Itraconazole inhibits CYP-mediated drug metabolism similar to ketoconazole but to less of an extent.²⁵ However drug-drug interactions with itraconazole may include those listed for ketoconazole. Itraconazole, similar to ketoconazole, is also a Pgp efflux pump inhibitor.¹¹ Itraconazole absorption is decreased when the drug is administered with gastric acid suppression treatment, so it should not be administered concurrently. Itraconazole has a negative inotropic effect, which may lead to congestive heart failure in patients with impaired ventricular function.¹⁶ Long-term administration of phenobarbital increases itraconazole metabolism and may require increased dosages to maintain similar efficacy.

FLUCONAZOLE

Fluconazole is available as tablets (50, 100, 150, and 200 mg) and as a 10-mg/ml suspension. The typical cost of fluconazole for a 44-lb dog (10 mg/kg orally once a day) is about 50¢/day.

Fluconazole has similar antifungal activity to itraconazole with a few notable exceptions. Typically, Aspergillus and Microsporum species are resistant to fluconazole.²⁶ Malassezia species are less sensitive to fluconazole than to other azoles.²⁷ Leishmania species may be more sensitive to fluconazole than to itraconazole, although extensive efficacy studies are lacking.¹⁷ Fluconazole is the treatment of choice for Cryptococcus species CNS infections because of the high drug concentrations achieved in the CNS.¹⁶

Pharmacokinetics

In contrast to the other antifungals, fluconazole exhibits low plasma protein binding (about 11%) in all species evaluated.²⁸ Limited studies have been done on the pharmacokinetics of fluconazole in dogs. In a study evaluating two dogs, fluconazole was completely absorbed after oral administration with a 15-hour half-life. The maximum plasma concentration (C_MAX) achieved in dogs was about 10 μg/ml at about four hours (T_MAX; the time to maximum plasma concentration) after 10 mg/kg was administered orally. In contrast to itraconazole and ketoconazole, fluconazole is well-absorbed in the fasted state.¹⁶ Greater than 70% of the dose was eliminated in the urine of dogs as unchanged drug.²⁸

The pharmacokinetics of fluconazole in cats is similar to that in dogs: a C_MAX of 12.9 μg/ml at a T_MAX of 1.3 hours with complete absorption after oral administration (10.8 mg/kg) and a terminal half-life of about 24 hours.²⁹ Fluconazole penetrates the cerebrospinal fluid, aqueous humor, and bronchial epithelial fluid well.²⁹

Drug interactions and adverse effects

Fluconazole is generally well-tolerated, but adverse effects similar to those of the other azoles can occur,¹ including nausea, anorexia, and vomiting. Severe hepatic reactions have been reported in people, so serum hepatic enzyme activities should be routinely monitored before and during long-term therapy.¹⁶ Rare hematologic adverse effects including anemia, thrombocytopenia, leukopenia, and neutropenia have been reported in people.

Fluconazole use during pregnancy is generally not recommended, as there are conflicting data on its mutagenic or teratogenic potential.^16,30 Fluconazole is excreted in milk, so it is not recommended to be administered to lactating animals.¹⁶

Fluconazole absorption is not affected by decreased gastric acidity, so concurrent administration with gastric acid suppression treatment is not expected to affect absorption.¹⁶ Fluconazole exhibits a slightly different CYP inhibitory profile than ketoconazole and itraconazole, so some differences in drug-drug interactions are expected. In people, the metabolism of cyclosporine, buspirone, warfarin, quinidine, and some benzodiazepines has been decreased when they are concurrently administered with fluconazole.¹⁶