(See CLINICAL PHARMACOLOGY: Drug Interaction
Studies and CONTRAINDICATIONS.) Fluconazole is a potent inhibitor of
cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In
addition to the observed/documented interactions mentioned below, there is a
risk of increased plasma concentration of other compounds metabolized by CYP2C9
and CYP3A4 coadministered 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. Clinically or potentially significant drug interactions between
fluconazole and the following agents/classes have been observed. These are
described in greater detail below:
Calcium Channel Blockers
Non-steroidal anti-inflammatory drugs
HMG-CoA reductase inhibitors
Clinically significant hypoglycemia may be precipitated
by the use of fluconazole with oral hypoglycemic agents; one fatality has been
reported from hypoglycemia in association with combined fluconazole and
glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide,
and glipizide and increases the plasma concentration of these agents. When fluconazole
is used concomitantly with these or other sulfonylurea oral hypoglycemic
agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction
Prothrombin time may be increased in patients receiving concomitant
fluconazole and coumarin-type anticoagulants. In post-marketing experience, 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. Careful monitoring of prothrombin time
in patients receiving fluconazole and coumarin-type anticoagulants is
recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction
Fluconazole increases the plasma concentrations of
phenytoin. Careful monitoring of phenytoin concentrations in patients receiving
fluconazole and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Fluconazole significantly increases cyclosporine levels
in renal transplant patients with or without renal impairment. Careful
monitoring of cyclosporine concentrations and serum creatinine is recommended
in patients receiving fluconazole and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies). This combination may be used by reducing the dosage
of cyclosporine depending on cyclosporine concentration.
Rifampin enhances the metabolism of concurrently
administered fluconazole. Depending on clinical circumstances, consideration
should be given to increasing the dose of fluconazole when it is administered
with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction
Fluconazole increases the serum concentrations of
theophylline. Careful monitoring of serum theophylline concentrations in
patients receiving fluconazole and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
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
coadministration of fluconazole at doses lower than 400 mg/day with terfenadine
should be carefully monitored.
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
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
There have been reports that an interaction exists when fluconazole
is administered concomitantly with rifabutin, leading to increased serum levels
of rifabutin up to 80%. There have been reports of uveitis in patients to whom
fluconazole and rifabutin were coadministered. Patients receiving rifabutin and
fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Avoid concomitant administration of voriconazole and
fluconazole. Monitoring for adverse events and toxicity related to voriconazole
is recommended; especially, if voriconazole is started within 24 h after the
last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Fluconazole may increase the serum concentrations of
orally administered tacrolimus up to 5 times due to inhibition of tacrolimus
metabolism through CYP3A4 in the intestines. No significant pharmacokinetic
changes have been observed when tacrolimus is given intravenously. Increased tacrolimus
levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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 short-acting benzodiazepines, which are metabolized by the cytochrome P450
system, are concomitantly administered with fluconazole, consideration should
be given to decreasing the benzodiazepine dosage, and the patients should be
appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Systemic exposure to tofacitinib is increased when
tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and
potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given
concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily
as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL
PHARMACOLOGY: Drug InteractionStudies.)
Fluconazole increases the AUC of triazolam (single dose)
by approximately 50%, Cmax by 20-32%, and increases t½ by 25-50% due to the
inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be
Two pharmacokinetic studies with a combined oral
contraceptive have been performed using multiple doses of fluconazole. There
were no relevant effects on 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
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.
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.)
In a pharmacokinetic interaction study, coadministration
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.
A study observed a reduction in clearance and
distribution volume as well as prolongation of T½ 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.
Fluconazole increases the effect of amitriptyline and
nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at
initiation of the combination therapy and after one week. Dosage of
amitriptyline/nortriptyline should be adjusted, if necessary.
Concurrent administration of fluconazole and amphotericin
B in infected normal and immunosuppressed mice showed the following results: a
small additive antifungal effect in systemic infection with C. albicans,
no interaction in intracranial infection with Cryptococcus neoformans,
and antagonism of the two drugs in systemic infection with A. fumigatus.
The clinical significance of results obtained in these studies is unknown.
An open-label, randomized, three-way crossover study in
18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin
on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as
the effects of fluconazole on the pharmacokinetics of azithromycin. There was
no significant pharmacokinetic interaction between fluconazole and
Fluconazole inhibits the metabolism of carbamazepine and
an increase in serum carbamazepine of 30% has been observed. There is a risk of
developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be
necessary depending on concentration measurements/effect.
Calcium Channel Blockers
Certain dihydropyridine calcium channel antagonists
(nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4.
Fluconazole has the potential to increase the systemic exposure of the calcium
channel antagonists. Frequent monitoring for adverse events is recommended.
During concomitant treatment with fluconazole (200 mg
daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and
134%, respectively. Half of the celecoxib dose may be necessary when combined
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.
One fatal case of possible fentanyl fluconazole
interaction was reported. The author judged that the patient died from fentanyl
intoxication. Furthermore, in a randomized crossover study with 12 healthy
volunteers it was shown that fluconazole delayed the elimination of fentanyl
significantly. Â Elevated fentanyl concentration may lead to respiratory
Fluconazole can increase halofantrine plasma concentration
due to an inhibitory effect on CYP3A4.
HMG-CoA Reductase Inhibitors
The risk of myopathy and rhabdomyolysis increases when fluconazole
is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4,
such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.
If concomitant therapy is necessary, the patient 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 creatinine kinase is observed or myopathy/rhabdomyolysis is
diagnosed or suspected.
Fluconazole inhibits the metabolism of losartan to its
active metabolite (E-31 74) which is responsible for most of the angiotensin
Il-receptor antagonism which occurs during treatment with losartan. Patients
should have their blood pressure monitored continuously.
Fluconazole may enhance the serum concentration of
methadone. Dosage adjustment of methadone may be necessary.
Non-steroidal Anti-inflammatory Drugs
The Cmax and AUC of flurbiprofen were increased by 23% and
81%, respectively, when coadministered with fluconazole compared to
administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically
active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively,
when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to
administration of racemic ibuprofen alone.
Although not specifically studied, 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.
There was a case report that a liver-transplanted patient
treated with prednisone developed acute adrenal cortex insufficiency when a
three month 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 is discontinued.
Fluconazole increases the AUC of saquinavir by
approximately 50%, Cmax by approximately 55%, and decreases clearance of
saquinavir by approximately 50% due to inhibition of saquinavir's hepatic
metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir
may be necessary.
Fluconazole increases plasma concentrations of sirolimus
presumably by inhibiting the metabolism of sirolimus via CYP3A4 and
P-glycoprotein. This combination may be used with a dosage adjustment of
sirolimus depending on the effect/concentration measurements.
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.
Based on a case report in one patient receiving
combination therapy with all-transretinoid acid (an acid form of vitamin A) and
fluconazole, CNS related undesirable effects have developed in the form of
pseudotumour 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.
Fluconazole increases Cmax and AUC of zidovudine by 84%
and 74%, respectively, due to an approximately 45% decrease in oral zidovudine
clearance. The half-life of zidovudine was likewise prolonged by approximately
128% following combination therapy with fluconazole. Patients receiving this combination
should be monitored for the development of zidovudine-related adverse
reactions. Â Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with
medications other than those listed in the CLINICAL PHARMACOLOGY section have
not been conducted, but such interactions may occur.