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Anticoagulants: Fluconazole increased the prothrombin time after Warfarin administration. As with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) 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.
Azithromycin: There was no significant pharmacokinetic interaction between Fluconazole and Azithromycin.
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.
Cisapride: Co-administered of Cisapride is contraindicated in patients receiving Fluconazole (see Contraindications).
Cyclosporin: Cyclosporin plasma concentration monitoring in patients receiving Fluconazole is recommended.
Hydrochlorothiazide: Co-administration of Hydrochlorothiazide and Fluconazole increase plasma concentration of Fluconazole. 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.
Oral contraceptives: Multiple dose use of Fluconazole is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Phenytoin: Concomitant administration of Fluconazole and Phenytoin may increase the levels of Phenytoin to a clinical 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.
Rifabutin: There have been report that an interactions exists when Fluconazole is administered concomitantly with Rifabutin, leading to increased serum levels of Rifabutin and uveitis. Patients receiving Rifabutin and Fluconazole concomitantly should be carefully monitored.
Rifampicin: Concomitant administration of Fluconazole and Rifampicin resulted in decrease AUC and shorter half-life of Fluconazole. In patients receiving concomitant Rifampicin, an increase of the Fluconazole dose should be considered.
Sulfonylurea: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (Chlorpropamide, Glibenclamide, Glipizide and Tolbutamide). Fluconazole and oral sulfonylurea maybe co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during co-administration.
Tacrolimus: There have been reports that an interaction exists when Fluconazole is administered concomitantly with Tacrolimus, leading to increased serum levels of Tacrolimus and nephrotoxicity. Patients receiving Tacrolimus and Fluconazole concomitantly should be carefully monitored.
Terfenadine: The combined use of Fluconazole at doses of 400 mg or greater with Terfenadine is contraindicated (see Contraindications). The co-administration of Fluconazole at doses lower than 400 mg per day with Terfenadine should be carefully monitored.
Astemizole: Concomitant administration of Fluconazole with Astemizole may decrease the clearance of Astemizole. Resulting increased plasma concentrations of Astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Co-administration of Fluconazole and Astemizole is contraindicated (see Contraindications).
Pimozide: Concomitant administration of Fluconazole and Pimozide may result in inhibition of Pimozide metabolism. Increased Pimozide plasma concentrations can lead to QT prolongation and occurrences of torsade de pointes. Co-administration of Fluconazole and Pimozide is contraindicated (see Contraindications).
Quinidine: Concomitant administration of Fluconazole and Quinidine may result in inhibition of Quinidine metabolism. Increased Pimozide plasma concentrations can lead to QT prolongation and occurrences of torsade de pointes. Co-administration of Fluconazole and Quinidine is contraindicated (see Contraindications).
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.
The effect of Fluconazole on other medicinal products: Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19 and a moderate inhibitor of CYP3A4. In addition to the observed/documented interactions mentioned as follows, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered with Fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of Fluconazole persists 4-5 days after discontinuation of Fluconazole treatment due to the long half-life of Fluconazole (see Contraindications).
Alfentanil: There have been reported a reduction in clearance and distribution volume as well as prolongation of T1/2 of Alfentanil following concomitant treatment with Fluconazole. A possible mechanism of action is Fluconazole's inhibition of CYP3A4. Dosage adjustment of Alfentanil may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy after one week. Dosage of amitriptyline should be adjusted, if necessary.
Amphotericin B: Fluconazole increase the AUC of triazolam (single dose) and increases T1/2 due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increase serum Carbamazepine. There is a risk of developing Carbamazepine toxicity. Dosage adjustment of Carbamazepine may be necessary depending on concentration measurements/effect.
Calcium channel blockers: Certain calcium channel antagonist (Nifedipine, Isradipine, Amlodipine, Verapamil, and Felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonist. Frequent monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with Fluconazole and Celecoxib Cmax and AUC increased. Half of the Celecoxib dose may be necessary when combined with Fluconazole.
Cyclophosphamide: Combination therapy with Cyclophosphamide and Fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: Fluconazole delayed the elimination of Fentanyl significantly. Elevated Fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase Halofantrine plasma concentration due to an inhibitory effect of CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when Fluconazole is co-administered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as Atorvastatin and Simvastatin, or through CYP2C9, such as Fluvastatin. If concomitant therapy is necessary, the patients should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of Losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with Losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of Methadone. Dosage adjustment of Methadone may be necessary.
Non-steroidal anti-inflammatory drugs: Fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. Naproxen, Lornoxicam, Meloxicam, Diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: Liver-transplanted patient treated with Prednisone developed acute adrenal cortex insufficiency when a three months therapy with Fluconazole was discontinued. The discontinuation of Fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of Prednisone. Patients on long-term treatment with Fluconazole and Prednisone should be carefully monitored for adrenal cortex insufficiency when Fluconazole discontinued.
Saquinavir: Fluconazole increase the AUC and decreases clearance of Saquinavir due to inhibition of Saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of Saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of Sirolimus presumably by inhibiting the metabolism of Sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with dosage adjustment of Sirolimus depending on the effect/concentration measurements.
Tofacitinib: Exposure of Tofacitinib is increased when Tofacitinib is co-administered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. Fluconazole). Dosage adjustment of Tofacitinib may be necessary.
Vinca alkaloids: Although not studied, Fluconazole may increase the plasma levels of the vinca alkaloids (e.g., Vincristine and Vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.
Vitamin A: Patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and Fluconazole, CNS related undesirable effects have developed in the form of pseudotumor cerebri, which disappeared after discontinuation of Fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.
Zidovudine: Fluconazole increases Cmax and AUC of Zidovudine due to decrease in oral Zidovudine clearance. The half-life of Zidovudine was likewise prolonged following combination therapy with Fluconazole. Patients receiving this combination should be monitored for the development of Zidovudine-related adverse reactions. Dosage reduction of Zidovudine may be considered.
Voriconazole: Concomitant administration of Voriconazole and Fluconazole at any dose is not recommended.
Erythromycin: Concomitant use of Fluconazole and Erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Co-administration of Fluconazole and Erythromycin is contraindicated (see Contraindications).
The use of Fluconazole in patients concurrently taking Astemizole 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.
The use of Fluconazole in patients concurrently taking Astemizole or other drugs metabolized by the cytochrome P-450 system may be associated with elevations in serum level of these drugs. Caution should be used when co-administering Fluconazole. Patients should be carefully monitored.
When oral Fluconazole is co-administered 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.
