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

Fluconazole has shown activity in vitro and in clinical infections against most of the following microorganisms: Candida albicans, Candida glabrata (strains are moderately sensitive), Candidaparapsilosis, Candida tropicalis, Cryptococcus neoformans. Fluconazole showed in vitro activity against the following microorganisms: Candida duhliniemis, Candida guilliermondii, Candida kefyr, Candida lusitaniae, but the clinical significance of this is unknown.

With intravenous administration fluconazole was active on various models of fungal infections in animals. The activity of the drug in opportunistic mycoses, including those caused by Candida spp., Was demonstrated. (including generalized candidiasis in animals with depressed immunity); Cryptococcus neoformans (including intracranial infections); Microsporum spp. and Trychophyton spp. Fluconazole activity was also established in the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitidis, Coccidioides immitis (including intracranial infections) and Histoplasma capsulation in animals with normal and suppressed immunity.

Fluconazole is highly specific for fungal enzymes that are dependent on cytochrome P450.Therapy with fluconazole at a dose of 50 mg / day for up to 28 days does not affect the testosterone concentration in the blood plasma in men or the concentration of steroids in women of childbearing age. Fluconazole in a dose of 200-400 mg / day does not have a clinically significant effect on the levels of endogenous steroids and their response to stimulation of adrenocorticotropic hormone (ACTH) in healthy male volunteers.

Mechanisms of development of resistance to fluconazole

Resistance to fluconazole may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosterol 14-a-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene encoding the target enzyme lead to a modification of the target and a decrease in the affinity for azoles. Increasing the expression of the ERG 11 gene results in the production of high concentrations of the target enzyme, which necessitates an increase in the concentration of fluconazole in the intracellular fluid to suppress all the enzyme molecules in the cell.

The second significant mechanism of resistance is the active excretion of fluconazole from the intracellular spaceby activating two types of transporter involved in the active excretion of drugs from the fungal cell. These transports include the main mediator, encoded by MDR (multidrug resistance) genes, and the superfamily of the transport ATP-binding cassette encoded by CDR genes (Candida fungal resistance genes to azole antimycotics).

Hyperexpression of the MDR gene leads to resistance to fluconazole, while overexpression of CDR genes can lead to resistance to various azoles. Resistance to Candida glabrata is usually mediated by the overexpression of the CDR gene, which leads to resistance to many azoles. For those strains in which the minimum

inhibitory concentration (MIC) is defined as an intermediate (16-32 μg / mL) it is recommended to apply the maximum dose of fluconazole.

Candida krusei should be considered as resistant to fluconazole. The mechanism of resistance is associated with a reduced sensitivity of the target enzyme to the inhibitory effect of fluconazole.

Pharmacokinetics:

Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, fluconazole is also an inhibitor of the isoenzyme CYP2C19. The pharmacokinetics of fluconazole is similar for intravenous administration and ingestion. The concentration in the blood plasma is proportional to the dose and reaches a maximum (Cmax) 0.5-1.5 hours after fasting fluconazole, and the half-life (Tc) is about 30 hours. 90% of the equilibrium concentration is reached by 4-5 days after initiation of therapy (with repeated administration of the drug once a day).

The introduction of a shock dose (on day 1), twice the usual daily dose, makes it possible to achieve 90% of the equilibrium concentration by the 2nd day. The volume of distribution approximates the total water content in the body. Binding to plasma proteins is low (11-12%).

Fluconazole well penetrates into all body fluids. The concentrations of fluconazole in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, the concentrations of fluconazole in the cerebrospinal fluid are about 80% of its concentrations in the blood plasma.

In the stratum corneum, the epidermis, the dermis and the sweat fluid, high concentrations are reached that exceed the serum levels. Fluconazole accumulates in the stratum corneum.When administered at a dose of 50 mg once a day, the concentration of fluconazole after 12 days is 73 μg / g, and after 7 days after discontinuation of treatment, only 5.8 μg / g. When applied at a dose of 150 mg once a week, the fluconazole concentration in the stratum corneum on day 7 is 23.4 μg / g, and 7 days after the second dose, 7.1 μg / g. The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 μg / g in healthy and 1.8 μg / g in the affected nails; 6 months after completion of therapy fluconazole is still determined in the nails. The drug is excreted mainly by the kidneys; approximately 80 % of the administered dose

is found in the urine unchanged. The clearance of fluconazole is proportional to the creatinine clearance. No circulating metabolites were detected.

A long half-life from plasma allows fluconazole once a day or once a week - with other indications.

Pharmacokinetics in children

The following pharmacokinetic parameters were obtained in children:

Age	Dose	Half-life (hour)	AUC (μg / hr / mL)
11 days - 11 months	Once - in / in 3 mg / kg	23	110,1
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*

* the indicator marked on the last day

Preterm infants (about 28 weeks of development) fluconazole were administered intravenously at a dose of 6 mg / kg every third day prior to administration of a maximum of 5 doses while the children remained in the intensive care unit. The average half-life was 74 h (within 44-185 h) on day 1, with a decrease on the 7th day on average to 53 h (within 30-131 h) and on the 13th day on average to 47 h (within the limits of 27-68 hours).

The area under the concentration-time curve (AUC) was 271 μg / h / mL (within 173-385 μg / h / mL) on day 1, then increased to 490 μg / h / mL (within 292 -734 mcg / hr) on the 7th day and decreased to an average of 360 μg / h / mL (within the range of 167-566 μg / h / mL) by the 13th day.

The volume of distribution was 1183 ml / kg (within 1070-1470 ml / kg) on day 1, then increased to an average of 1,184 ml / kg (range 510-2130 ml / kg) on day 7 and up to 1328 ml / kg (within 1040-1680 ml / kg) on the 13th day.

Pharmacokinetics in elderly patients

It was found that with a single application of fluconazole at a dose of 50 mg orally in elderly patients aged 65 years and older, some of whom concurrently took diuretics, the Stach was achieved 1.3 hours after ingestion and was 1.54 μg / ml, the mean AUC is 76.4 ± 20.3 μg / h / ml, and the average half-life is 46.2 hours.The values of these pharmacokinetic parameters are higher than in young patients, which is probably associated with a decreased renal function characteristic of the elderly. Simultaneous reception of diuretics did not cause a pronounced change in AUC and Stach. Creatinine clearance (74 ml / min), the percentage of fluconazole excreted by the kidneys unchanged (0-24 hours, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients is lower compared to the young ones.

Indications:

Application in adults

cryptococcosis, including cryptococcal meningitis and infections of other locations (eg, lungs, skin), both in patients with normal immune response, and in patients with different forms of immunosuppression (including patients in HIV-infected patients at high risk for recurrence, organ transplantation); supportive therapy for the prevention of recurrence of cryptococcosis in HIV-infected patients with a high risk of recurrence;

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

candidiasis of the mucous membranes, oropharyngeal candidiasis, esophageal candidiasis, candiduria, chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures), when oral hygiene or local treatment is not enough, chronic cutaneous mucocutaneous candidiasis; prevention of recurrence of oropharyngeal candidiasis in HIV-infected patients with a high risk of recurrence;

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.

Use in children

treatment of candidiasis of the mucous membranes (oropharyngeal candidiasis and esophageal candidiasis);

invasive candidiasis;

cryptococcal meningitis;

prevention of candidal infections in patients with a weakened immune system;

maintenance therapy to prevent the recurrence of cryptococcal meningitis in children at high risk of recurrence.

Contraindications:

hypersensitivity to fluconazole, other components of the drug or azole substances with a similar fluconazole structure;
simultaneous reception of terfenadine during multiple use of fluconazole at a dose of 400 mg / day or more (see the section "Interaction with other medicinal products");
simultaneous use with drugs that increase the QT interval and metabolized with the isoenzyme CYP3A4, such as cisapride, astemizole, erythromycin, pimozide and quinidine (see the section "Interaction with other medicinal products"),

Carefully:

violation of liver function;

impaired renal function;

the appearance of rash against the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections;

simultaneous application of terfenadine and fluconazole in a dose of less than 400 mg / day;

potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease,disturbance of electrolyte balance and accompanying therapy contributing to the development of such disorders).

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 linking these congenital anomalies with low-dose fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy. During pregnancy, the use of fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment for the mother exceeds the possible risk to the fetus.

Women of childbearing age should use contraception.

Fluconazole is found in breast milk in concentrations close to plasma, so its appointment to women during breastfeeding is not recommended.

Dosing and Administration:

Intravenous infusion, injected at a rate of not more than 200 mg / h.

Therapy can begin before the results of sowing and other laboratory tests. However, antifungal therapy must be changed accordingly when the results of these studies become known.

When transferring a patient from an intravenous to an oral intake of the drug or vice versa, a daily dose change is not required.

Fluconazole solution for intravenous administration contains 0.9% solution of sodium chloride, which is equivalent to 7.7 mmol of sodium in each 50 ml bottle. Therefore, in patients who need to limit the intake of sodium or liquid, the rate of fluid administration must be considered.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. In infections requiring repeated use of an antifungal drug, treatment should continue until the disappearance of clinical or laboratory signs of an active fungal infection.Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis to prevent recurrence of infection usually require supportive therapy.

Application in adults

1. In cryptococcal meningitis and cryptococcal infections of other localization, 400 mg is usually administered on the first day, and then the treatment is continued at a dose of 200-400 mg once a day. In the case of treatment of life-threatening infections, the daily dose can be increased to 800 mg. The duration of treatment for cryptococcal infections depends on the presence of a clinical and mycological effect; In cryptococcal meningitis, treatment usually lasts at least 6-8 weeks.

2. To prevent the recurrence of cryptococcal meningitis in HIV-infected patients, after the completion of the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can continue indefinitely.

3. With candidemia, disseminated candidiasis and other invasive candidiasis infections, the saturating dose is 800 mg per day, the subsequent dose of 400 mg per day. The general recommendation for the duration of treatment is 2 weeks after the first negative result of blood culture and the disappearance of signs and symptoms of candidemia. The duration of therapy depends on clinical effectiveness.

4. The saturation dose in the treatment of oropharyngeal candidiasis is 200-

400 mg in the first day, the subsequent dose: 100-200 mg per day. The duration of treatment is 7-21 days (until the remission of oropharyngeal candidiasis is achieved). Patients with severe impairment of the immune system may require a longer treatment period.

With atrophic candidiasis of the oral cavity associated with the wearing of dentures, the drug is usually applied at a dose of 50 mg once a day for 14 days in combination with local antiseptic agents for prosthesis treatment.

The effective dose for candiduria is 200-400 mg per day with a duration of treatment of 7-21 days. Patients with severe impairment of the immune system may require a longer treatment period.

The saturation dose in the treatment of esophageal candidiasis is 200-400 mg in the first day, the subsequent dose: 100-200 mg per day. Duration of treatment is 14-30 days (until remission of candidiasis of the esophagus is achieved). Patients with severe impairment of the immune system may require a longer treatment period.

To prevent the recurrence of oropharyngeal candidiasis in HIV-infected patients with a high risk of recurrence fluconazole apply 100-200 mg per day or 200 mg 3 times a week for an indefinite period of time in patients with chronic low immunity.

5. For the prevention of candidiasis in patients with malignant tumors on the background of chemotherapy or radiation therapy, the recommended dose of fluconazole is 50-400 mg once a day, depending on the degree of risk of fungal infection. For patients at high risk of generalized infection, such as severe or persistent neutropenia, the recommended dose is 400 mg once daily. Fluconazole apply a few days before the expected development of neutropenia and, after

about

an increase in the number of neutrophils more than 1000 in mm, treatment continues for another 7 days.

6. With koshchidioidomycosis, it may be necessary to use the drug at 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; at a histoplasmosis - 3-17 months (transition to the oral form is possible). For some infections, especially with damage to the meninges, a dose of 800 mg per day can be considered.

Use in children

As with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. For children, the daily dose of the drug should not exceed that for adults. The maximum daily dose is 400 mg. Fluconazole apply daily once a day.

When candidiasis mucous membranes the recommended dose of fluconazole is

3 mg / kg / day. On the first day, to achieve a more rapid equilibrium concentration, a shock dose of 6 mg / kg can be used.

For treatment of invasive candidiasis and cryptococcal meningitis in children, the recommended dose is 6-12 mg / kg / day, depending on the severity of the disease.

To suppress recurrence of cryptococcal meningitis in children in HIV-infected children, the recommended dose of fluconazole is 6 mg / kg / day.

For the prevention of fungal infections in children with depressed immunity, in whom the risk development of infection associated with neutropenia, developing in result

cytotoxic chemotherapy or radiotherapy, the drug is used for

3-12 mg / kg / day depending on the manifestations and duration conservation of

induced neutropenia (see Fig.dose for adults; for children with renal insufficiency - see dose for patients with renal insufficiency).

Use in children aged 4 weeks and less

In newborns fluconazole output slowly. In the first 2 weeks of life, the drug is administered at the same dose (in mg / kg) as for older children, but at intervals of 72 hours. Do not exceed the maximum dose of 12 mg / kg every 72 hours. Children aged 3 and 4 weeks the same dose is administered at an interval of 48 hours. Do not exceed the maximum dose of 12 mg / kg every 48 hours.

Application in the elderly

In the absence of signs of renal failure, the drug is used in a usual dose. Patients with renal insufficiency (creatinine clearance <50 ml / min) dose of the drug is corrected, as described below.

Use in patients with renal insufficiency

With a single admission dose changes are not required. In patients (including children) with impaired renal function, repeated use of the drug should initially be given a shock dose of 50 mg to 400 mg, after which the daily dose (depending on the indication) is set according to the following table:

Creatinine clearance (ml / min)

Percent recommended dose

>50

<50 (without dialysis) Routine dialysis

100%

50%

100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended

dose after each dialysis session. On days when dialysis is not performed, patients should receive a reduced dose (depending on the creatinine clearance) of the drug. Use in patients with liver failure

There are limited data on the use of fluconazole in patients with liver failure. In this regard, when using fluconazole in this category of patients, you should be careful.

Side effects:

Drug tolerance is usually very good.

In clinical and post-marketing (*) studies of fluconazole, the following adverse reactions were noted:

From the nervous system: headache, dizziness *, convulsions *, taste change *, paresthesia, insomnia, drowsiness, tremor.

On the part of the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia *, vomiting *, dryness of the oral mucosa, constipation.

On the part of the hepatobiliary system: hepatotoxicity, in some cases fatal,increasing the concentration of bilirubin, serum transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), alkaline phosphatase, liver dysfunction * * hepatitis, hepatocellular necrosis * * jaundice, cholestasis, hepatocellular damage.

For the skin: rash, alopecia *, exfoliative skin lesions *, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

From the hematopoietic organs and lymphatic system *: leucopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

From the immune system *: anaphylaxis (including angioedema, edema of the face, hives, itching).

Cardio-vascular system *: increase in the QT interval on the ECG, ventricular tachycardia of the type "pirouette" (torsade de pointes) (see section "Special instructions".).

From the side of metabolism *: increased concentration of cholesterol and triglycerides in blood plasma, hypokalemia.

From the musculoskeletal system: myalgia.

Other: weakness, asthenia, fatigue, fever, increased

sweating, vertigo.

In some patients, especially with serious diseases such as AIDS or cancer, changes in blood counts, renal and hepatic function were observed with fluconazole and similar drugs (see section "Special instructions"), but the clinical significance of these changes and their relationship to treatment not installed.

Overdose:

There are reports of an overdose of fluconazole, and in one case, a 42-year-old patient infected with human immunodeficiency virus received hallucinations and paranoid behavior after taking 8200 mg of fluconazole. The patient was hospitalized; his condition returned to normal within 48 hours.

Symptoms: nausea, vomiting, diarrhea, in severe cases, convulsions, hallucinations, paranoid behavior.

Treatment: symptomatic therapy (including supportive measures and gastric lavage).

Fluconazole is excreted mainly through the kidneys, so forced diuresis, probably, can speed up the elimination of the drug. The hemodialysis session lasting 3 hours reduces the concentration of fluconazole in blood plasma by approximately 50%.

Interaction:

A single or multiple administration of fluconazole in a dose of 50 mg does not affect the metabolism of phenazone when they are simultaneously taken.

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 ventricular tachycardia of the type "pirouette" (torsade de pointes), are possible. The use of fluconazole at a dose of 200 mg / day and cisapride at a dose of 20 mg four 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 fluconazole was taken at a dose of 200 mg / day, there was no increase in the QT interval, however, the use of fluconazole at doses of 400 mg / day and higher causes a significant increase in the concentration of terfenadine in the plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated (see section

AND

"Contraindications"), Treatment with fluconazole in doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemisop: simultaneous application of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in the serum concentrations of these agents.Elevated concentrations of astemizole in the blood plasma can lead to lengthening of the QT interval and in some; cases to the development of ventricular tachycardia of the type "pirouette" (torsade de pointes). Simultaneous use of astemizole and fluconazole is contraindicated. Pimozide: Although 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 QT interval and in some cases to the development of a ventricular tachycardia of the type "pirouette" (torsade de pointes). Simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Although no appropriate in vitro or in vivo studies have been performed, the simultaneous use of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with the prolongation of the QT interval and in some cases with the development of ventricular tachycardia of the pirouette type. Simultaneous use of quinidine and fluconazole is contraindicated. Euituumiyin: simultaneous application of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the QT interval,ventricular tachycardia of the type "pirouette" (torsade de pointes) and, as a result, to sudden cardiac arrest. The simultaneous use of fluconazole and erythromycin is contraindicated.

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.

Care should be taken and, possibly, dose adjustments should be made while using the following drugs and fluconazole:

Drugs affecting fluconazole:

Hydrochlorothiazide: multiple application of hydrochlorothiazide simultaneously with

fluconazole leads to an increase in the concentration of fluconazole in 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.

Rifamins: simultaneous application of fluconazole and rifampicin leads to a 25% decrease 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 CYP2C9 isoenzyme cytochrome P450 and a moderate inhibitor of the CYP3A4 isoenzyme. In addition, there is a risk of an increase in plasma concentrations and other drugs metabolized by the isozymes CYP2C9 and CYP3A4 with simultaneous administration with fluconazole. In this regard, care should be taken with the simultaneous use of these drugs, 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 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 onset of combination therapy with fluconazole and a week after initiation.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 systemic infection caused by Candida albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans, and antagonism in systemic infection caused by Aspergillus fumigatus . The clinical significance of these results is not clear.

Anticoagulants: like other antifungal agents - azole derivatives, fluconazole, with simultaneous application with warfarin, increases prothrombin time (by 12%), which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). Patients receiving coumarin anticoagulants should constantly monitor prothrombin time. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

Azithromycin: with simultaneous application of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, no pronounced pharmacokinetic interaction between the two drugs has been established.

Beziodiazetes (short action): after taking midazolam, fluconazole

significantly increases the concentration of midazolam and psychomotor effects (most pronounced when fluconazole is administered orally than intravenously). If concomitant therapy with benzodiazepines is required in patients taking fluconazole, should be observed with a view to a corresponding reduction in the dose of benzodiazepine. With the simultaneous administration of a single dose of triazolam, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-32% and Tsh by 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and increases

serum carbamazepine 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.

Kalyi 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.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.

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 with HMG-CoA reductase inhibitors should be discontinued.

Lozautai: fluconazole inhibits the metabolism of losartan to its active metabolite

(E-3174), which is responsible for most of the effects associated with the antagonism of angiotensin-P 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): Cmax and AUC of flurbiprofen are increased by 23 % and 81 %, respectively. Similarly, Cmax and AUC

of the pharmacologically active isomer [8 - (+) - ibuprofen] increased by 15% and 82%, respectively, with the simultaneous use 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, Cmax and AUC of celecoxib are 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 application 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, the AUC of ethinyl estradiol and levonorgestrel increase by 40% and 24% respectively, and with 300 mg of fluconazole once a week, AUC of ethinylestradiol 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 is caused by 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: 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 simultaneously receiving rifabutin and fluconazole, must be carefully observed.

Saquinavir: AUC increases by approximately 50%, Cmax by 55%, saquinavir clearance decreases 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.

Preparations of sulfonylurea. 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 can be given joint use of fluconazole and oral sulfonylureas, but the possibility of developing hypoglycemia should be considered, in addition, regular monitoring of glucose in the blood and, if necessary, correction of the dose of sulfonylurea drugs.

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 simultaneously taking tacrolimus 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.

Zidovudine: when used concomitantly with fluconazole, there is an increase in Cmax and AUC of 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, patients with AIDS and AIDS-related complex (ARC) had a significant increase in zidovudine AUC (20%).

Patients receiving this combination should be observed to identify side effects of zidovudine.

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4): simultaneous oral administration 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, followed by 200 mg / day for 4 days) in 8 healthy men resulted in an increase in the maximum plasma concentration (Cmax) and AUC of 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 ..

Special instructions:

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

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including fatalities, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with the use of fluconazole, their apparent dependence on the total daily dose of the drug, the duration of therapy, the sex and age of the patient was not noted. The hepatotoxic effect of the drug was usually reversible; signs of it disappeared after discontinuation of therapy. Patients who, at the time of drug treatment, are impaired by liver function tests, should be monitored in order to identify signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with the use of fluconazole, the drug should be discarded.

As with the use of other azoles, fluconazole in rare cases can cause anaphylactic reactions.

During treatment with fluconazole, exfoliative skin lesions rarely developed in patients, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients with AIDS are more likely to develop severe skin reactions with many drugs. When a patient develops a rash during treatment of a superficial fungal infection that can be associated with the use of fluconazole, the drug should be discarded. When rashes appear in patients with invasive or systemic fungal infections, they should be carefully monitored and discontinued if bulleous lesions or multiforme exudative erythema occur.

Simultaneous use of fluconazole in doses less than 400 mg / day and terfenadine should be carefully monitored.

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,disturbances of electrolyte balance and accompanying therapy contributing to the development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole with caution.

Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using the drug. When fluconazole 150 mg is used for vaginal candidiasis, patients should be warned that symptom improvement usually occurs after 24 hours, but it often takes several days to completely disappear. If symptoms persist for several days, you should consult your doctor.

Fluconazole infusion solution is compatible with the following solutions:

20% dextrose solution

Ringer's solution

Hartmann's solution

potassium chloride solution in dextrose

4.2% solution of sodium bicarbonate

aminofusine

0.9% solution of sodium chloride.

Fluconazole can be injected into the infusion system together with one of the solutions listed above. Although cases of specific incompatibility of fluconazole with other agents are not described, nevertheless, it is not recommended to mix it with any other drugs before infusion.

Evidence of the efficacy of fluconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis, sporotrichosis and histoplasmosis is limited, which does not allow the determination of specific dosage recommendations. 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.

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

Patients should be careful when driving vehicles or when working with machinery, since dizziness and convulsions may occur during fluconazole treatment.

Form release / dosage:

Solution for infusions 2 mg / ml.

Packaging:To 50 ml in bottles of colorless glass I of hydrolytic class, hermetically sealed with rubber stoppers, crimped with aluminum or combined caps.

For 1, 2, 5 or 10 vials together with the instruction for use are placed in a pack of cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002673

Date of registration:23.10.2014

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

R-PHARM, JSC Russia

Representation: & nbspR-PHARM, JSC R-PHARM, JSC Russia

Information update date: & nbsp22.09.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)