Fluconazole - instructions for use, dose, side effects, contraindications

conversion of lanosterol of fungal cells to ergosterol; increases the permeability of the cell membrane, disrupts its growth and replication. Fluconazole, being highly selective for cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole to a lesser extent suppresses oxidative processes dependent on cytochrome P450 in human liver microsomes). Does not have anti-androgenic activity. It is active in opportunistic mycoses, including those caused by Candida spp. (including generalized forms of candidiasis on the background of immunodepression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp .; with endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).

There have been reports of superinfection caused by Candida strains other than Candida albicans, which often have a natural resistance to fluconazole (eg, Candida krussei). In such cases, alternative antifungal therapy may be required. Pharmacokinetics

Pharmacokinetics:

After intravenous administration fluconazole well penetrates into tissues and body fluids.

Distribution

The concentration in the blood plasma is in direct proportion to the dose. Concentrations of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid are similar to those in blood plasma.

In the fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding plasma levels are achieved.

Well penetrates into the cerebrospinal fluid; with fungal meningitis, the concentration in the cerebrospinal fluid is about 85% of that in the blood plasma.

90% equilibrium concentration of fluconazole in blood plasma (Css) is reached by 4-5 days. The introduction of a "shock" dose (on the first day), which is 2 times greater than the usual daily dose, allows one to achieve a concentration corresponding to 90% Css by day 2.

The apparent volume of distribution (Vd) approximates the total fluid content in the body. The connection with blood plasma proteins is low -11-12%. Metabolism and excretion

The half-life (Ti / 2) is 30 hours. It is an inhibitor of the isoenzyme CYP2C9 in the liver. It is excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). The clearance of fluconazole is proportional to the clearance of creatinine (CC).

The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T1 / 2 and KK. After hemodialysis, within 3 hours, the concentration of fluconazole in the blood plasma is reduced by 50%.

Pharmacokinetics of fluconazole is similar for intravenous administration and oral administration, which makes it easy to switch from one application to another. Pharmacokinetics in children

The following pharmacokinetic parameters were obtained in children:

Age	Dose (mg / kg)	Half-life (hour)	Area under the curve (μg-h / ml)
11 days - 11 months	Once - in / in 3 mg / kg	23	110,1
9 months - 13 years	Once - inside 2 mg / kg	25,0	94,7
9 months - 13 years	Once - inside 8 mg / kg	19,5	362,5
5 years - 15 years	Repeatedly - in / in 2 mg / kg	17,4*	67,4*
5 years - 15 years	Repeatedly - iv 4 mg / kg	15,2*	139,1*
5 years - 15 years	Multiple - IV dose of 8 mg / kg	17,6*	196,7*
Average age 7 years	Repeatedly - inside 3 mg / kg	15,5	41,6

* the indicator marked on the last day of Uninvited Children (about 28 weeks of development) fluconazole was administered intravenously at a dose of 6 mg / kg every third day before administration of a maximum of 5 doses at a time

time until the children stayed in the intensive care unit. The mean half-life was 74 h (within 44-185 h) on day 1,with a decrease on the 7th day on the average to 53 h (within 30-131 h) and on the 13th day, on average, to 47 h (within 27-68 h). The values of the area under the curve were 271 mcg / ml (within 173-385 mcg / ml) on day 1, then increased to 490 mcg / ml (within 292-734 mcg / ml) on day 7 and decreased to an average of 360 μg-h / ml (within the limits of 167-566 μg-h / ml) by the 13th day. The volume of distribution was 1183 ml / kg (within 1070-1470 ml / kg) on the 1 st day, then increased in the average to 1184 ml / kg (within 510-2130 ml / kg) on the 7th day and up to 1328 ml / kg (within 1040-1680 ml / kg) on the 13th day. Pharmacokinetics in elderly patientsA single application of fluconazole at a dose of 50 mg orally to elderly patients aged 65 years and older, some of whom concurrently took diuretics, found that the maximum concentration in the blood plasma of Stach was achieved 1.3 hours after admission and was 1.54 μg / ml, mean AUC values of 76.4 ± 20.3 μg-h / ml, and an average half-life of 46.2 hours. The values of these pharmacokinetic parameters are higher than in young patients. Simultaneous reception of diuretics did not cause a pronounced change in AUC and Cmax. The clearance of creatinine (74 ml / min), the percentage of fluconazole excreted unchanged by the kidneys (0-24 hours, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients is lower than in young patients, which is probably , is associated with a decreased renal function, characteristic of the elderly.Pharmacokinetics in patients with renal failure In patients with severe renal failure (glomerular filtration rate <20 ml / min), the elimination half-life increased from 30 to 98 hours.

Indications:

- Cryptococcosis, including cryptococcal meningitis and infections of other localization (eg, lungs, skin), both in patients with normal immune response, and in patients with various forms of immunodepression (including those with AIDS, organ transplantation); maintenance therapy to prevent recurrence of cryptococcosis in AIDS patients.

- Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infection, such as peritoneal, endocardial, eye, bronchopulmonary and urinary tract infections, including in patients with malignant tumors in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis.

- Prevention of fungal infections in patients with malignant tumors on the background of chemo- or radiation therapy.

- Deep endemic mycoses (coccidiomycosis and histoplasmosis) in patients with normal immunity.

- Candidiasis of the esophagus and mucous membranes in children.

Contraindications:

Hypersensitivity to the components of the drug, as well as to other antifungal agents - azole derivatives; simultaneous reception of terfenadine (against the background of the continuous use of fluconazole at a dose of 400 mg / day or more), as well as other drugs that extend the QT interval and are metabolized by the CYP3A4 isoenzyme: astemizole,

cisapride, erythromycin, pimozide and quinidine; lactation period.

Carefully:

Hepatic failure, renal insufficiency, the appearance of rash against the background of fluconazole in patients with superficial fungal

infection and invasive / systemic fungal infections,

simultaneous use of terfenadine and fluconazole in a dose of less than 400 mg / day, potentially proaritmogenic states in patients with multiple risk factors (organic heart disease, disorders electrolyte balance, simultaneous application of

drugs that cause arrhythmias, simultaneous use with rifabutin and other inducers of cytochrome P450, acetylsalicylic acid), pregnancy.

Pregnancy and lactation:

Adequate and controlled studies of pregnant women have not been conducted. Cases of multiple congenital malformations in newborns whose mothers received high-dose fluconazole (400-800 mg / day) for coccidioidomycosis for most or all of the first trimester have been reported. The following developmental disorders were noted: brachycephaly, development of the facial part of the skull, violation of the formation of the cranial vault, wolf mouth, bending of the femurs, thinning and lengthening of the ribs, arthrogryposis and congenital heart defects. At present, there is no evidence of a relationship of the listed congenital anomalies with the use of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

Avoid the use of fluconazole in pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of fluconazole for the mother significantly exceeds the possible risk to the fetus. Since the concentration of fluconazole in breast milk and in blood plasma is the same, the use of the drug during breastfeeding is contraindicated.

Dosing and Administration:

Solution for infusion is administered intravenously drip at a rate of no more than 200 mg / hour.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. When transferred from an intravenous administration to the use of the drug in the form intended for oral administration, and vice versa, there is no need to change the daily dose.

The infusion solution is compatible with 20% dextrose solution, Ringer's solution, Hartmann's solution, 5% dextrose solution and 0.9% potassium chloride solution, 4.2% sodium bicarbonate solution, 0.9% sodium chloride solution. Infusions can be performed with conventional transfusion kits using one of the above solvents. Adults

- In cryptococcal meningitis and cryptococcal infections of other sites, an average of 400 mg of fluconazole is used on the first day, and then treatment is continued at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; In cryptococcal meningitis, treatment usually lasts a minimum of 6-8 weeks.

- To prevent the recurrence of cryptococcal meningitis in patientsAIDS after completion of the full course of primary treatment with fluconazole 200 mg / day can be continued for a very long time (it is possible to switch to an oral form).

- With candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose averages 400 mg on the first day, and then at 200 mg per day. With insufficient clinical efficacy, the dose of fluconazole can be increased to 400 mg / day. The duration of therapy depends on clinical effectiveness.

- Prevention of fungal infections in patients with malignant tumors on the background of chemotherapy or radiation therapy, the recommended dose is 400 mg 1 time / day. Fluconazole apply a few days before the expected appearance of neutropenia and after an increase in the number of neutrophils more than 1000 / μL treatment is continued for another 7 days.

- With deep endemic mycoses, it may be necessary to use the drug in a dose of 200-400 mg / day for up to 2 years. The duration of therapy is determined individually; with coccidioidomycosis it is 11-24 months, with histoplasmosis - 3-17 months (it is possible to switch to an oral form).

Children

In children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose, which would exceed that of adults, that is, not more than 400 mg per day. The drug is used daily 1 time / day. If you need long-term therapy use special dosage forms for children.

- In cryptococcal meningitis and cryptococcal infections of other localizations, as well as in generalized candidiasis in children, the recommended dose is 6-12 mg / kg / day, depending on the severity of the disease. The duration of therapy is 10-12 weeks (before laboratory confirmation of absence of pathogens in cerebrospinal fluid).

- To prevent the recurrence of cryptococcal meningitis in children with AIDS, after the completion of the full course of primary treatment with fluconazole at a dose of 6 mg / kg / day can continue for a long time.

- When candidiasis of mucous membranes in children the recommended dose of fluconazole is 3 mg / kg / day. On the first day, a shock dose of 6 mg / kg can be administered in order to achieve a more rapid equilibrium equilibrium concentration.The duration of therapy is at least 3 weeks.

- When candidiasis of the esophagus in children fluconazole apply once in a dose of 3 mg / kg / day. On the first day, a shock dose of 6 mg / kg / day can be administered.

The duration of the therapy is at least 3 weeks and 2 weeks after the regression of the symptoms.

- For the prevention of fungal infections in children with reduced immunity, whose risk of infection is associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, fluconazole used once in a dose of 3-12 mg / kg / day. The duration of therapy is until elimination of induced neutropenia. Use of the drug in children under 4 weeks of age

It should be borne in mind that in newborns fluconazole output slowly. The first 2 weeks of life the drug is used in the same dose (in mg / kg) as in older children, but with an interval of 72 hours. Children at the age of 3 and 4 weeks the same dose administered at intervals of 48 hours.

Aged people

In the absence of violations of the kidneys should follow the usual dosage regimen.

Patients with impaired renal function

At QC less than 50 ml / min, the dosage regimen is required. Fluconazole is excreted mainly by the kidneys in unchanged form. With a single application, a dose change is not required. In patients with impaired renal function with repeated use of the drug, a shock dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indications) is determined according to the following table:

Creatinine clearance (ml / min)	Percent recommended dose
>50	100%
<50 (without dialysis)	50%
Patients on permanent dialysis	100% after each dialysis session

In children with impaired renal function, the daily dose of the drug should be reduced (in the same proportion as in adults), according to the degree of renal insufficiency. The drug solution contains sodium chloride; in each 100 ml bottle contains 15 mmol Na + (sodium ions) and SG (chloride ions), therefore, in patients who require a restriction of sodium or liquid intake, the rate of fluid administration must be considered.

Side effects:

Fluconazole, as a rule, is well tolerated.

Depending on the frequency of occurrence, the following groups of side effects are distinguished: often - more than 1%, infrequently - 0.1-1%, rarely - 0.01-0.1%; very rarely - less than 0.01%.

Allergic reactions: often - skin rash, infrequent - drug rash, urticaria, itchy skin, rarely - multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, edema person), acute generalized

exanthematous pustulosis, exfoliative dermatitis.

From the side of the central nervous system: often - headache, infrequently - dizziness, paresthesia, insomnia, drowsiness, convulsions, taste change, vertigo, rarely - tremor.

From the side of the digestive system: often - abdominal pain, nausea, vomiting, diarrhea, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (AF), infrequently - dyspepsia, flatulence, constipation, dryness of the oral mucosa, cholestasis , jaundice, hyperbilirubinemia, rarely liver failure, hepatitis, hepatocellular defeat,

hepatocellular necrosis, hepatotoxicity, in some cases with a fatal outcome.

On the part of the organs of hematopoiesis: infrequently - anemia, rarely - leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the cardiovascular system: rarely - prolongation of the interval QT, arrhythmia ventricular tachysystolic type "pirouette" (torsade de pointes).

Other: infrequent - decreased appetite, increased sweating, myalgia, weakness, asthenia, fatigue, fever, rarely - renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Overdose:

Symptoms, hallucinations, paranoid behavior.

Treatment: symptomatic, forced diuresis. Hemodialysis within 3 hours reduces the concentration of fluconazole in the blood plasma by approximately 50%.

Interaction:

Astemizole. The simultaneous use of fluconazole and astemizole can reduce the clearance of the latter. An increase in the concentration of astemizole in the blood plasma can lead to an elongation of the QT interval and a rare occurrence of torsade de pointes. Joint use of astemizole and fluconazole is contraindicated.

Pimozide. The simultaneous use of fluconazole and pimozide can lead to the suppression of the metabolism of pimozide, which increases the concentration of pimozide in the blood plasma, which can lead to an elongation of the QT interval and the rare occurrence of torsade de pointes.The combined use of pimozide and fluconazole is contraindicated. Terfenadine. The simultaneous 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 done under the close supervision of a physician.

Quinidine. The combined use of fluconazole and quinidine can lead to suppression of quinidine metabolism, which can lead to lengthening of the QT interval and rare cases of torsade de pointes. The combined use of quinidine and fluconazole is contraindicated.

Cisapride. With the simultaneous use of fluconazole and cisapride, unwanted reactions from the heart, including paroxysms of ventricular tachycardia (torsade de pointes). Simultaneous use of cisapride and fluconazole is contraindicated.

Erythromycin. The simultaneous use of fluconazole and erythromycin increases the risk of cardiotoxicity (prolongation of the QT interval, the appearance of torsade de pointes) and, consequently, sudden cardiac arrest. The combined use of erythromycin and fluconazole is contraindicated.

Lizromycin. In an open, randomized, three-way, cross-over study, 18 healthy volunteers evaluated the effect of azithromycin at a dose of 1200 mg on the pharmacokinetics of a single oral dose of 800 mg fluconazole,and the effect of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Alfentanil. In a combination of fluconazole (400 mg) and intravenous alfentanil (20 μg / kg) in healthy volunteers, the area under the concentration-time curve from 0 to 10 hours (AUCjo) of alfentanil was doubled, probably due to inhibition of the CYP3A4 isoenzyme. Alfventanyl dosage adjustment may be required.

Vinca alkaloids. Although the interaction between fluconazole and vinca alkaloids has not been studied, fluconazole can increase the concentration of vinca alkaloids in the blood plasma (for example, vincristine

or vinblastine), which leads to neurotoxicity, due to inhibition of the CYP3A4 isoenzyme.

Amitriptyline, nortriptylin. Fluconazole increases the effect of amitriptyline and nortriptyline. The concentration of 5-nortriptyline and / or S-amitriptyline should be measured at the start of the combination therapy and after one week. The dose of amitriptyline / nortriptyline should be adjusted if necessary.

Amphotericin B. Simultaneous administration of fluconazole and amphotericin In infected mice withnormal immunity and immunodeficiency has yielded the following results: slight increase in antifungal

effect in systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans, and antagonism of two drugs in systemic infection caused by A. fumigatus. The clinical significance of the results obtained in these studies is not known.

Anticoagulants. Fluconazole increases prothrombin time of indirect anticoagulants - coumarin derivatives (eg, warfarin) by an average of 12%, therefore careful monitoring of prothrombin time in patients taking fluconazole and indirect anticoagulants - coumarin derivatives. It may be necessary to adjust the dose of warfarin.

Acetylsalicylic acid. With concomitant use with acetylsalicylic acid, care should be taken (the risk of developing bronchial asthma).

Short-acting benzodiazepines (midazolam, triazolam). Fluconazole increases the plasma concentration of midazolam, which increases the risk of developing psychomotor effects (most pronounced when fluconazole is administered orally than intravenously).

With the combined use of fluconazole at a dose of 200 mg per day and triazolam at a dose of 0.25 mg orally, the AUC increases and the half-elimination period of triazolam is 4.4-fold and 2.3-fold, respectively. Potentiation and prolongation of the triazolam effect was detected when combined with fluconazole. With concomitant therapy

benzodiazepines in patients, receiving fluconazole, dose

benzodiazepines should be reduced, and patients should be properly observed.

Calcium channel blockers. Some antagonists of calcium channels (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole can potentially enhance the systemic effects of calcium channel antagonists. With the combined use of calcium channel blockers and fluconazole, frequent monitoring of side effects is recommended.

Vitamin A. One patient who received combination therapy with all-trans retinoic acid (acid form of vitamin A) and fluconazole reported the development of undesirable effects from the central nervous system (CNS) in the form of benign intracranial hypertension that resolved after fluconazole withdrawal.The combination of fluconazole and vitamin A can be used if you take into account the risk of side effects from the CNS.

Voriconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4). Simultaneous ingestion of voriconazole (400 mg every 12 hours on the first day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg / day for 4 days) in 8 healthy men led to an increase in the maximum plasma concentration (Stach) and AUC voriconazole by an average of 57% (90% confidence interval: 20%, 107%) and 79% (90% confidence interval: 40%, 128%), respectively. A reduction in the dose and / or frequency of the use of voriconazole and fluconazole, which would eliminate these effects, has not been established. Patients,

simultaneously receiving voriconazole and fluconazole, must be carefully observed.

Halofantrine. Fluconazole can increase the concentration of halophanthin in the blood plasma by inhibiting the iso-ferment CYP3A4. The simultaneous use of fluconazole and halofantrine may increase the risk of cardiotoxicity (prolongation of the QT interval, torsade de pointes) and, consequently, sudden cardiac arrest. Simultaneous use of fluconazole and halofantrine is not recommended.

Hydrochlorothiazide increases the concentration of fluconazole in blood plasma by 40%, but this does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time.

Zidouudin. Fluconazole increases Stach and AUC of zidovudine by 84% and 74%, respectively, due to a decrease of about 45% of zidovudine clearance after oral administration. The half-elimination period of zidovudine was also extended by approximately 128% after simultaneous administration with fluconazole. Patients receiving a combination of zidovudine and fluconazole should be carefully monitored for side effects of zidovudine, and if necessary, reduce the dose of zidovudine.

Inhibitors of HMG-CoA reductase. The risk of developing myopathy and rhabdomyolysis increases with the combined use of fluconazole and HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme, such as atorvastatin and simvastatin, or the isoenzyme CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be carefully monitored for the development of symptoms of myopathy and rhabdomyolysis, and the level of creatine kinase should be monitored.HMG-CoA reductase inhibitors should be abolished if there is an increase in the concentration of creatine kinase or whether myopathy or rhabdomyolysis is diagnosed or suspected.

Carbamazepine. Fluconazole inhibits the metabolism of carbamazepine and

increases the concentration of carbamazepine in blood plasma by 30%. There is a risk of developing toxicity of carbamazepine. You may need to adjust the dose of carbamazepine depending on its concentration in the blood plasma or side effects.

Losartan. Fluconazole inhibits the conversion of losartan to its active metabolite (E-31 74), the main effect of which is manifested in the blockade of angiotensin II receptors, which occurs during treatment with losartan. In patients receiving concomitantly fluconazole and losartan, blood pressure should be constantly monitored.

Methadone. Fluconazole can increase the concentration of methadone in the blood plasma, so you may need to adjust the dose of the latter. Non-steroidal anti-inflammatory drugs (NSAIDs). With the combined use of fluconazole and flurbiprofen, Stach and AUC of flurbiprofen increase by 23% and 81%, respectively.In addition, Stach and AUC of the pharmacologically active isomer of [8 - (+) - ibuprofen] are increased by 15% and 82%, respectively, when fluconazole is combined with the ibuprofen racemate (400 mg) compared with the intake of only racemic ibuprofen.

Also fluconazole can increase the systemic exposure of NSAIDs that are metabolized by the CYP2C9 isoenzyme (eg, naproxen, lornoxicam, meloxicam, diclofenac). It is recommended to carefully monitor the development of side effects caused by the intake of NSAIDs. It is possible to correct the dose of NSAIDs.

Oral hypoglycemic drugs, derivatives

sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). With their simultaneous use with fluconazole, the half-life of oral hypoglycemic drugs, derivatives

sulfonylureas, lengthens, which can lead to the development of hypoglycemia. Periodically monitor the concentration of glucose in the blood plasma and, if necessary, reduce the dose of hypoglycemic drugs.

Oral contraceptives. Multiple application of fluconazole (in doses of 50-200 mg) does not affect the effectiveness of combined oral contraceptives.

Prednisolone.A case of the development of acute adrenocortical insufficiency in a patient with a transplanted liver was reported, prednisolone, when fluconazole therapy, conducted for 3 months, was canceled. Presumably, the elimination of fluconazole caused an increase in the activity of the isoenzyme CYP3A4, which led to an increase in the metabolism of prednisolone. Patients who undergo long-term treatment with fluconazole and prednisolone should be carefully monitored for adrenocortical insufficiency after fluconazole withdrawal. Rifabutin. The simultaneous use of fluconazole and rifabutin can lead to an increase in plasma concentrations of the latter. AUC rifabutin increases to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients simultaneously receiving rifabutin and fluconazole, must be carefully observed.

Rifampicin. Simultaneous application of fluconazole and rifampicin resulted in a 25% reduction in AUC and a 20% increase in the half-life of fluconazole. With the simultaneous use of rifampicin and fluconazole, it is necessary to increase the dose of fluconazole.

Saquinavir. Fluconazole increases AUC and Saquinavir stax by approximately 50% and 55%, respectively, by inhibiting the hepatic metabolism of saquinavir with the CYP3A4 isoenzyme and inhibiting the P-glycoprotein. Interaction with saquinavir / ritonavir has not been studied and may be more pronounced, with a dose adjustment of saquinavir may be required.

Sirolimus. Fluconazole increases the concentration of sirolimus in blood plasma

presumably by inhibiting the metabolism of sirolimus

isoenzyme CYP3A4 and P-glycoprotein. At simultaneous

the use of sirolimus and fluconazole may require correction of the dose of sirolimus depending on its effect or concentration in the blood plasma. Tacrolimus. Fluconazole increases the plasma concentration of tacrolimus 5-fold when administered last inward due to the inhibition of tacrolimus metabolism by the CYP3A4 isoenzyme, which increases the risk of nephrotoxic action. Depending on the concentration of tacrolimus in the blood plasma, its dose should be reduced.

Theophylline. Fluconazole prolongs the half-life of theophylline and increases the risk of intoxication (it is necessary to correct its dose). Phenytoin. The simultaneous use of fluconazole and phenytoin is accompanied by an increase in the concentration of the latter in a clinically significant degree. Therefore, it is necessary to monitor the concentration of phenytoin and to select its dose to provide a therapeutic concentration in the blood plasma.

Fentanyl. One fatal case of fentanyl intoxication was recorded because of the possible simultaneous use with fluconazole. In addition, it has been shown in healthy volunteers that fluconazole significantly delayed excretion of fentanyl. Increased concentrations of fentanyl may lead to respiratory depression. Patients should be closely monitored in connection with the potential risk of respiratory depression. If necessary, adjust the dose of fentanyl.

Celecoxib. With the combined use of fluconazole (200 mg / day) and celecoxib (200 mg), Stach and AUC of the latter increase by 68% and 134%, respectively. When combined with fluconazole, the dose of celecoxib can be reduced by a factor of 2.

Cyclosporine. Fluconazole significantly increases the concentration in the blood plasma and AUC cyclosporine. With the simultaneous use of fluconazole at a dose of 200 mg / day and cyclosporine at a dose of 2.7 mg / kg / day, an increase in the AUC of cyclosporine is 1.8 times.This combination is possible if the dose of cyclosporine is reduced depending on its concentration in the blood plasma.

Cyclophosphamide. Combination therapy with cyclophosphamide and fluconazole leads to an increase in the concentration of bilirubin and creatinine in the blood plasma. The combination can be applied only after assessing the risk of increasing the concentration of bilirubin and creatinine in the blood plasma.

Everolimus. Fluconazole can increase the plasma concentration of everolimus due to inhibition of the CYP3A4 isoenzyme.

Special instructions:

Treatment should continue until the appearance of clinical-hematologic remission. Premature termination of treatment leads to relapse. Treatment can be started in the absence of seeding results or other laboratory tests, but if appropriate, appropriate correction of antifungal therapy is recommended.

During the treatment, it is necessary to monitor the blood counts (cellular composition, coagulability), kidney and liver function. It is necessary to monitor the prothrombin index when used simultaneously with indirect anticoagulants - coumarin derivatives. If there is a violation of kidney and liver function, stop using the drug.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver.

In the case of hepatotoxic effects associated with fluconazole, no dependence of their development on the total daily dose, duration of therapy, sex and age of the patient was noted.

The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued.

Against the background of taking the drug, patients had rare cases of development of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients with AIDS and malignant neoplasms are more likely to develop severe skin reactions with many drugs. In those cases where the rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When rashes appear in patients with systemic fungal infections, they should be carefully monitored, and with the appearance of bullous changes or multiform erythema fluconazole necessary cancel.It is recommended to monitor the concentration of cyclosporine in the blood plasma in patients receiving fluconazole, since in patients with kidney transplantation the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in the blood plasma. Caution should be exercised when using fluconazole with rifabutin or other drugs metabolized by the cytochrome P450 system. As with the use of other azoles, fluconazole in rare cases can cause anaphylactic reactions. Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. With fluconazole, an increase in the QT interval and fibrillation or flutter of the ventricles were very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and accompanying therapy contributing to the development of such disorders. Therefore, in such patients with potentially dangerous proarrhythmic conditions, fluconazole with caution. Evidence of the effectiveness of fluconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis,Sporotrichosis and histoplasmosis are limited, which makes it impossible to determine

specific recommendations for dosing. Fluconazole is a potent inhibitor of the CYP2C9 isoenzyme and a moderate inhibitor of the CYP3A4 isoenzyme. Fluconazole is also an inhibitor of the isoenzyme CYP2C19. With simultaneous therapy with drugs with a narrow therapeutic profile, metabolized isoenzymes CYP2C9, CYP2C19 and CYP3A4, caution is recommended. Women of childbearing age should use contraception.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. When using the drug should take into account the possibility of developing dizziness and seizures.

Form release / dosage:

Solution for infusions 2 mg / ml.

Packaging:

For 100 ml in bottles of polyethylene without a cap or with a welded euro bag, or a plastic cap, or an infusion plug.

One bottle together with instructions for medical use is placed in a pack of cardboard box. 10, 15, 24, 36, 40, 42, 48, 72, 80, 84, 96 bottles in packs are placed in a cardboard box.

For hospitals

For 1 bottle in a sealed bag of polymer film, or without a bag. 10, 15, 24, 36, 40, 42, 48, 72, 80, 84, 96 bottles in the hermetically sealed

sealed bags or without packages, along with instructions for medical use are placed in a box of cardboard. The number of instructions is equal to the number of bottles.

Storage conditions:

In a dry, dark place at a temperature of 2 to 30 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002126

Date of registration:05.07.2013

The owner of the registration certificate:EAST-FARM, CJSC EAST-FARM, CJSC Russia

Manufacturer: & nbsp

EAST-FARM, CJSC Russia

Representation: & nbspEAST-FARM, CJSCEAST-FARM, CJSC

Information update date: & nbsp25.09.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)