FLUCONAZOLE

Chemistry - A synthetic triazole antifungal agent, fluconazole occurs as a white crystalline powder.
It is slightly soluble (8 mg/ml) in water.

Storage, Stability, Compatibility

Fluconazole tablets should be stored at temperatures less than30°C in tight containers. Fluconazole injection should be stored at temperatures from 5-30°C (5-25°C for the Viaflex® bags); avoid freezing. Do not add additives to the injection.

Pharmacology - FLUCONAZOLE

Fluconazole is a fungistatic triazole compound. Triazole-derivative agents, like theimidazoles (clotrimazole, ketoconazole, etc.), presumably act by altering the cellular membranes ofsusceptible fungi, thereby increasing membrane permeability and allowing leakage of cellularcontents and impaired uptake of purine and pyrimidine precursors. Fluconazole has efficacy againsta variety of pathogenic fungi including yeasts and dermatophytes. In vivo studies using laboratorymodels have shown that fluconazole has fungistatic activity against some strains of Candida,
Cryptococcus, Histoplasma and Blastomyces. In vivo studies of efficacy against Aspergillus strainshave been conflicting.
Uses, Indications - Fluconazole may have use in veterinary medicine in the treatment of systemicmycoses, including cryptococcal meningitis, blastomycosis, and histoplasmosis. It may also beuseful for superficial candidiasis or dermatophytosis. Because of the drug's unique pharmacokinetic qualities it is probably more useful in treating CNS infections than other azole derivatives.
Fluconazole does not have appreciable effects (unlike ketoconazole) on hormone synthesis and mayhave fewer side effects than ketoconazole in small animals.

Pharmacokinetics - FLUCONAZOLE

Fluconazole is rapidly and nearly completely absorbed (90%) after oral administration. It has low protein binding and is widely distributed throughout the body and has goodpenetration into the CSF, eye, and peritoneal fluid. Fluconazole is eliminated primarily via thekidneys and achieves high concentrations in the urine. In humans, fluconazole's serum half life isabout 30 hours in patients with normal renal function. Patients with impaired renal function mayhave half-lives extended significantly and dosage adjustment may be required.

Contraindications, Precautions, Reproductive Safety

Fluconazole should not be used in patients hypersensitive to it or other azole antifungal agents and in patients with hepatic impairmentonly when the potential benefits outweigh the risks. Because fluconazole is eliminated primarily bythe kidneys, fluconazole doses or dosing intervals may need to be adjusted in patients with renalimpairment.
Safety during pregnancy has not been established and it is not recommended to be used in pregnant animals unless the benefits outweigh the risks.

Adverse Effects, Warnings

At the time of writing there is limited experience with this drug indomestic animals. Thus far, it appears to be safe to use in dogs. In humans, the side effects havebeen generally limited to occasional GI effects (vomiting, diarrhea, anorexia/nausea), and headache.
Rarely, increased liver enzymes and hepatic toxicity, exfoliative skin disorders, andthrombocytopenia have been reported.

Overdosage, Acute Toxicity

There is very limited information on the acute toxicity of fluconazole. Rats and mice survived doses of 1 g/kg, but died within several days after receiving 1-2 g/kg.
Rats and mice receiving very high dosages demonstrated respiratory depression, salivation, lacrimation, urinary incontinence, and cyanosis. If a massive overdose occurs, consider gutemptying and give supportive therapy as required. Fluconazole may be removed by hemodialysis orperitoneal dialysis.

Drug Interactions

Lab animal studies have shown that fluconazole used concomitantly withamphotericin B may have additive activity against Candida, indifferent effects on Cryptococcusand the effects may be antagonistic against Aspergillus. The clinical importance of these findings isnot yet clear.
Fluconazole may cause increased prothrombin times in patients receiving warfarin or othercoumarin anticoagulants. Rifampin may enhance the rate of metabolism of fluconazole; fluconazole dosage adjustment may be required. Fluconazole may increase the serum levels of oral antidiabetic agents (e.g., chlorpropamide, glipizide, etc.) which may result in hypoglycemia.
Fluconazole may decrease the metabolism of phenytoin or cyclosporin. Veterinary significanceis unclear.
Fluconazole may increase the risks of cardiovascular effects occurring if used concomitantly witheither terfenadine or astemizole. If fluconazole is required, it is best to switch to anotherantihistamine.