indication

For the treatment of fungal infections.

pharmacology

Fluconazole, a synthetic antifungal agent of the imidazole class, is used to treat vaginal candidiasis. It inhibits the fungal lanosterol 14 alpha-demethylase which thereby prevents the formation of ergosterol which is an essential component in the fungal cell membrane.

mechanism of action

Fluconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

toxicity

Symptoms of overdose include hallucinations and paranoid behavior.

biotransformation

Hepatic

absorption

90%

half life

30 hours (range 20-50 hours)

route of elimination

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug.

drug interactions

Acenocoumarol: Fluconazole may increase the serum concentration of acenocoumarol by decreasing its metabolism.

Alfentanil: Increases the effect and toxicity of alfentanil

Alprazolam: Fluconazole may increase the effect of the benzodiazepine, alprazolam.

Amitriptyline: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of amitriptyline if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Anisindione: Fluconazole may increase the serum concentration of anisindione by decreasing its metabolism.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atorvastatin: Increased risk of myopathy/rhabdomyolysis

Bromazepam: Fluconazole may increase the serum concentration of bromazepam by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bromazepam if fluconazole is initiated, discontinued or dose changed.

Carbamazepine: Fluconazole may increase the therapeutic and adverse effects of carbamazepine.

Carisoprodol: Strong CYP2C19 inhibitors such as fluconazole may decrease the metabolism of CYP2C19 substrates such as carisoprodol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of the substrate. Some combinations are specifically contraindicated by manufacturers. Suggested dosage adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor for increased effects of the CYP substrate if a CYP inhibitor is initiated/dose increased, and decreased effects if a CYP inhibitor is discontinued/dose decreased.

Celecoxib: Fluconazole may increase the effect of celecoxib.

Chlordiazepoxide: Fluconazole may increase the effect of the benzodiazepine, chlordiazepoxide.

Cilostazol: Fluconazole may decrease the effect of cilostazol.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonazepam: Fluconazole may increase the effect of the benzodiazepine, clonazepam.

Clorazepate: Fluconazole may increase the effect of the benzodiazepine, clorazepate.

Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Concomitant use of conivaptan with strong CYP3A4 inhibitors (e.g., azole antifungals) is contraindicated.

Cyclophosphamide: Fluconazole reduces metabolism and clearance of cyclophosphamide.

Cyclosporine: Fluconazole may increase the therapeutic and adverse effects of the cyclosporine.

Diazepam: Fluconazole may increase the effect of the benzodiazepine, diazepam.

Dicumarol: Fluconazole may increase the serum concentration of dicumarol by decreasing its metabolism.

Dihydroergotamine: Possible ergotism and severe ischemia with this combination

Eplerenone: This CYP3A4 inhibitor increases the effect and toxicity of eplerenone

Ergotamine: Possible ergotism and severe ischemia with this combination

Estazolam: Fluconazole may increase the effect of the benzodiazepine, estazolam.

Ethotoin: Increases the effect of hydantoin

Everolimus: Fluconazole may increase everolimus levels/toxicity.

Fentanyl: Fluconazole may increase levels/toxicity of fentanyl.

Flurazepam: Fluconazole may increase the effect of the benzodiazepine, flurazepam.

Fluvastatin: Fluconazole may increase the serum concentration of fluvastatin by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of fluvastatin if fluconazole is initiated, discontinued or dose changed.

Fosphenytoin: Fluconazole may increase the effect of hydantoin.

Halazepam: Fluconazole may increase the effect of the benzodiazepine, halazepam.

Haloperidol: Fluconazole may increase the effect and toxicity of haloperidol.

Imipramine: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of imipramine if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Lovastatin: Increased risk of myopathy/rhabdomyolysis

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephenytoin: Increases the effect of hydantoin

Midazolam: Fluconazole may increase the effect of the benzodiazepine, midazolam.

Nortriptyline: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of nortriptyline if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Phenytoin: Fluconazole may increase the therapeutic and adverse effects of phenytoin.

Pimozide: Increased risk of cardiotoxicity and arrhythmias

Quazepam: Fluconazole may increase the effect of the benzodiazepine, quazepam.

Ramelteon: Fluconazole may increase the serum levels and toxcity of ramelteon.

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifabutin: Fluconazole may increase levels/toxicity of rifabutin.

Rifampin: Rifampin may decrease the effect of fluconazole.

Simvastatin: Increased risk of myopathy/rhabdomyolysis

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The antifungal, fluconazole, may also increase serum concentrations of tacrolimus.

Tamoxifen: Fluconzole may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Fluconazole is initiated, discontinued or dose changed.

Tamsulosin: Fluconzole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Fluconazole is initiated, discontinued, or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Fluconazole may increase the serum concentration of Tipranavir. Dose adjustments are not required.

Tolbutamide: Fluconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Fluconazole therapeutic and adverse effects if Delavirdine is initiated, discontinued or dose changed.

Tolterodine: Fluconazole may decrease the metabolism and clearance of tolterodine. Adjust tolterodine dose and monitor for efficacy and toxicity.

Torasemide: Fluconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluconazole is initiated, discontinued or dose changed.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Fluconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Fluconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fluconazole is initiated, discontinued or dose changed.

Triazolam: Fluconazole may increase the effect of the benzodiazepine, triazolam.

Trimethoprim: The strong CYP2C9 inhibitor, Fluconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluconazole is initiated, discontinued or dose changed.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Fluconazole, a strong CYP2C19 inhibitor, may also decrease the metabolism and clearance of Trimipramine, a CYP2C19 substrate. Concomitant therapy should be used with caution.

Valdecoxib: Fluconazole may increase the effect and toxicity of valdecoxib.

Verapamil: Fluconazole may increase the serum concentration of Verapamil by decreasing Verapamil metabolism. This likely occurs via Fluconazole-mediated CYP3A4 inhibition. Monitor for changes in the therapeutic/adverse effects of Verapamil if Fluconazole is initiated, discontinued, or dose changed.

Vinblastine: Increases the effect and toxicity of anticancer agent

Vincristine: Increases the effect and toxicity of anticancer agent

Voriconazole: Fluconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for QTc prolongation and changes in the therapeutic and adverse effects of voriconazole if fluconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Warfarin: Fluconazole, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if fluconazole is initiated, discontinued or dose changed.

Zafirlukast: Fluconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if fluconazole is initiated, discontinued or dose changed.

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolpidem: Fluconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if fluconazole is initiated, discontinued or dose changed.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).