Most drug interactions with azole antifungals occur by means of one of two basic mechanisms: impairment of the absorption of the azole compound leading to reduced blood concentrations; or interference with hepatic microsomal enzymes which alters the metabolism and blood concentrations of the azole, the interacting drug, or both.
Unlike itraconazole and ketoconazole, absorption of fluconazole is not reduced if it is given together with drugs that reduce gastric acid secretion. Concomitant administration of fluconazole and rifampicin has resulted in a modest reduction in blood levels of the antifungal agent. The effect is less marked than with itraconazole or ketoconazole and is due to induction of P-450 cytochrome oxidases by rifampicin with resulting enhanced hepatic metabolism of the azole drug.
Like rifampicin, phenytoin undergoes cytochrome P-450-mediated hepatic metabolism and its concomitant administration with fluconazole may reduce its clearance. If these drugs are given together, serum concentrations of phenytoin should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Fluconazole has been shown to prolong the serum half-life, thus augmenting the hypoglycaemic effects of drugs, such as chlorpropamide, glibenclamide, glipizide and tolbutamide. Fluconazole can also increase the serum concentration of warfarin, augmenting its anticoagulant effects. Careful monitoring of prothrombin time in patients receiving concomitant treatment with fluconazole and anticoagulants is recommended.
Fluconazole may prolong the half-life of cyclosporin in transplant recipients, leading to increased blood levels of that drug. Serum concentrations of cyclosporin should be monitored if these drugs are given together.
Fluconazole: Interactions
In general, fewer interactions are considered to occur with fluconazole than with either itraconazole or ketoconazole. Use of rifampicin with fluconazole results in reduced plasma concentrations of fluconazole. Use of hydrochlorothiazide and fluconazole has resulted in clinically insignificant increases in plasma-fluconazole concentrations.
Fluconazole may interfere with the metabolism of some other drugs, mainly through inhibition of the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. This may account for the reported increases in plasma concentrations of bosentan, ciclosporin, midazolam, nevirapine, amitriptyline, nortriptyline, phenytoin, rifabutin, sulfonylurea hypoglycaemics and nateglinide, selective cyclooxygenase-2-inhibitors such as celecoxib and parecoxib, tacrolimus, triazolam, warfarin, and zidovudine fluconazole may inhibit the formation of a toxic metabolite of sulfamethoxazole. Increases in terfenadine concentrations following high doses of fluconazole have been associated with ECG abnormalities.
A similar effect may be anticipated with astemizole. Use of fluconazole with cisapride could result in increased cisapride concentrations and associated toxicity. The use of fluconazole with astemizole, cisapride, or terfenadine should therefore be avoided because of the risk of cardiac arrhythmias. Syncope attributed to increased amitriptyline concentrations has occurred when amitriptyline was given with fluconazole.
Fluconazole may also reduce the clearance of theophylline. The concentration of contraceptive steroids has been reported to be both increased and decreased in patients receiving fluconazole and the efficacy of oral contraceptives may be affected. For further information on interactions between drugs metabolised by the cytochrome P450 isoenzyme CYP3 A and azoles, see under Itraconazole.
Antineoplasties
For the effect of azole antifungals on cyclophosphamide metabolism.
Fluoroquinolones
Both levofloxacin and fluconazole can cause a prolonged QT interval. The simultaneous use of intravenous levofloxacin and fluconazole resulted in an episode of torsade de pointes in a patient on haemodialysis.
Nitrofurans
For a report ofpulmonary and hepatic toxicity due to a possible interaction between nitrofurantoin and fluconazole.
Antimicrobial Action
Fluconazole is a triazole antifungal drug which in sensitive fungi inhibits cytochrome P450-dependent enzymes, resulting in impairment of ergosterol synthesis in fungal cell membranes. It is active against Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Epidermophyton spp., Histoplasma capsulatum, Microsporum spp., and Trichophyton spp. Resistance has developed in some Candida spp. following long-term prophylaxis with fluconazole, and cross-resistance with other azoles has been reported.
Microbiological interactions
A synergistic antifungal effect was seen in vitro with terbinafine and fluconazole against strains of Candida ahicans. For effects on the antifungal activity of fluconazole when given with amphotericin B.
Resistance
The emergence of strains of Candida spp. resistant to fluconazole has become increasingly important, particularly in immunocompromised patients receiving long-term prophylaxis with fluconazole. In addition to resistance in Candida albicans, infections with Candida dubliniensis, Candida glabrata, and Candida krusei, all of which may be less sensitive to fluconazole than Candida albicans, have been noted in these patients, and secondary resistance of Candida glabrata has been reported during fluconazole therapy.
Resistance to fluconazole has been reported to occur more frequently than resistance to either ketoconazole or itraconazole and may be related to the widespread use of this drug. Cross-resistance with other azoles’ and with amphotericin B has been reported.
Fluconazole resistance has also been reported in Cryptococcus neoformans and Histoplasma capsulation Histoplasmosis developed during treatment with fluconazole in a patient with HIV infection. Fluconazole-resistant C. neoformans has been isolated from an immunocompetent patient who had not been exposed to azole antifungals previously.
Preparations
International Brand Drug Names
The information about drugs around the world. Many drugs are marketed under different names in different countries.
Proprietary Preparations
Australia: Diflucan; Dizole; Fluzole; Ozole; Canada: Diflucan; France: Beagyne; Triflucan; Germany: Canex; Diflucan; Fluc; Flucobeta; Flucoderm; FlucoLich; Flunazul; Fungata; India: Flumyc; Fluzon; Forcan; Logican; Nipcan; Syscan; Italy: Biozolene; Diflucan; Elazor; Portugal: Azoflune; Diflucan; Fludocel; Maxflin; Reforce; Supremase; France: Diflucan; Difluzole; Flucoric; Fluzol; Spain: Diflucan; Lavisa; Loitin; Solacap; Switzerland: Diflucan; Flucazol; Fluconax; Flunizol; Mykantol; UK or Britain: Canesten Oral; Diflucan; US or USA: Diflucan.
Fluconazole: Drug-Drug Interactions
Alfentanil
In a randomized, double-blind, placebo-controlled, crossover study in nine subjects, fluconazole 400 mg reduced the clearance of alfentanil 20 micrograms/kg by 55% and increased alfentanil-induced subjective effects.
Amitriptyline
An interaction of fluconazole with amitriptyline has been reported.
- A 12-year-old boy with prostatic rhabdomyosarcoma had episodes of syncope periodically over 7 months while taking fluconazole for chemotherapy-induced mucositis. He had taken fluconazole in the past without problems but had also taken a stable dose of amitriptyline for neuropathic pain. On withdrawal of amitriptyline he had no further episodes. The effect was confirmed by readministration.
Concurrent administration of fluconazole probably causes increased exposure to amitriptyline. Three reports of adults have shown increased amitriptyline plasma concentrations with concurrent administration of fluconazole; in one patient, a 57-year-old woman, the QT interval was prolonged and torsade de pointes occurred.
Amphotericin
In vitro studies and experiments in animals have given conflicting results relating to potential antagonism between the effects of fluconazole and amphotericin on Candida species. However, large, randomized, double-blind comparisons of fluconazole with and without amphotericin for 5 days in non-neutropenic patients with candidemia showed no evidence of antagonism, but faster clearance of the organism from the blood and a trend toward an improved outcome in those who received the combination.
Antacids
Fluconazole absorption after oral administration is not influenced by gastric pH; thus there is no effect of antacids such as co-magaldrox.
Antihistamines
The concurrent use of terfenadine with fluconazole can lead to dangerously high terfenadine concentrations, with resulting cardiotoxicity. It is suspected that the same may happen with astemizole.
Benzodiazepines
The interaction of fluconazole with bromazepam has been studied in 12 healthy men in a randomized, double-blind, four-way, crossover study. They received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment with oral fluconazole (100 mg/day) or placebo. Fluconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of oral or rectal bromazepam.
Fluconazole increased blood concentrations of midazo-lam and triazolam.
The effects of fluconazole (400 mg loading dose followed by 200 mg/day) on the kinetics of midazolam have been studied in 10 mechanically ventilated adults receiving a stable infusion of midazolam. Concentrations of midazolam were increased up to four-fold after the start of fluconazole therapy; these changes were most marked in patients with renal insufficiency. During the study, the ratio of a-hydroxymidazolam to midazolam progressively fell. The authors concluded that in ICU patients receiving fluconazole, reduction of the dose of midazolam should be considered if the degree of sedation is increasing.
In a study of the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg, switching from inhibition of metabolism by itraconazole 200 mg/day to induction of metabolism by rifampicin 600 mg/day caused an up to 400-fold change in the AUC of oral midazolam.
Calcium channel blockers
Fluconazole enhanced the blood pressure-lowering effects of nifedipine by increasing its plasma concentrations in a 16-year-old patient with malignant pheochromocytoma taking chronic nifedipine for arterial hypertension who was given fluconazole for Candida septicemia.
Carbamazepime
Fluconazole can cause carbamazepine toxicity, presumably by inhibition of CYP3A4.
- A 33-year-old man on stable therapy with carbamazepine (400 mg tds) for a seizure disorder became stupor-ose due to carbamazepine toxicity after taking fluconazole 150 mg/day for 3 days. Withdrawal of both drugs resulted in a fall in carbamazepine concentrations (maximum concentration 25 µg/ml) and return of the patient’s baseline mental status. Carbamazepine was restarted and the patient had no further adverse events.
- Carbamazepine serum concentrations increased during concomitant fluconazole administration (400 mg/day) in a 38-year-old man.
Ciclosporin
Fluconazole can increase concentrations of ciclosporin by inhibiting CYP3A4. In some studies, minimal or no effects were recorded, but in others ciclosporin concentrations were increased by fluconazole. Differences in the dosage and duration of fluconazole treatment could have explained these discrepancies. For example, there was no interaction at a fluconazole dosage of 100 mg/day, but high dosages of fluconazole (400 mg/day or more) increase blood ciclosporin and tacrolimus concentrations.
The interaction of ciclosporin with fluconazole has been retrospectively evaluated in 19 kidney and pancreas/kidney transplant recipients. Both intravenous and oral fluconazole altered the blood concentration of ciclosporin. Five subjects did not have a significant interaction and 15 did. No patient had nephrotoxicity or transplant rejection related to antifungal therapy.
The effects of higher dosages of fluconazole on ciclosporin immunosuppression have been investigated in six renal transplant patients in a prospective, unblinded, crossover study. Baseline renal function, ciclosporin AUC, Cmax, Cmm, fmax, and clearance were compared with those 2,4, and 7 days after starting fluconazole orally in a dosage of 200 mg/ day. From day 8 onwards the ciclosporin dose was reduced by 50% and the above parameters were repeated on day 14. The results are shown in Table 1. On repeated-measures ANOVA only the AUC and Cmax on day 4 of fluconazole were significantly higher than on day 0. There were no significant changes in ciclosporin clearance and fmax. The authors concluded that changes in Cmin may not be sensitive enough to detect the described interaction and suggested monitoring the AUC near day 4 of treatment to guide ciclosporin dosage adjustments in all patients taking concomitant fluconazole.
Cimetidine
Fluconazole absorption after oral administration is not influenced by gastric pH; thus there is no effect of cimetidine.
Clarithromycin
The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabutin have been studied in 10 HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds. There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin.
Cyclophosphamide
Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to produce alkylating species, which are cytotoxic, and the extent of cyclophosphamide metabolism correlates with both treatment efficacy and toxicity. In vitro studies in six human liver microsomes showed that the IC50 of fluconazole for reduction of 4-hydroxycyclophosphamide production was 9-80 µmol/l.
A retrospective study in 22 children with cancers addressed the potential interaction between fluconazole and cyclophosphamide. Children with an established profile of cyclophosphamide metabolism who were not receiving other drugs known to affect drug metabolism were selected; 9 were taking fluconazole and 13 were controls. The plasma clearance was significantly lower in patients taking concomitant fluconazole (2.4 versus 4.2 1/ hour/m. It is unclear whether this interaction is associated with a reduction in the therapeutic efficacy of cyclophosphamide.
Doxorubicin
The effect of fluconazole on the plasma pharmacokinetics of doxorubicin has been investigated in a randomized, crossover study in non-human primates. Fluconazole (10 mg/kg/day) was given intravenously for 4 days before doxorubicin (2.0 mg/kg intravenously). Pretreatment with fluconazole had no effect on the pharmacokinetics of doxorubicin, and the incidence of severe neutropenia (absolute neutrophil count below 0.5 x 109/1) was higher with doxorubicin alone than with the combination of doxorubicin and fluconazole. Thus, fluconazole does not appear to contribute to the marrow-suppressive effects of doxorubicin.
Flucytosine
The concurrent use of fluconazole with flucytosine may have an additive effect. This combination could be useful in the treatment of cryptococcal meningitis.
HIV protease inhibitors
The pharmacokinetic interaction of fluconazole 400 mg od and indinavir 1000 mg tds has been evaluated in a placebo-controlled, crossover study for 8 days; there was no significant interaction.
The effect of fluconazole on the steady-state pharmacokinetics of ritonavir and saquinavir has been studied in patients infected with HIV-1. They received the protease inhibitor (saquinavir 1200 mg tds, n = 5, or ritonavir 600 mg bd, alone on day 1 and then with fluconazole 400 mg on day 2 and 200 mg on days 3-8. The median increase in saquinavir AUC was 50%, and the median increase in Cmax was 56%. In contrast, fluconazole had no effect on the disposition of ritonavir.
Methadone
An interaction between fluconazole and methadone (a substrate of CYP3A4, CYP2C9, and CYP2C has been reported.
While taking a stable dose of methadone, a 60-year-old man with advanced cancer developed respiratory depression 2 days after receiving intravenous fluconazole for refractory oral candidiasis. Intravenous naloxone reversed the respiratory depression.
In a randomized, double-blind, placebo-controlled study in 25 patients, fluconazole 200 mg/day increased methadone concentrations, but patients treated with fluconazole did not have signs or symptoms of significant narcotic overdose.
Omeprazole
Fluconazole absorption after oral administration is not influenced by gastric pH; thus there is no effect of omeprazole. Omeprazole is extensively metabolized in the liver by 5-hydroxylation and sulfoxidation reactions, catalysed predominantly by CYP2C19 and CYP3A4 respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. The effect of fluconazole on the pharmacokinetics of a single oral dose of omeprazole 20 mg has been evaluated after a single oral dose of fluconazole 100 mg and after 4 days of oral administration of 100 mg/day in 18 healthy male volunteers. Fluconazole increased the Cmax and the mean AUC of omeprazole and prolonged its half-life (2.59 versus 0.85 hours).
Oral contraceptives
Fluconazole did not significantly alter the pharmacokinetics of ethinylestradiol or norgestrel, and this finding was interpreted by the investigators as suggesting that treatment with fluconazole in a user of oral contraceptives would not increase the risk of pregnancy. However, the study was carried out using a 50 mg dose of fluconazole, and experience with higher dosages has shown different results.
In another study, fluconazole reduced the systemic availability of ethinylestradiol in an oral contraceptive, but there was no information about the doses used.
In an open, crossover study in 10 young healthy subjects, fluconazole 150 mg increased the serum concentrations of ethinylestradiol 30-35 µg/day.
The potential pharmacokinetic interaction between fluconazole 300 mg once weekly and an oral contraceptive containing ethinylestradiol and norethindrone (Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical Inc, Raritan, NJ) has been studied in a placebo-controlled, double-blind, randomized, two-way, crossover study in 26 healthy women aged 18-36 years. During the first cycle they took the oral contraceptive only. During the second cycle they were assigned randomly to oral contraceptive + fluconazole or oral contraceptive + placebo. In the third cycle they were given the other treatment.
Fluconazole caused small but statistically significant increases in the AUCo-24 of both ethinylestradiol and norethindrone. There were no adverse events related to treatment in those given fluconazole.
It therefore appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.
Phenytoin
Co-administration of fluconazole and phenytoin resulted in markedly higher phenytoin concentrations.
Rifamycins
The combination of rifampicin with fluconazole has insignificant effects.
Statins
The effects of fluconazole on plasma fluvastatin and pravastatin concentrations have been studied in two separate, randomized, double-blind, two-phase, crossover studies. Healthy volunteers were given oral fluconazole (400 mg on day 1 and 200 mg on days or placebo. On day 4, they took a single oral dose of fluvastatin 40 mg or pravastatin 40 mg.
Fluconazole increased the plasma AUC and the half-life of fluvastatin by 80% but had no significant effects on the pharmacokinetics of pravastatin. The mechanism of the prolonged elimination of fluvastatin was probably inhibition of CYP2C9. Pravastatin, in contrast, appears not to be susceptible to interactions with fluconazole and other CYP2C9 inhibitors.
The effect of fluconazole on the pharmacokinetics of rosuvastatin has been investigated in a randomized, double-blind, two-way, crossover, placebo-controlled study. Healthy male volunteers were given fluconazole 200 mg/day or matching placebo for 11 days; rosuvastatin 80 mg was co-administered on day 8. Plasma concentrations of rosuvastatin, N-desmethylrosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after the dose.
Fluconazole increased the AUC and Cmax of rosuvastatin by 14% and 9% respectively. Limited data available for the N-desmethylated metabolite showed that the Cmax fell by about 25%. Fluconazole did not affect the proportion of circulating active or total HMG-CoA reductase inhibitors accounted for by circulating rosuvastatin. Thus, fluconazole produced only small changes in rosuvastatin kinetics, which were not considered to be of clinical relevance.
Sulfonylureas
The concurrent administration of fluconazole with tolbutamide resulted in increased tolbutamide concentrations.
- A 56-year-old HIV-positive patient with diabetes mellitus taking gliclazide 160 mg/day developed severe hypoglycemia when treated with co-trimoxazole 480 mg/day and fluconazole 200 mg/day. The authors speculated that fluconazole might have inhibited gliclazide metabolism by inhibiting CYP2C9.
The effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride have been studied in a randomized, double-blind, crossover study in 12 healthy volunteers who took fluconazole 200 mg/day (400 mg on day, fluvoxamine 100 mg/day, or placebo once daily for 4 days. On day 4 they took a single oral dose of glimepiride 0.5 mg.
Fluconazole increased the mean total AUC of glimepiride to 238% and the peak plasma concentration to 151% of control values, and the half-life of glimepiride was prolonged from 2.0 to 3.3 hours. This was probably due to inhibition of CYP2C9-mediated biotransformation of glimepiride by fluconazole. However, fluconazole did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations.
Tacrolimus
Since tacrolimus is metabolized by intestinal and hepatic CYP3A4, drugs that inhibit CYP3A4 can reduce the metabolism of tacrolimus and increase tacrolimus blood concentrations.
The effect of fluconazole on the blood concentrations of tacrolimus have been investigated in eight liver transplant patients in whom prophylactic fluconazole (200 mg/day) was withdrawn because of rises in hepatic transaminases, renal dysfunction, or eosinophilia (n = 1 each). Calculated tacrolimus concentrations fell by 13-81% (median 41%) between the fourth and ninth days after withdrawal of fluconazole. Tacrolimus blood concentrations should be carefully monitored and dosages increased as necessary after withdrawal of fluconazole.
The interaction of tacrolimus with fluconazole has been retrospectively evaluated in 19 kidney and pancreas/kidney transplant recipients. Both intravenous and oral fluconazole altered the blood concentration of tacrolimus. Five subjects did not have a significant interaction and 15 did. No patient had nephrotoxicity or transplant rejection related to antifungal therapy.
- A 17-year-old man with cystic fibrosis who took itra-conazole after a lung-liver transplant had high trough concentrations of tacrolimus, despite the relatively low dosage (0.1-0.3 mg/kg/day).
- A patient taking tacrolimus 0.085 mg/kg bd with itraconazole 200-400 mg/day developed ketoacidosis, neutropenia, and thrombocytopenia, requiring the withdrawal of both drugs.
- A 34-year-old renal transplant recipient taking a stable regimen of tacrolimus and methylprednisolone was given itraconazole 100 mg bd for a yeast infection of the urinary tract. Concomitant therapy with itraconazole led to a marked increase in tacrolimus trough concentrations on the second day of therapy (from 13 to 21 µg/ml) and an increase in serum creatinine concentrations, necessitating dosage reduction of tacrolimus by 50%.
When itraconazole was withdrawn the effect of itraconazole on the kinetics of tacrolimus took 12 days to reverse. The inhibitory effect of itraconazole occurred quickly, while the time of disappearance was much longer, which is important for clinical management. Thus, during co-administration of itraconazole with tacrolimus, close monitoring of tacrolimus blood concentrations and careful dosage adjustments are essential to avoid toxicity.
Warfarin
Co-administration of fluconazole and warfarin has led in some cases to prolongation of the prothrombin time.
Zidovudine
Zidovudine glucuronidation in human hepatic microsomes in vitro was inhibited more by the combination of fluconazole with valproic acid than with other drugs, such as atovaquone and methadone.