Anticoagulants: 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 (cholorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be coadministered to diabetic patients, but the possibility of a hypoglycemic 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 fluoconazole by 40%. An effect of this magnitude should not necessitate a change in the fluoconazole 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 does 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 fluoconazole 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. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.
Zidovudine: Concomitant administration of fluconazole appears to interfere with the metabolism and clearance of zidovudine. In one study in men with HIV infections who received zidovudine (200 mg every 8 hours) alone or in conjunction with fluconazole (400 mg daily), the AUC of zidovudine was increased 74% (range: 20-173%), peak serum zidovudine concentrations were increased 84% (range: -1 to 227%) and the terminal elimination half-life of the drug was increased 128% (range: -4 to 189%) in patients receiving concomitant fluconazole. Although the clinical importance of this effect is unknown, it has been suggested that patients receiving concomitant zidovudine and fluconazole therapy by monitored closely for zidovudine-associated adverse effects.
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.
Terfenadine: The possibility that fluconazole may interact with terfenadine (no longer commercially available in the US), resulting in potentially serious adverse cardiovascular effects, should be considered. Prolongation of the QT interval and QT interval corrected for rate (QTc) and rarely, serious cardiovascular effects, including arrhythmias (e.g., ventricular tachycardia, atypical ventricular tachycardia [torsades de pointes, ventricular fibrillation]), cardiac arrest, palpitations, hypotension, dizziness, syncope and death, have been reported in patients receiving recommended dosage of terfenadine.
Theophylline: In 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 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.