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Instructions for use FLUCONAZOLE

Fluconazole is used intravenously at a rate of no more than 10 ml/min once a day. When converting from intravenous administration to taking tablets and vice versa, there is no need to change the daily dose.

Fluconazole solution for infusion is compatible with the following solvents:

20% glucose solution, Ringer's solution, Hartmann's solution, potassium chloride solution in glucose, sodium bicarbonate solution 4.2%, aminofusin, isotonic sodium chloride solution.

For vaginal candidiasis and candidal balanitis, 100-200 mg/day is prescribed; often after a single administration of the drug recovery occurs. For other forms of mucosal candidiasis, 50-100 mg 1 time / day is recommended for 14-30 days.

For systemic candidiasis and cryptococcal infections, including meningitis, on the first day 400 mg, then 200-400 mg 1 time / day depending on the severity of the infection; the duration of therapy depends on clinical effectiveness; Usually the course of treatment for cryptococcal meningitis lasts 6-8 weeks.

To prevent relapse of cryptococcal meningitis in patients with AIDS, after completing the full course of primary therapy, the drug is prescribed to the patient in doses of at least 200 mg/day for a long period.

For skin mycoses, the recommended dose is 150-200 mg once a week or 50 mg 1 time / day, the duration of therapy is usually 2-4 weeks. However, athlete's foot may require treatment for up to 6 weeks. For onychomycosis, the recommended dose is 150-200 mg once a week; Treatment should be carried out until the affected nail is completely replaced with a healthy one.

Prevention of fungal infections in patients with malignant neoplasms - 100 mg every other day, while the patient is at high risk due to radiation or chemotherapy.

Elderly patients in the absence of renal dysfunction should adhere to the usual dosage regimen of the drug.

If renal function is impaired, the dose of fluconazole does not change after a single dose. When re-prescribing the drug to patients with impaired renal function, a loading dose of 50 mg to 400 mg should first be administered. If creatinine clearance (CC) is more than 50 ml/min, the usual dose of the drug is used (100% of the recommended dose). When CC is from 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used. For patients regularly undergoing hemodialysis, one dose of the drug is administered after each hemodialysis session.

For children over one year of age with normal kidney function, fluconazole is administered daily 1 time/day at the rate of 1-3 mg/kg/day (for candidiasis of the mucous membranes) and 3-12 mg/kg/day (for systemic candidiasis or cryptococcosis), depending on the severity of the disease. For children with impaired renal function, the daily dose of the drug should be reduced (in the same proportion as for adults), in accordance with the severity of renal failure.

In newborns, fluconazole is eliminated slowly. In the first 2 weeks of life, the drug is prescribed in the same dose (in mg/kg) as for older children, but with an interval of 72 hours. For children aged 2-4 weeks, the same dose is administered with an interval of 48 hours.

Fluconazole, 2 mg/ml, solution for infusion, 100 ml, 1 pc.

When used simultaneously with warfarin, fluconazole increases prothrombin time (by 12%), and therefore bleeding may develop (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time must be constantly monitored.

After oral administration of midazolam, fluconazole significantly increases midazolam concentrations and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally than when administered intravenously. If concomitant benzodiazepine therapy is necessary, patients taking fluconazole should be monitored for an appropriate benzodiazepine dose reduction.

With the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. ventricular fibrillation/flutter (ari). The use of fluconazole at a dose of 200 mg 1 time / day and cisapride at a dose of 20 mg 4 times / day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concomitant use of cisapride and fluconazole is contraindicated.

In patients after kidney transplantation, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine concentrations. However, with repeated doses of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. When using fluconazole and cyclosporine concomitantly, it is recommended to monitor the concentration of cyclosporine in the blood.

Repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in plasma concentrations of fluconazole by 40%. An effect of this magnitude does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but this should be taken into account.

With the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily intake of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole 1 time per day week - AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole in the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentrations. With this combination, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.

Concomitant use of fluconazole and rifabutin may lead to increased serum concentrations of the latter. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

The simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T1/2 of fluconazole by 20%. In patients concomitantly taking rifampicin, the advisability of increasing the dose of fluconazole must be considered.

Fluconazole, when taken simultaneously, leads to an increase in T1/2 of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide). In patients with diabetes mellitus, fluconazole and oral sulfonylureas can be prescribed together, but the possibility of hypoglycemia should be taken into account.

The simultaneous use of fluconazole and tacrolimus leads to an increase in plasma concentrations of the latter. Cases of nephrotoxicity have been described. Patients with this combination should be carefully monitored.

With the simultaneous use of azole antifungals 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 has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

When used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of developing theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.

When used simultaneously with fluconazole, an increase in zidovudine concentrations is observed, which is likely 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 in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was found.

When zidovudine 200 mg every 8 hours for 7 days was used in HIV-infected patients with or without fluconazole 400 mg/day with an interval of 21 days between the two regimens, a significant increase in zidovudine AUC was found (74%) when used simultaneously with fluconazole. Patients receiving this combination should be monitored for side effects of zidovudine.

The simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by isoenzymes of the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Patients with such combinations should be carefully monitored.

Fluconazole Canon (50mg, 150mg)

Single or multiple doses of fluconazole at a dose of 50 mg do not affect the metabolism of phenazone (Antipyrine) when taken simultaneously.

Concomitant use of fluconazole with the following drugs is contraindicated:

Cisapride: with simultaneous use of fluconazole with cisapride, adverse reactions from the heart are possible, including ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). 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 QT interval on the ECG. Concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine: When azole antifungals are used concomitantly with terfenadine, serious arrhythmias may occur as a result of prolongation of the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole in doses

400 mg/day and above causes a significant increase in the concentration of tefenadine in the blood plasma. Concomitant use of fluconazole at a dose 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 carried out under close monitoring.

Astemizole: Concomitant use of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Elevated concentrations of astemizole in blood plasma can lead to prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “torsade de pointes” type. The simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: No relevant in vitro or in vivo studies have been conducted, however, 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, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Although no in vitro or in vivo studies have been conducted, concomitant use of fluconazole and quinidine may also result in inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and, in some cases, can lead to the development of ventricular tachysystolic arrhythmias of the “torsade de pointes” type. The simultaneous use of fluconazole and quinidine is contraindicated.

Erythromycin: Concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (QT prolongation, torsade de pointes) and consequently sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.

Amiodarone: Concomitant use of fluconazole and amiodarone may result in inhibition of amiodarone metabolism. Amiodarone use has been associated with QT prolongation. The simultaneous use of fluconazole and amiodarone is contraindicated (see section "Contraindications").

Caution and possible dosage adjustments should be used when fluconazole and the following drugs are used concomitantly

Drugs that affect fluconazole:

Hydrochlorothiazide: repeated use of hydrochlorothiazide concomitantly with fluconazole leads to an increase in plasma concentrations of fluconazole by 40%. An effect of this severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, however, the doctor should take this into account.

Rifampicin: Combination with rifampicin results in a 25% reduction in the area under the concentration-time curve (AUC) and a 20% reduction in the plasma half-life of fluconazole. Therefore, in patients receiving rifampicin at the same time, it is advisable to increase the dose of fluconazole.

Drugs Affected by Fluconazole

Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9 and CYP2C19 and a moderate inhibitor of the CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations of other drugs metabolized by the isoenzymes CYP2C9, CYP2C19 and CYP3A4 when taken simultaneously with fluconazole. In this regard, when using these drugs and fluconazole simultaneously, caution should be exercised; if such combinations are necessary, patients should be under close medical supervision. It should be taken into account that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.

Tofacitinib: Tofacitinib exposure is increased when coadministered with drugs that are both moderate CYP3A4 inhibitors and strong CYP2C19 inhibitors (such as fluconazole). Dose adjustment of tofacitinib may be necessary.

Alfentanil: There is a decrease in clearance and volume of distribution, and an increase in the half-life of alfentanil. This may be due to inhibition of the CYP3A4 isoenzyme by fluconazole. Alfentanil dosage adjustment may be required.

Amitriptyline, nortriptyline: increased effect. Concentrations of 5-nortriptyline and/or S-amitriptyline can be measured at the start of combination therapy with fluconazole and one week after the start of treatment. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: In studies in mice (including immunosuppressed mice), the following results were observed: small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Criptococcus neoformans, and antagonism in systemic infection with A .fumigatus. The clinical significance of these results is unknown.

Anticoagulants: like other antifungal agents (azole derivatives), fluconazole, when used simultaneously with warfarin, increases prothrombin time (by 12%), and therefore bleeding may develop (hematomas, bleeding from the nose and gastrointestinal tract, hematuria , melena). In patients receiving coumarin anticoagulants and fluconazole, prothrombin time must be constantly monitored during therapy and for 8 days after simultaneous use. The advisability of adjusting the warfarin dose should also be assessed.

Azithromycin: with simultaneous oral administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, no pronounced pharmacokinetic interaction has been established.

Benzodiazepines (short-acting): After oral administration of midazolam, fluconazole significantly increases its concentration and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally than when administered intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate reduction in the benzodiazepine dose.

When coadministered with a single dose of triazolam, fluconazole increases triazolam AUC by approximately 50%, Cmax by 25-50%, and half-life by 25-50%, due to inhibition of triazolam metabolism. Triazolam dose adjustment may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. The risk of carbamazepine toxicity must be taken into account. The need for carbamazepine dose adjustment based on concentration/effect should be assessed.

Calcium channel blockers: Some calcium channel antagonists (nifedipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole may increase the systemic effect of calcium channel antagonists. It is recommended to monitor the development of side effects.

Cyclosporine: in kidney transplant patients, fluconazole dose

200 mg/day leads to a slow increase in plasma concentrations of cyclosporine. With repeated use of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. It is recommended to monitor cyclosporine blood concentrations in patients receiving fluconazole.

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 increased bilirubin and creatinine concentrations.

Fentanyl: There has been a report of a fatality possibly associated with the concomitant use of fluconazole and fentanyl. Fluconazole significantly prolongs the elimination time of fentanyl. Side effects may be related to fentanyl intoxication. It should be borne in mind that increased concentrations of fentanyl can lead to respiratory depression.

Halofantrine: Due to inhibition of CYP3A4, fluconazole may increase plasma concentrations of halofantrine. When used simultaneously with fluconazole and other azole antifungal drugs, the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes) is possible. Their combined use is not recommended.

HMG-CoA reductase inhibitors: with simultaneous use of fluconazole with HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 isoenzyme (for example, atorvastatin, simvastatin) or the CYP2D6 isoenzyme (fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If concomitant therapy with these drugs is necessary, patients should be monitored for symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatine kinase. If the concentration of this enzyme increases significantly 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-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular monitoring of blood pressure is necessary.

Methadone: Fluconazole may increase plasma concentrations of methadone. Methadone dose adjustment may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Flubiprofen Cmax and AUC increased by 23% and 81%, respectively. With the simultaneous use of fluconazole and racemic ibuprofen

(400 mg) Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively. With simultaneous use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg, the Cmax and AUC of celecoxib increased by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

Fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac), but no targeted studies have been conducted. NSAID dose adjustment may be required.

When fluconazole and NSAIDs are used concomitantly, patients should be closely monitored medically to identify and monitor NSAID-related adverse events and toxicities.

Oral contraceptives: with simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established. With daily dosing of 200 mg fluconazole, the AUCs of ethinyl estradiol and levonorgestrel increased by 40% and 24%, respectively; with 300 mg fluconazole once weekly, the AUCs of ethinyl estradiol and northethindrone increased by 24% and 13%, respectively. Thus, repeated use of fluconazole in the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Phenytoin: Concomitant use of fluconazole and phenytoin may increase plasma phenytoin concentrations to a clinically significant extent. Therefore, if it is necessary to use these drugs together, it is necessary to monitor phenytoin concentrations with dose adjustment in order to maintain drug concentrations within the therapeutic interval.

Prednisone: there is a report of the development of acute adrenal insufficiency in a patient after liver transplantation while fluconazole was discontinued after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased metabolism of prednisone. Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to evaluate the condition of the adrenal cortex.

Rifabutin: simultaneous use of fluconazole and rifabutin may be accompanied by an increase in the serum concentration of the latter by up to 80%. Cases of uveitis have been described with the simultaneous use of fluconazole and rifambutin. Patients receiving rifabutin and fluconazole concomitantly should be closely monitored.

Saquinavir: When used together, the AUC of saquinavir increases by approximately 50%, Cmax by 55%, and clearance decreases by 50% due to inhibition of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be necessary.

Sirolimus: with simultaneous use, an increase in the concentration of sirolimus in the blood plasma is observed, probably associated with inhibition of the CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Sulfonylureas: fluconazole increases the plasma half-life of oral hypoglycemic agents - sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide). The combined use of fluconazole and oral hypoglycemic agents in patients with diabetes mellitus is permitted, but the physician must be aware of the possibility of developing hypoglycemia. Regular monitoring of blood glucose levels and, if necessary, dose adjustment of sulfonylurea drugs is necessary.

Tacrolimus: when used concomitantly, fluconazole increases the concentration of tacrolimus (orally) in the blood plasma by 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine with the participation of the CYP3A4 isoenzyme. In this regard, the risk of nephrotoxicity increases. Patients taking tacrolimus by mouth should be closely monitored. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood. When tacrolimus is administered intravenously, no significant changes in the pharmacokinetics of the drug are observed.

Theophylline: when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. Patients receiving high doses of theophylline or who are at risk of developing theophylline toxicity should be monitored for early detection of symptoms of theophylline overdose. If necessary, therapy should be adjusted accordingly.

Vinca alkaloid: Fluconazole may increase plasma concentrations of vinca alkaloids (vincristine and vinblastine) and contribute to neurotoxicity. This may be due to inhibition of the CYP3A4 isoenzyme, however, targeted studies have not been conducted.

Vitamin A: There is a report of one case of the development of adverse reactions from the central nervous system (CNS) in the form of pseudotumor cerebri with simultaneous use of fluconazole with all-trans retinoic acid, which disappeared after discontinuation of fluconazole. The use of this combination is possible, but the possibility of developing adverse reactions from the central nervous system should be taken into account.

Zidovudine: In patients receiving a combination of fluconazole and zidovudine, there is an increase in Cmax and AUC of zidovudine by 84% and 74%, respectively, which is caused by a decrease in the conversion of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was found. Increased side effects of zidovudine should be expected when used together.

Nevirapine: Concomitant use of fluconazole and nevirapine results in an approximately 100% increase in nevirapine exposure. If these drugs are used together and there is a risk of increased exposure to nevirapine, use caution and monitor patients closely. There was no clinically significant effect of nevirapine on fluconazole.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): simultaneous use of fluconazole and 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 every day). first day, then 200 mg twice daily for 4 days) increased voriconazole concentrations and AUC by 57% and 79%, respectively. It has been shown that this effect persists when the dose is reduced and/or the frequency of administration of any of the drugs is reduced. Concomitant use of voriconazole and fluconazole is not recommended.

Ivacaftor: When coadministered with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) stimulator, there was a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl-ivacaftor (M1) exposure. For patients taking moderate CYP3A inhibitors concomitantly, such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.

Studies of the interaction of fluconazole when taken simultaneously with food, cimetidine, antacids, and also after total body irradiation in preparation for bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.

The listed interactions were established with repeated use of fluconazole; There are no known drug interactions resulting from a single dose of fluconazole. Doctors should note that interactions with other drugs have not been specifically studied, but are possible.