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Anticoagulants: In an interaction study, fluconazole increased the prothrombin time after warfarin administration in healthy males. Though the magnitude of change was small (12%), careful monitoring of prothrombin time in patients receiving coumarin-type anticoagulants is recommended.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.
Hydrochlorothiazide: In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Phenytoin: Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Oral Contraceptives: Two kinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased, 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. ln patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.
Cyclosporin: A kinetic study in renal transplant patients found fluconazole 200 mg daily to slowly increase cyclosporin concentrations. However, in another multiple-dose study with 100 mg daily, fluconazole did not affect cyclosporin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Theophylline: ln a placebo-controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and therapy modified appropriately if signs of toxicity develop.
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of ≥400 mg/day significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of ≥400 mg with terfenadine is contraindicated (see Contraindications). The co-administration of fluconazole at doses <400 mg/day with terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events including torsade de pointes in patients to whom fluconazole and cisapride were coadministered.
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 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 been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.
Zidovudine: Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A 2nd randomized, 2-period, 2-treatment cross-over study examined zidovudine levels in HIV infected patients. On 2 occasions, 21 days apart, patients received zidovudine 200 mg every 8 hrs either with or without fluconazole 400 mg daily for 7 days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
The use of fluconazole in patients concurrently taking cisapride, astemizole, rifabutin, tacrolimus or other drugs metabolized by the cytochrome P-450 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. (See Precautions.)
Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but such interactions may occur.
