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 reactions from the heart, including arrhythmia, ventricular tachysystolic type of "pirouette" (torsade dc pointes) are possible. 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 marked increase in plasma concentrations of cisapride and an increase in the Q-T interval on the ECG.
Terfenadine.With the simultaneous use of azole antifungal agents and terfinadine, serious arrhythmias can occur as a result of an increase in the Q-T interval. When taking fluconazole at a dose of 200 mg / day, an increase in the Q-T interval is not established. However, the use of fluconazole at doses of 400 mg / day and higher 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. The simultaneous use of fluconazole with astemizol or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these agents. Elevated concentrations of astemizole in the blood plasma can lead to lengthening of the Q-T interval and in some cases to the development of torsade dc pointes (ventricular tachysystolic type). Simultaneous use of astemizole and fluconazole is contraindicated.
Pimozide.Despite the fact that no appropriate in vitro or in vivo studies have been performed, the simultaneous use of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide may lead to an elongation of the Q-T interval and, in some cases, the development of a torsade de pointes ventricular tachysystolic type arrhythmia. Simultaneous use of pimozide and fluconazole is contraindicated.
Quinidine. Despite. that no appropriate in vitro or in vivo studies have been performed, the simultaneous use of flucoazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with lengthening of the Q-T interval and in some cases with the development of torsade dc pointes (ventricular tachysystolic type). Simultaneous use of quinidine and fluconazole is contraindicated.
Erythromycin. The simultaneous use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the Q-T 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 flucoazole:
Hydrochlorothiazide. Simultaneous multiple use of flucoazole and hydrochlorothiazide can lead 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. Combination with rifampicip leads to a decrease in AUC (area under the concentration-time curve) by 25% and a shorter half-life of fluconazole from the plasma by 20%. Therefore, patients receiving concomitantly
rifampicin, it is advisable to increase the dose of fluconazole.
Fluconazole is a potent inhibitor of the enzyme CYP2C9 and CYP2C19 cytochrome P450 and a moderate inhibitor of the isoenzyme CYP3A4. In addition to the effects listed below, there is a risk of a rise in plasma concentrations of other drugs, which are mutilated by CYP2C9, CYP2C19 and CYP3A4 isoenzymes while being administered with fluconazole.
In this regard, care should be taken when using the following drugs at the same time,and if necessary, such combinations 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 a prolonged half-life.
Alfentanil. There is a decrease in clipping 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. Increase the effect. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured at the onset of combination therapy with fluconazole and a week after initiation of treatment. If necessary, adjust the dosage of amitriptyline / nortrintiline.
Amphotospin B. In studies in mice (including immunosuppression), the following results were noted: a slight additive antifungal effect in systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neofonmms and antagonism in systemic infection caused by A fumigants.The clinical significance of these results is not clear.
When fluconazole and other antifungal agents (azole derivatives) are used with warfarin, prothrombin time increases (on average by 12%). Possible development of bleeding (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, it is necessary to constantly monitor prothrombin time during therapy and for 8 days after the simultaneous addition. 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, there is no pronounced pharmacokinetic interaction between the two drugs.
Benzodiazepines. (short action). 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 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.
With the simultaneous administration of a single dose of triazolam,
fluconazole increases the AUC of triazolam by approximately 50%, C max by 25-50% and half-life by 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.
Cappamazepine.
Fluconazole inhibits the metabolism of carbamazepine and increases its serum concentration 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.
Cyclosporine. It is recommended to monitor the concentration of cyclosporine in the blood in patients receiving
fluconazole, since in patients with transplanted night, the administration of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in the plasma.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.
Cyclophosphamide. With the simultaneous use of cyclophosphamide and fluconazole, there is an increase in serum concentrations of bilirubin and creatinine. The combination of drugs is possible, taking into account the risk of these disorders.
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 halofaitin in the blood plasma in connection with the inhibition of the isoenzyme CYP3A4. With simultaneous use with fluconazole, as with other antifungal azole agents, the development of ventricular tachycystolic type arrhythmia pirouette is possible, so joint application is not recommended.
Inhibitors of GMC-CoA reductase.At simultaneous application of fluconazole with inhibitors of GMC-CoA reductase, metabolized by the isoenzyme CYP3A4 (such as
atorvastatin and
simvastatin) or isoenzyme CYP2D6 (fluvastagin), 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 with MMC-CoA reductase inhibitors should be discontinued.
Losartan. The flucopase inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular monitoring of blood pressure is necessary.
Methadone. A flucoid band can increase the plasma concentration of methadone. It may be necessary to adjust the dose of methadone /
Non-steroidal anti-inflammatory drugs (NSAIDs). Cmax and AUC of flurbiprofen are increased by 23% and 81% respectively.Similarly, Cmax and AUC of the pharmacologically active isomer [S - (+) - 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 of Cmax and AUC of celecoxib are increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.
With the simultaneous use of IPVP and fluconazole, patients should be under close medical supervision to identify and control adverse events and toxicity manifestations associated with NSAIDs.
Oral contraceptives. When combined combined oral contraceptive with fluconazole at a dose of 50 mg is not significantly affected by the level of hormones. With a daily intake of 200 mg of fluconazole AUC, ethinyl estradiol and levonorgestrel are increased by 40% and 24%, respectively.When 300 mg of fluconazole is taken once a week, the AUC of ethinyl estradiol and norethindrone increases 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. The simultaneous use of fluconazole and phenytoin can lead to an increase in the concentration of phenytoin in the plasma to a clinically significant degree. Therefore, when it is necessary to jointly use these drugs, it is necessary to monitor the concentrations of phenytoin with correction of its dose in order to maintain the drug level within the therapeutic interval.
Prednisone. There is a report on the development of acute adrenocortical insufficiency in a patient after liver transplantation with a withdrawal 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 under close medical supervision with the withdrawal of fluconazole in order to assess the state of the adrenal cortex.
Rifabutin.There have been reports of the interaction of fluconazole and rifabutin, accompanied by an increase in serum concentrations of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. It is necessary to carefully observe patients who simultaneously receive
rifabutin and
fluconazole.
Saquinavir. AUC is increased by approximately 50%. Сmax - by 55%. The clearance of saquinavir decreases approximately 50% due to the inhibition of hepatic metabolism of the isoenzyme CYP3A4 and P-glycoprotein. You may need to adjust the dose of saquinavir.
Sirolimus. An increase in the concentration of sirolimus in the blood plasma is presumably due to the inhibition of the metabolism of sirolimus through the 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.
Oral hypoglycemic agents.
Fluconazole increases the half-life of plasma from oral hypoglycemic agents - sulfonylurea derivatives (
chlorpropamide,
glibenclamide,
glipizide, tolbutamide). Joint use of fluconazole and oral hypoglycemic agents is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.It is necessary to regularly monitor blood glucose and, if necessary, dose adjustment of sulfonylurea drugs.
Tacrolimus. The use of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter by a factor of 5 by inhibiting the metabolism of tacrolimus occurring in the intestine through the isoenzyme CYP3A4. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of efflorescence 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. When using fluconazole at a dose of 200 mg for 14 days simultaneously (or in combination) with theophylline, the average plasma cleansing rate of theophylline is reduced by 18%. When fluconazole is prescribed for patients taking tsofillin in high doses, or for patients with an increased risk of developing the toxic effect of theophylline, one should observe the symptoms of theophylline overdose and, if necessary, adjust the therapy in the appropriate way.
Vinca alkaloid. Despite the lack of targeted research, it is
fluconazole can increase the concentration of vinca alkaloids (eg, vincristine and vinblastine) in the blood plasma and, thus, lead to isyrotoxicity, 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 central nervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of a fully 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. In patients receiving a combination of fluconazole and zidovudine, an increase in Cmax and AUC of zidovudine is observed at 84% and 74%, respectively, which is caused by 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 the isoenzyme CYP2C9, CYP2C19 and CYP3A4). The simultaneous use 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 in the concentration and AUC of voriconazole by 57% and 79%, respectively. It was shown that this effect persists with a decrease in the dose and / or the frequency of administration of any of the drugs. Simultaneous use of voriconazole and fluconazole is not recommended.
Tofacitinib: exposure to tofacitinib increases with its combination with drugs that are both moderate inhibitors of iso-ferment CYP3A4 and potent inhibitors of the isoenzyme CYP2C19 (for example,
fluconazole). It may be necessary to correct the dose of tofacitinib.
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 listed interactions are established at repeated application of a fluctuation band; interactions with drugs as a result of a single administration of fluconazole are not known.
Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible.