
Voriconazole may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions.
Phenytoin or Efavirenz: with co-administration, increase maintenance oral and intravenous dosage of Voriconazole.
Contradiction
Voriconazole is contraindicated in patients with known hypersensitivity to the drug or other azoles.
Side Effect
Most common adverse reactions: visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations.
Pregnancy
There are no adequate data on the use of voriconazole in pregnant women available. Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.?ÿThe excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with voriconazole.
Precaution
Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to voriconazole.
Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term voriconazole treatment.
Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis voriconazole discontinuation should be considered after multidisciplinary advice.
Overdose
In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported. There is no known antidote to voriconazole. Voriconazole is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole and SBECD from the body
Storage
Keep below 30?øC temperature, away from light & moisture. Keep out of the reach of children.