A single or multiple administration of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrin) when they are taken concomitantly.
The simultaneous use of fluconazole with the following drugs is contraindicated:
Cisapride: with the simultaneous use of fluconazole and cisapride, unwanted heart reactions are possible, including torsade de pointes, ventricular tachysystolic type arrhythmia. The use of fluconazole at a dose of 200 mg once a day and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG.Simultaneous administration 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 receiving Fluconazole, 200 mg / day increasing QT interval is not set, but the use of fluconazole in doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated (see section "Contraindications"). Treatment with fluconazole in doses less than 400 mg / day in combination with terfenadine should be carefully monitored.
Astemizole: simultaneous application of fluconazole with astemizole or other drugs the metabolism of which the cytochrome P450 system may be accompanied by increased serum concentrations of these agents. Astemizole elevated plasma concentrations can lead to QT prolongation, and in some cases, to the development of ventricular arrhythmias tahisistolicheskoy type "pirouette" (torsade de pointes). Simultaneous use of astemizole and fluconazole is contraindicated.
Pimozide: despite the fact that no relevant studies have been conducted in vitro or in vivo, simultaneous application of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide can lead to an extension of the QT interval and, in some cases, to the development of a torsade de pointes ventricular tachycystolic type arrhythmia. Simultaneous use of pimozide and fluconazole is contraindicated.
Quinidine: despite the fact that no relevant studies have been carried out in vitro or in vivo, simultaneous application of fluconazole and quinidine may 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 torsade de pointes, a ventricular tachysystolic type arrhythmia. Simultaneous use of quinidine and fluconazole is contraindicated.
Erythromycin: simultaneous application of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the QT interval, torsade de pointes) and, as a result, sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.
Care should be taken and, possibly, dose adjustments should be made while using the following drugs and fluconazole.
Drugs affecting fluconazole:
Hydrochlorothiazide: repeated application of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in blood plasma by 40%. The effect of this degree of expression does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the doctor should take this into account.
Rifampicin: simultaneous application of fluconazole and rifampicin leads to a 25% reduction in AUC and a 20% decrease in the half-life of fluconazole. In patients who simultaneously take rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.
Drugs affected by fluconazole: fluconazole is a potent inhibitor of the isoenzyme CYP2C9 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 a rise in plasma concentrations of other drugs metabolized by CYP2C9, CYP2C19 and CYP3A4 isoenzymes while being administered with fluconazole.In this regard, caution should be exercised when using these drugs at the same time, and if necessary, such combinations should be carefully monitored by patients. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to a prolonged half-life.
Alfentanil: there is a decrease in clearance and volume of distribution, an increase in the half-life of alfentanil. Perhaps this is due to the inhibition of the isoenzyme CYP3A4 by fluconazole. Alfventanyl dosage adjustment may be required.
Amitriptyline, nortriptyline: increased effect. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured at the beginning of the combined therapy with fluconazole and a week after the start. If necessary, adjust the dose of amitriptyline / nortriptyline.
Amphotericin B: In studies on mice (including immunosuppression), the following results were noted: a slight additive antifungal effect in case of systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans and antagonism in case of systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.
Anticoagulants: like other antifungal agents (azole derivatives), fluconazole, with simultaneous use with warfarin increases prothrombin time (by 12%), which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, it is necessary to constantly monitor prothrombin time. Also, the appropriateness of correcting the dose of warfarin should be evaluated.
Azithromycin: with the simultaneous administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg of pronounced pharmacokinetic interaction between both drugs is not established.
Benzodiazepines (short-acting): after ingestion of midazolam, fluconazole significantly increases the concentration midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole orally than with its use intravenously. If concomitant therapy with benzodiazepines is required in patients taking fluconazole, should be monitored to assess the appropriateness of an appropriate dose reduction for benzodiazepine.
At simultaneous reception of a single dose triazolam, fluconazole increases the area under the "concentration-time" curve of the triazolam by approximately 50%, the maximum con centration - by 25-32% and half-life by 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.
Carbamazepine: fluconazole It inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. It is necessary to consider the risk of development of toxicity of carbamazepine. It is necessary to evaluate the need for correcting the dose of carbamazepine as a function of concentration / effect.
Calcium channel blockers: some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the isoenzyme CYP3A4. Fluconazole increases the systemic exposure of calcium channel antagonists. It is recommended to control the development of side effects.
Cyclosporin: 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, changes in the concentration of cyclosporin in bone marrow recipients were not observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.
Cyclophosphamide: with the simultaneous use of cyclophosphamide and fluconazole, there is an increase in serum concentrations of bilirubin and creatinine. This combination is acceptable given the risk of increasing concentrations of bilirubin and creatinine.
Fentanyl: there is a report of one fatal outcome, possibly associated with simultaneous administration of fentanyl and fluconazole. It is assumed that the violations are associated with intoxication with fentanyl. It was shown that fluconazole significantly prolongs the excretion time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl may lead to inhibition of respiratory function.
Halofantrine: fluconazole can increase the concentration of halophanthin in the blood plasma in connection with the inhibition of the isoenzyme CYP3A4.
Inhibitors of HMG-CoA reductase: when fluconazole is simultaneously used with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as, atorvastatin and simvastatin) or the isoenzyme CYP2D6 (such as, fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If it is necessary to simultaneously treat these drugs, patients should be observed to identify the symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. In the case of a significant increase in the concentration of creatinine kinase or if there is a diagnosis or suspected development of myopathy or rhabdomyolysis, therapy inhibitors of HMG-CoA reductase 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 the antagonism of angiotensin-II receptors. Regular monitoring of blood pressure is necessary.
Methadone: fluconazole can increase the plasma concentration of methadone. Methadone dose adjustment may be necessary.
Non-steroidal anti-inflammatory drugs (NSAIDs): maximum concentration and area under the concentration-time curve of flurbiprofen increased by 23% and 81%, respectively. Similarly maximum concentration and area under the "concentration-time" curveof the pharmacologically active isomer [8 - (+) - ibuprofen] increased by 15% and 82%, respectively, with simultaneous application of fluconazole with racemic ibuprofen (400 mg). With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib at a dose of 200 mg maximum concentration and area under the "concentration-time" curve celecoxib increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.
Despite the lack of targeted research fluconazole can increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (eg, naproxen, lornoxicam, meloxicam, diclofenac). You may need to adjust the dose of NSAIDs.
With the simultaneous use of NSAIDs and fluconazole, patients should be carefully monitored to detect and control adverse events and 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 the level of hormones, whereas with a daily intake of 200 mg fluconazole area under the curve "concentration-time" ethinyl estradiol and levonorgestrel are increased by 40% and 24%, respectively, and when 300 mg of fluconazole is taken once a week, area under the curve "concentration-time" Ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, the repeated use of fluconazole at 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 simultaneous use of both drugs is necessary, the concentration of phenytoin should be monitored and its dose adjusted accordingly to ensure therapeutic serum concentration.
Prednisone: There is a report on the development of acute adrenal insufficiency in the patient after liver transplantation on the background of the cancellation of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the isoenzyme CYP3A4, which led to an increased metabolism of prednisone.Patients receiving combination therapy with prednisone and fluconazole should be carefully monitored when fluconazole is withdrawn to evaluate the condition of the adrenal cortex.
Rifabutin: simultaneous application 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 concurrently rifabutin and fluconazole, must be carefully observed.
Saquinavir: area under the curve "concentration-time" increases by approximately 50%, maximum concentration - by 55%, saquinavir clearance is reduced by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. You may need to adjust the dose of saquinavir.
Sirolimus: an increase in the concentration of sirolimus in the blood plasma, presumably due to the inhibition of the metabolism of sirolimus through inhibition of the isoenzyme CYP3A4 and P-glycoprotein. This combination can be applied with appropriate correction of the dose of sirolimus depending on the effect / concentration.
Sulfonylurea preparations: fluconazole, with simultaneous admission, leads to an increase in the half-life of oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus may be prescribed joint use of fluconazole and oral sulfonylureas, but this should take into account the possibility of developing hypoglycemia, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylureas.
Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter up to 5 times by inhibiting the metabolism of tacrolimus occurring in the intestine via the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of nephrotoxicity are described. Patients who simultaneously take tacrolimus inside and fluconazole, should be carefully observed. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.
Theophylline: with simultaneous application with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. In the administration of fluconazole to patients receiving theophylline in high doses, or patients with an increased risk of toxic theophylline, one should observe the symptoms of theophylline overdose and, if necessary, adjust the therapy accordingly.
Tofacitinib: exposure to tofacitinib increases with its combination with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). It may be necessary to correct the dose of tofacitinib.
Vinca alkaloid: despite the lack of targeted studies, it is assumed that fluconazole can increase the concentration of vinca alkaloids (eg, vincristine and vinblastine) in the blood plasma and, thus, lead to neurotoxicity, which may possibly be due to inhibition of the CYP3A4 isoenzyme.
Vitamin A: there is a report of one case of development of undesirable reactions from the centralnervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of all transretinic acid and fluconazole, which disappeared after the withdrawal of fluconazole. The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the CNS.
Zidovudine: with simultaneous application with fluconazole, there is an increase maximum concentration and area under the "concentration-time" curve zidovudine 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 treatment with fluconazole at a dose of 200 mg / day for 15 days, a significant increase in AUC of zidovudine (20%) was found in patients with AIDS and ARC (AIDS-related complex). Patients receiving this combination should be observed to identify side effects of zidovudine.
Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4): simultaneous application of voriconazole (400 mg twice a day on the first day, then 200 mg twice daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) leads to an increase maximum concentration and area under the "concentration-time" curve voriconazole by 57% and 79%, respectively. It was shown that this effect persists with a reduction in the dose and / or a decrease in the frequency of administration of any of the drugs. Simultaneous use of voriconazole and fluconazole is not recommended.
Investigations of the interaction of oral forms of fluconazole with its simultaneous administration with food, cimetidine, antacids, and after total body irradiation for the preparation of bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.
The above interactions were established with repeated application of fluconazole; interactions with drugs as a result of a single dose of fluconazole are unknown.
Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible.