A single or multiple intake of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrine) when taken simultaneously.
The simultaneous use of fluconazole with the following drugs is contraindicated:
Cisapride: with the simultaneous use of fluconazole and cisapride, undesirable reactions of the heart are possible, including arrhythmia ventricular tachysystolic type "pirouette" (torsade de points). The use of fluconazole at a dose of 200 mg 1 time per day and cisapride at a dose of 20 mg 4 times a day leads to a pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Simultaneous use of cisapride and fluconazole is contraindicated.
Terfenadine: with the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval is not established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in plasma terfenadine concentration. Simultaneous administration of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses of less than 400 mg/day in combination with terfenadine should be carried out under close supervision.
Astemizol: the simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these agents. Elevated plasma concentrations of astemizol can lead to a prolongation of the QT interval and in some cases to the development of ventricular tachysystolic arrhythmias of the "pirouette" type (torsade de points). The simultaneous use of astemizole and fluconazole is contraindicated.
Pimozide: although no appropriate in vitro or in vivo studies have been conducted, the simultaneous use of fluconazole and pimozide may lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide can lead to a prolongation of the QT interval and, in some cases, the development of ventricular tachysystolic arrhythmias of the "pirouette" type (torsade de points). The simultaneous use of pimozide and fluconazole is contraindicated.
Quinidine: although no appropriate in vitro or in vivo studies have been carried out, the simultaneous use of fluconazole and quinidine can also lead to inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of ventricular tachysystolic arrhythmias of the "pirouette" type (torsade de points). Simultaneous use of quinidine and fluconazole is contraindicated.
Erythromycin: the simultaneous use of fluconazole and erythromycin potentially leads to an increased risk of developing cardiotoxicity (prolongation of the QT interval, torsade de points) and, as a result, sudden cardiac death. Simultaneous use of fluconazole and erythromycin is contraindicated.
Amiodarone: the combined use of fluconazole and amiodarone can lead to inhibition of the metabolism of amiodarone. The use of amiodarone was associated with prolongation of the QT interval. Simultaneous use of fluconazole and amiodarone is contraindicated.
Caution should be exercised and, possibly, adjust the dose while using the following drugs and fluconazole:
Drugs affecting fluconazole:
Hydrochlorothiazide: repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in plasma concentration of fluconazole by 40%. The effect of this severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the physician should take this into account.
Rifampicin: the simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of the half-life of fluconazole by 20%. In patients simultaneously receiving rifampicin, it is necessary to consider the feasibility of increasing the dose of fluconazole.
Drugs that are affected by fluconazole:
Fluconazole is a potent inhibitor of CYP2C9 isoenzyme and CYP2C19 cytochrome P450 and a moderate inhibitor of the isoenzyme CYP3A4. In addition, in addition to the effects listed below, there is a risk of increased concentrations in the blood plasma and other drugs metabolized by the isoenzymes CYP2C9, CYP2C19 and CYP3A4 while taking it with fluconazole. In this regard, caution should be exercised with the simultaneous use of these drugs, and if necessary, such combinations of patients should be under close medical supervision. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.
Alfentanil: a decrease in clearance and volume of distribution, an increase in the half-life of Alfentanil. Perhaps this is due to inhibition of the CYP3A4 isoenzyme by fluconazole. Alfentanil dosage adjustment may be required.
Amitriptyline, nortriptyline: an increase in effect. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured at the start of combination therapy with fluconazole and one week after the start. If necessary, adjust the dose of amitriptyline / nortriptyline.
Amphotericin B: The following results were observed in mouse studies (including immunosuppression): a small additive antifungal effect on systemic infection caused by C. albicans, no interaction with intracranial infection caused by Cryptococcus neoformans and antagonism on systemic infection caused by A fumigatus. The clinical significance of these results is not clear.
Anticoagulants: like other antifungal agents (azole derivatives), fluconazole, while used with warfarin, increases the prothrombin time (by 12%), and therefore, bleeding may develop (hematomas, bleeding from the nose and the gastrointestinal tract, hematuria melena). In patients receiving coumarin anticoagulants and fluconazole, it is necessary to constantly monitor the prothrombin time during therapy and for 8 days after simultaneous use. You should also evaluate the feasibility of dose adjustment of warfarin.
Azithromycin: with simultaneous oral administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, the pronounced pharmacokinetic interaction between the two drugs has not been established.
Benzodiazepines (short-acting): after ingestion of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole orally than when administered intravenously. If necessary, concomitant benzodiazepine therapy of patients taking fluconazole should be monitored to assess the feasibility of appropriately reducing the dose of benzodiazepine.
While taking a single dose of triazolam, fluconazole increases the AUC of triazolam by about 50%, Cmax - by 25-50% and half-life by 25-50% due to inhibition of triazolam metabolism. You may need a dose adjustment of triazolam.
Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. The risk of carbamazepine toxicity must be considered. The need to adjust the dose of carbamazepine depending on the concentration / effect should be evaluated.
Calcium channel blockers: Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by the CYP3A4 isoenzyme. Fluconazole increases the systemic exposure of calcium channel antagonists. Recommended to control the development of side effects.
Nevirapine: co-administration of fluconazole and nevirapine increases approximately 100% the exposure of nevirapine compared with control data on the individual use of nevirapine. Due to the risk of increased excretion of nevirapine with the concomitant use of medications, some precautions and careful monitoring of patients are necessary.
Cyclosporine: in patients with a transplanted kidney, the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporin in bone marrow recipients was observed. With simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.
Cyclophosphamide: with simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is observed. This combination is acceptable given the risk of increasing concentrations of bilirubin and creatinine.
Fentanyl: there is a report of one lethal outcome, possibly associated with the simultaneous administration of fentanyl and fluconazole. It is assumed that the violations are associated with intoxication with fentanyl. Fluconazole has been shown to significantly prolong fentanyl elimination time. It should be borne in mind that increasing the concentration of fentanyl can lead to depression of the respiratory function.
Halofantrine: fluconazole may increase plasma concentration of halofantrine due to inhibition of the CYP3A4 isoenzyme. It is possible to develop arrhythmias of ventricular tachysystolic type "pirouette" (torsade de points) with simultaneous use with fluconazole, as with other antifungal drugs of the azole series, therefore their combined use is not recommended.
HMG-CoA reductase inhibitors: with simultaneous use of fluconazole with HMG-CoA reductase inhibitors metabolized by a CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or a CYP2D6 isoenzyme (such as fluvastatin, the risk of developing myopathy, myopathy, and myopathy). If necessary, simultaneous therapy with these drugs, patients should be monitored to identify symptoms of myopathy and rhabdomyolysis. It is necessary to control the concentration of creatinine kinase. In the case of a significant increase in the concentration of creatinine kinase, or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the effects associated with antagonism of angiotensin-II receptors. Regular blood pressure monitoring is required.
Methadone: Fluconazole may increase the plasma concentration of methadone. You may need a dose adjustment of methadone.
Non-steroidal anti-inflammatory drugs (NSAIDs): Cmax and AUC of flurbiprofen are increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S - (+) - ibuprofen] increased by 15% and 82%, respectively, with simultaneous use of fluconazole with racemic ibuprofen (400 mg).
With simultaneous use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg Cmax and AUC celecoxib are increased by 68% and 134%, respectively. In this combination, you can halve the dose of celecoxib.
Despite the lack of targeted research, fluconazole may increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (for example, naproxen, lornoxicam, meloxicam, diclofenac). You may need a dose adjustment of NSAIDs.
With simultaneous use of NSAIDs and fluconazole, patients should be under close medical supervision in order to identify and control adverse events and manifestations of toxicity associated with NSAIDs.
Oral contraceptives: with simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, there is no significant effect on hormone levels, whereas with daily administration of 200 mg of fluconazole, AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and at 300 mg of fluconazole once a week, AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole in these doses is unlikely to affect the effectiveness of the combined oral contraceptive.
Phenytoin: simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If necessary, the simultaneous use of both drugs should monitor the concentration of phenytoin and adjust its dose accordingly to ensure therapeutic serum concentrations.
Ivacafluoro: when applied simultaneously with iwacafluoro, a stimulator of the cystic fibrosis transmembrane conductivity regulator (CFTR), an increase in ivacafluoro exposure by 3 times and hydroxymethyl ivacaphthore (M1) was observed by 1.9 times. Patients who simultaneously take moderate inhibitors of the CYP3A isoenzyme, such as fluconazole and erythromycin, are recommended to reduce the dose of iwacafluoro to 150 mg once a day.
Prednisone: there is a report on the development of acute adrenal insufficiency in a patient after liver transplantation against the background of withdrawal of fluconazole after a three-month course of therapy. Presumably, cessation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to an increased metabolism of prednisone.
Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole in order to assess the state of the adrenal cortex.
Rifabutin: simultaneous use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients receiving rifabutin and fluconazole simultaneously should be carefully monitored.
Saquinavir: AUC increases by approximately 50%, Cmax by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. You may need a dose adjustment of saquinavir.
Sirolimus: an increase in plasma sirolimus concentration, presumably due to inhibition of sirolimus metabolism through inhibition of CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with an appropriate dose adjustment for sirolimus depending on the effect / concentration.
Sulfonylurea preparations: fluconazole, while taking it, leads to an increase in the half-life of oral sulfonylurea preparations (chlorpropamide, glibenclamide, glipizide, and tolbutamide). Patients with diabetes mellitus can be prescribed the combined use of fluconazole and oral sulfonylurea drugs, but the possibility of hypoglycemia should be considered, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylurea drugs are necessary.
Tacrolimus: simultaneous use of fluconazole and tacrolimus (inside) leads to an increase in serum concentrations of the latter by 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine through the isoenzyme CYP3A4. Significant changes in the pharmacokinetics of drugs were not observed with the use of tacrolimus intravenously. Cases of nephrotoxicity are described. Patients taking both tacrolimus orally and fluconazole should be carefully monitored. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.
Theophylline: when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. When administering fluconazole to patients taking high-dose theophylline, or to patients with an increased risk of developing the toxic effect of theophylline, the symptoms of a theophylline overdose should be monitored and, if necessary, the therapy adjusted accordingly.
Tofacitinib: Exposure of tofacitinib is increased when it is combined with drugs that are both mild inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). It may be necessary to adjust the dose of tofacitinib.
Vinca alkaloid: despite the lack of targeted research, it is assumed that fluconazole may increase the concentration of vinca alkaloids (for example, vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may be due to inhibition of the CYP3A4 isoenzyme.
Vitamin A: there is a report of one case of undesirable reactions from the central nervous system (CNS) in the form of a brain pseudotumor with simultaneous use of all-transretinoic acid and fluconazole, which disappeared after the withdrawal of fluconazole. The use of this combination is possible, but you should remember about the possibility of unwanted reactions from the central nervous system.
Zidovudine: in case of simultaneous use with fluconazole, the increase in Cmax and AUC of zidovudine is noted by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg / day for 15 days, a significant increase in zidovudine AUC (20%) was found for patients with AIDS and ARC (AIDS-related complex).
Patients receiving such a combination should be monitored to identify side effects of zidovudine.
Voriconazole (an inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): simultaneous use of voriconazole (400 mg 2 times a day on the first day, then 200 mg twice a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively. It was shown that this effect persists with decreasing the dose and / or decreasing the frequency of administration of any of the drugs. The simultaneous use of voriconazole and fluconazole is not recommended.
Studies of the interaction of oral forms of fluconazole with its simultaneous intake with food, cimetidine, antacids, as well as after total body irradiation to prepare for bone marrow transplantation showed that these factors do not have a clinically significant effect on fluconazole absorption.
These interactions are established with repeated use of fluconazole; drug interactions resulting from a single dose of fluconazole are not known.
Doctors should be aware that interaction with other drugs has not been specifically studied, but it is possible.