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FLUCONAZOLE
DIR Classification
Classification:Moderate-DIR concern
Severity Score:3
Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF
- PRECAUTIONS
- General
- Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.
- Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
- 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.
- Fluconazole should be administered with caution to patients with renal dysfunction.
- Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored.
- [Drug Interactions]
- 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 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: DRUG INTERACTION STUDIES.) The coadministration of fluconazole at doses lower than 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. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: DRUG INTERACTION STUDIES.)
- 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 torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.
- Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.
- Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS. )
- CONTRAINDICATIONS
- Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See CLINICALPHARMACOLOGY: DRUG INTERACTION STUDIESand PRECAUTIONS.)
- ADVERSE REACTIONS
- Post-Marketing Experience
- Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
- CLINICAL PHARMACOLOGY
- Drug Interaction Studies
- Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS. )
- Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONSand PRECAUTIONS.)
- Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride C max. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride C max. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONSand PRECAUTIONS.)
Postmarketing Surveillance
Contingency Table:
Current Drug
Other Drugs
Rhabdomyolysis
113
42799
Other ADRs
10970
14106309
Odds Ratio = 3.396
Drug Property Information
ATC Code(s):
- D01AC15 - fluconazole
- D01AC - Imidazole and triazole derivatives
- D01A - ANTIFUNGALS FOR TOPICAL USE
- D01 - ANTIFUNGALS FOR DERMATOLOGICAL USE
- D - DERMATOLOGICALS
- J02AC01 - fluconazole
- J02AC - Triazole derivatives
- J02A - ANTIMYCOTICS FOR SYSTEMIC USE
- J02 - ANTIMYCOTICS FOR SYSTEMIC USE
- J - ANTIINFECTIVES FOR SYSTEMIC USE
- J01RA07 - fluconazole
- J01RA - Combinations of antibacterials
- J01R - COMBINATIONS OF ANTIBACTERIALS
- J01 - ANTIBACTERIALS FOR SYSTEMIC USE
- J - ANTIINFECTIVES FOR SYSTEMIC USE
Active Ingredient:fluconazole
Active Ingredient UNII:8VZV102JFY
Drugbank ID:DB00196
PubChem Compound:3365
CAS Number:86386-73-4
Dosage Form(s):powder, for suspension
Route(s) Of Administrator:oral
Daily Dose:
- 200.0 mg/day J02AC01
Chemical Structure: 
SMILE Code:
C1=CC(=C(C=C1F)F)C(CN2C=NC=N2)(CN3C=NC=N3)O
C1=CC(=C(C=C1F)F)C(CN2C=NC=N2)(CN3C=NC=N3)O
Reference
COHORT STUDY:
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