Flucon Drug Interactions

The following drug interactions relate to the use of multiple-dose fluconazole; their relevance to single-dose fluconazole has not yet been established.
Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12 %) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melaena) have been reported in association with increases in prothrombin time, in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored.
Benzodiazepines (short acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole, than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored.
Endogenous steroids: Fluconazole 50 mg daily does not affect endogenous steroid levels in females: 200-400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.
Sulphonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be given jointly to diabetic patients, although the possibility of a hypoglycaemic episode must be considered. Blood glucose levels must therefore be monitored and the dose of sulphonylurea adjusted accordingly.
Hydrochlorothiazide: In a pharmacokinetic interaction study, the co-administration of multiple doses of hydrochlorothiazide in healthy volunteers receiving fluconazole, increased the plasma concentrations of fluconazole by 40 %. An effect of this magnitude should not require any change in the dosage regimen of fluconazole in patients simultaneously receiving diuretics, although this should be taken into consideration by the prescriber.
Phenytoin: The concomitant administration of fluconazole and phenytoin may increase levels of phenytoin to a clinically significant degree. If both drugs need to be given concomitantly, levels of phenytoin must be monitored and the dose of phenytoin adjusted to maintain therapeutic levels.
Oral contraceptives: Two pharmacokinetic studies were conducted with combined oral contraceptives and multiple fluconazole doses. In the study using 50 mg fluconazole, there were no relevant effects on hormone level. However, using 200 mg fluconazole daily, the area under the curve (AUC) for ethinyloestradiol and levonorgestrel, increased by 40 % and 24 % respectively. Thus, multiple dose use of fluconazole at these levels is unlikely to affect the efficacy of combined oral contraceptives.
Rifampicin: The concomitant administration of fluconazole and rifampicin gave rise to a 25 % reduction in the AUC and a 20 % shorter half-life of fluconazole. Thus, an increase in the dose of fluconazole should be considered for patients receiving concomitant rifampicin.
Cyclosporin: A pharmacokinetic study conducted on kidney transplant patients, showed that a daily dose of 200 mg fluconazole slowly increased the concentrations of cyclosporin. However, another multiple-dose study using 100 mg fluconazole daily, showed that levels of cyclosporin were not affected in patients following bone marrow transplants. Thus, the monitoring of the plasma concentration of cyclosporin is recommended in patients taking fluconazole.
Theophylline: In a placebo-controlled interaction study, the administration of 200 mg fluconazole daily for 14 days, led to a reduction of 18% in the mean plasma clearance figure of theophylline. Therefore, patients receiving high doses of theophylline or patients with high risk of theophylline toxicity, should be carefully monitored for signs of theophylline toxicity when receiving fluconazole. Treatment should be appropriately modified if signs of toxicity develop.
Terfenadine: Due to the occurrence of serious dysrrhythmias (secondary to prolongation of the QTc interval), in patients receiving other azole antifungals in conjunction with terfenadine, interaction studies have been performed. In one study, a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. In another study, a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole, taken in multiple doses of 400 mg per day or greater, significantly increased plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness and chest pain in patients taking concomitant fluconazole and terfenadine, where the relationship of the reported adverse events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, it is recommended that terfenadine should not be taken in combination with fluconazole.
Cisapride: There have been reports of cardiac events including torsades de pointes, in patients to whom fluconazole and cisapride were co-administered. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. There have been no formal drug interaction studies with fluconazole and cisapride. Because of the potential seriousness of such an interaction, it is recommended that cisapride is not taken in combination with fluconazole.
Zidovudine: Two pharmacokinetic studies have shown increases in levels of zidovudine, caused very probably by the fall in the conversion of zidovudine to its main metabolite. One study determined the levels of zidovudine in AIDS or ARC patients, before and after the daily administration of 200 mg fluconazole for 15 days. A significant increase was observed in the zidovudine AUC (20%). A second randomised two-period, two-treatment crossover study, examined the levels of zidovudine in patients infected with HIV. On two occasions, with an interval of 21 days, patients received 200 mg zidovudine every 8 hours, either with or without 400 mg of fluconazole daily, for 7 days. The AUC of zidovudine increased significantly (74%) during joint administration with fluconazole. Therefore, patients receiving this combination should be monitored for the appearance of adverse reactions related to zidovudine.
Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have also been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.
Tacrolimus: There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have also been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.
The use of fluconazole in patients concurrently taking astemizole or other drugs metabolised by the cytochrome P450 system, may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering fluconazole. Patients should be carefully monitored.
While no interaction studies have been conducted with other drugs, the possible appearance of other pharmacological interactions is not ruled out.