Fluconazole Tablets

Mechanism

Fluconazole is a highly selective inhibitor of fungal cytochrome P 450 dependent enzyme lanosterol 14-α-demethylase.This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition Activity. In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

• Candida albicans
• Candida glabrata (many strains are intermediately susceptible)
• Candida parapsilosis
• Candida tropicalis
• Cryptococcus neoformans

Pharmacokinetics

The bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20–50 hours) after oral administration. The Cmax and AUC data from a food-effect study involving administration of Fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals. Steady-state concentrations are reached within 5–10 days following oral doses of 50–400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11–12%). Following either single- or multiple oral doses for up to 14 days.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole is markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

Side Effects

• Nausea
• Headache
• Abdominal pain
• Diarrhea
• Skin rash

Contraindication

• Hypersensitivity to fluconazole or other azoles
• Severe liver disease (use with caution)
• Concurrent use with drugs causing QT prolongation

Interaction

• Warfarin (increased bleeding risk)
• Phenytoin (increased levels)
• Oral hypoglycemics
• CYP450 substrates (increased drug levels)

Warning and Precautions

• Monitor liver function
• Use cautiously in renal impairment
• Avoid in pregnancy unless necessary
• Complete full course of treatment