Fluconazole (Diflucan, Pfizer) is a synthetic compound known as a bis-triazole. It was first used in patients 1994/95 and licensed for use in 1990. It went off patent in 2003. It works by inhibiting the production of ergosterol, a central chemical in the cell walls of fungi.
Dose & Delivery
The drug is available as a capsule, oral suspension and intravenous infusion. A typical dose for oral thrush is 100mg per day. The typical dose for vaginal thrush is a 150mg per day. For the prevention of fungal infections in leukaemia, doses from 50-400mg per day have been used and studied. Most authorities recommend between 100 and 400mg. For the treatment of candidemia and other serious Candida infections a minimum dose of 400mg per day (after a loading dose of 800mg) is recommended with increased doses in patients on haemofiltration and/or rifampicin (see below). Some authors have suggested that 800mg is superior for candidaemia, but the data is not compelling. For the treatment of cryptococcal meningitis after amphotericin B, a minimum of 400mg per day initially is used until the patient is stable and then typically 200mg per day. Much larger doses e.g. 800-1200mg per day should be used as an alternative primary regimen (preferably with flucytosine) or for patients failing therapy. Larger doses such as 800-1200mg per day have been used for coccidioidal meningitis. Almost all other treatments have been for 100-400mg per day. Reduced doses may be appropriate in severe renal dysfunction.
Fungi the drug is active against:
Fluconazole is active against most Candida species, with the absolute exception of Candida krusei and partial exception of Candida glabrata and a small number of isolates of Candida albicans, Candida tropicalis, Candida parapsilosis and other rare species. It is also active against the vast majority of Cryptococcus spp. isolates. It is active against many other yeasts including Trichosporon spp., Rhodotorula rubrum, and the dimorphic endemic fungi including Blastomyces dermatitidis, Coccidioides spp., and Histoplasma spp. It is less active than itraconazole against these dimorphic fungi. It is not active against Aspergillus spp. or Mucorales. It is active against skin fungi such as Trichophyton spp.
Some fluconazole resistance is documented in Candida albicans, especially among oral isolates in patients with AIDS treated with fluconazole. Typical rates of resistance, in Candida albicans in a general hospital are 3-6%.
Metabolism distribution and excretion.
Fluconazole is water soluble, well absorbed after oral administration and serum concentration parallels dose. Babies and children, especially those with fevers, have accelerated metabolism. Most of the drug is excreted in the urine; very little is metabolised by the liver. The drug penetrates well into cavities such as around the brain, the eyes, saliva and urine. A maximum 17% of the dose is excreted in breast milk in lactating women, with minimal or no side effects in babies exposed to it.
Drug/ Drug interactions
There are very few drug/drug interactions with fluconazole. The most profound is with rifampin (rifampicin) and phenytoin which accelerate the metabolism of fluconazole in liver and reduce serum levels. In addition fluconazole can cause a rise in serum levels of phenytoin and diabetic drugs, such as chlorpropamide, glibenclamide, glipizide and tolbutamide and warfarin. It also increases cyclosporin levels slightly. More details on interactions provided here. Link to drug interaction database.
Fluconazole is generally well tolerated, and is probably the least toxic of all the systemic antifungal drugs. Its common side effects are nausea and abdominal discomfort; raised liver function tests occasionally occur. Skin rashes occur in up to 1 in 20 patients and these may be severe in rare cases. There are no endocrine effects of fluconazole. Fluconazole should not be given in pregnancy.