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

Excipients: lactose monohydrate - 138.8 mg; corn starch - 49,0 mg; povidone (low molecular weight polyvinylpyrrolidone) - 7.0 mg; calcium stearate - 3.0 mg; silicon dioxide colloidal - 1.5 mg; sodium lauryl sulfate - 0.7 mg; capsules hard gelatinous № 0: [titanium dioxide - 2.0%, gelatin - up to 100%].

Description:

Hard gelatin capsules No. 3 with white body, orange lid (for 50 mg dosage) and No. 0 white (for a dosage of 150 mg). The contents of the capsules are a powder or compacted mass of white or white with a yellowish tinge color, disintegrating when pressed.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Fluconazole - a triazole antifungal agent, is a potent selective inhibitor of the synthesis of sterols in a fungal cell.

Fluconazole demonstrated activity against the following microorganisms: Candida albicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

) showed the activity of fluconazole in vitro for the following microorganisms, however, the clinical significance of this is unknown: Candida dubliniensis, Candida guilliermondii, Candida kelyr, Candida lusitaniae.

Ingestion fluconazole shows activity on various models of fungal infections in animals. Fluconazole Effective in opportunistic mycoses, in that mule caused Candida spp. (including generalized candidiasis in animals with immunosuppression), Cryptococcus neoformans (including intracranial \ infection), Microsporum spp. and Trychophyton spp. The activity of olunconazole on the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Coccidioidcs immitis (including intracranial I infections) and Histoplasma capsuiatum in animals with normal and depressed 1 mhmunitetom.

Fluconazole is highly specific for fungal enzymes. dependent on the cytochrome P450 system. Therapy with fluconazole at a dose of 50 mg / day for up to 28 days does not affect the concentration of testosterone 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 concentrations 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 can develop in the following cases: a qualitative or quantitative change in the enzyme, which is a target for fluconazole (lanosteryl 14-a-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

"'Mutation mutations in the gene ERG 11, which encodes the target enzyme, lead to a modification of the target and a decrease in the affinity for azoles. Increased gene expression ERG 11 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.

A second significant mechanism of resistance is the active excretion of luconazole from the intracellular space by activating two types of transporter involved in the active excretion of drug substances 13 fungal cells. These transports include the main intermediary, coded by ■ dreams MDR (multidrug resistance - multiple drug resistance), and; the ATP-binding transporter cassette family, encoded by genes CDR genes of resistance of fungi Candida to azole antimycotics).

Hyperexpression of the gene MDR leads to resistance to fluconazole, while at the same time overexpression of genes CDR can lead to resistance to various azoles. Resistance Candida glabrata is usually mediated by gene overexpression CDR, 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 doses 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:

Suction

After oral administration fluconazole it is well absorbed, its bioavailability is 90%. The maximum concentration (C_max) after oral administration of 150 mg is 90% of the blood plasma level when administered intravenously at a dose of 2.5-3.5 mg / kg. Simultaneous food intake does not affect the absorption of fluconazole ingested. The concentration in the blood plasma reaches a maximum after 0.5-1.5 hours (TCmax) after administration. The concentration in the blood plasma is in direct proportion to the dose.

90% of the equilibrium concentration is reached by the 4th-5th day after initiation of therapy (when n repeated administration of the drug once a day).

The use on the first day of a dose, which is 2 times higher than the usual daily dose, allows you to achieve a plasma concentration of fluconazole equal to 90% of the equilibrium concentration by the second day. Apparent volume of distribution (Vd) approaches the total volume of water in the body. Binding to blood plasma proteins - low (11-12%).

Distributed not

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

In the stratum corneum, the epidermis, the dermis and the sweat fluid, high concentrations are reached, which exceed the plasma concentration.

Metabolism

Less than 5% of fluconazole is metabolized by primary passage through the liver. The half-life (T1/2) of fluconazole is about 30 hours. Long-term T1/2 from the blood plasma allows you to take fluconazole once for vaginal candidiasis and once in the bluish or once a week - with other indications.

Excretion

Fluconazole is excreted mainly by the kidneys. Approximately 80% of the administered dose is excreted in unchanged form. The clearance of fluconazole is proportional to the clearance of creatinine (CC). Metabolites of fluconazole in peripheral blood were not detected.

Pharmacokinetics in children

Age	Dose	Period half-life (hour)	The area under the concentration-time curve (AUC) (μg-h / ml)
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
Average age 7 years	Repeatedly - inside 3 mg / kg	15,5	41,6

Pharmacokinetics in special patient groups Patients with renal insufficiency

In patients with severe renal failure (glomerular filtration rate <20 ml / min) T1/2 increased from 30 to 98 hours. Therefore, in the future, it is necessary to reduce the dose of the drug.

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 simultaneously took diuretics, Cmax was 1.54 μg / ml and was achieved after 1.3 hours after taking the drug.Mean values AUC were 76.4 ± 20.3 μg-h / ml, the mean terminal T1/2 was 46.2 hours. These pharmacokinetic parameters are higher than those described in healthy young volunteers. Simultaneous reception of diuretics did not significantly change AUC or C_max CK (74 ml / min), fluconazole concentration found unchanged in urine (0-24 h, 22%), and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients were generally lower than in young volunteers. Therefore, a change in the distribution of fluconazole in elderly patients appears to be associated with a decreased renal function in this age group.

Indications:

Fluconazole is indicated for the treatment of the following diseases in adults: cryptococcal meningitis; coccidioidomycosis; invasive candidiasis;

mucous candidiasis, including oropharyngeal candidiasis, esophageal candidiasis, candiduria and chronic cutaneous mucocutaneous candidiasis;

chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures), when compliance with oral hygiene or local treatment is not enough;

vaginal candidiasis, acute or recurrent, when local therapy is not applicable;

Candidiasis balanitis, when local therapy is not applicable;

dermatomycosis, including foot dermatophytosis, torso dermatophyte, inguinal dermatophytosis, varicoloured skin and skin candidiasis infections when systemic treatment is indicated;

nail dermatophytosis (onychomycosis), when treatment with other drugs is acceptable.

Fluconazole is indicated for the prevention of the following diseases in adults:

recurrence of cryptococcal meningitis in patients with a high risk of recurrence; relapses of oropharyngeal candidiasis and esophageal candidiasis in HIV-infected patients with a high risk of recurrence;

to reduce the frequency of recurrence of vaginal candidiasis (4 or more episodes per year); for the prevention of candidal infections in patients with prolonged neutropenia (such as patients with hemoblastosis undergoing chemotherapy, or patients undergoing hematopoietic stem cell transplantation).

Fluconazole is indicated for the treatment of children.

Fluconazole is used to treat mucosal candidiasis (oropharyngeal candidiasis and esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and the prevention of candidal infections in patients with a weakened immune system. Fluconazole can be used as 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 other azole compounds;
simultaneous reception of terfenadine (against the background of a constant intake of fluconazole at a dose of 400 mg per day or more);
simultaneous application with cisapride, astemizole, pimozide, quinidine, erythromycin and other drugs capable of lengthening the interval QT and cause ventricular tachycardia, including ventricular pirouette tachycardia, which are metabolized by the cytochrome P450 isoenzyme CYP3A4;
lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
the period of breastfeeding;
Children under 3 years old (for this dosage form).

Carefully:

- Hepatic and / or renal insufficiency;

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

- simultaneous reception of tfrfenadina and fluconazole in a dose of less than 400 mg per day;

- potentially proaritmogennoe condition in a patient with multiple risk factors (organic heart diseases, disorders of electrolyte balance, simultaneous reception of drugs that cause arrhythmias);

- simultaneous with rifabutin or other drugs the metabolism of which is carried isozymes of cytochrome P450;

- simultaneous reception of potentially hepatotoxic drugs;

- Alcoholism;

intolerance to acetylsalicylic acid;

-- Pregnancy.

Pregnancy and lactation:

Adequate and controlled studies of the use of fluconazole in pregnant women have not been conducted. Described several cases of multiple congenital Torok neonates whose mothers throughout most or all Gerwen trimester of pregnancy obtained fluconazole in high dose therapy 400-800 mg / day).

BThe following developmental disorder marked yli: brachycephaly, violation of the front part of the skull, a violation of the formation of the cranial vault, a cleft palate, the curvature of the femoral bone thinning and elongation of the ribs, arthrogryposis and congenital malformations: erdtsa.At present, there is no evidence of a link between the listed congenital anomalies: the use of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

During pregnancy, fluconazole should be avoided, except for severe or life-threatening forms of fungal infections, if the intended benefit to the mother exceeds the possible risk to the fetus.

Fluconazole is found in breast milk in the same concentration as in blood plasma, so its appointment during breastfeeding is contraindicated.

Dosing and Administration:

Inside. Capsules swallow whole.

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 intravenous to oral administration of the drug or vice versa, a daily dose change is not required.

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

Application in adults

- When cryptococcal meningitis and krintococcal infections of other localization on the first day usually use the drug at a dose of 400 mg, and then continue treatment at a dose of 200-400 mg once a day. 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. In cases of treatment of life-threatening infections, the daily dose can be increased to 800 mg. To prevent the recurrence of cryptococcal meningitis in patients at high risk, after the completion of the full course of primary treatment with fluconazole at a dose of 200 mg / day can continue for an indefinite period of time.

- With coccidioidomycosis, it may be necessary to use the drug in a dose of 200-400 mg / day. For some infections, especially with damage to the meninges, a dose of 800 mg per day can be considered.The duration of therapy is determined individually; it can be up to 2 years, namely, 11-24 months - with coccidioidomycosis, 2-17 months - with paracoccidioidomycosis, 1-16 months - with sporotrichosis and 3-17 months - with histoplasmosis.

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

Treatment of mucosal candidiasis:

1) with oropharyngeal candidiasis saturating dose of 200-400 mg on the first day, the subsequent dose of 100-200 mg once a day for 7-21 days. If necessary, patients with severe suppression of immune function treatment can continue for a longer time;

2) with candiduria, the effective dose is usually 200-400 mg / day with the duration of treatment 7-21 days. In patients with severe impairment of the function of the immune system, longer periods of therapy can be used;

3) with chronic mucocutaneous candidiasis apply 50-100 mg per day to 28 days of treatment. Depending on the severity of the course of the infection or concomitant damage to the immune system and infection, longer periods of therapy can be used;

4) with candidiasis of the esophagus saturating dose of 200-400 mg on the first day, the subsequent dose of 100-200 mg per day. The course of treatment is 14-30 days (until the remission of candidiasis of the esophagus). If necessary, patients with severe suppression of immune function treatment can continue for a longer time;

5) for the prevention of 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 chronically reduced immunity;

6) to prevent recurrences of esophageal 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 chronically reduced immunity.

- At a chronic atrophic candidiasis of an oral cavity,related to 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.

- With acute vaginal candidiasis, candida balanitis fluconazole apply one time orally in a dose of 150 mg. To reduce the frequency of recurrences of vaginal candidiasis, the drug can be used at a dose of 150 mg every three days - only 3 doses (on days 1, 4 and 7), then maintaining a dose of 150 mg once a week. The maintenance dose can be used up to 6 months.

- Treatment of dermatomycosis:

1) for skin infections, including foot dermatophyte, trunk torso, inguinal dermatophyte and candidal infections, the recommended dose is 150 mg once a week or 50 mg once a day. The duration of therapy is usually 2-4 weeks, with foot mycoses may require a longer therapy up to 6 weeks;

2) with varicoloured lisen, the recommended dose is 300-400 mg once a week for 1-3 weeks. An alternative treatment regimen is the use of the drug at 50 mg once a day for 2-4 weeks.

With onychomycosis, the recommended dose is 150 mg once a week.Treatment should continue until the replacement of the infected nail (growth of uninfected nail). For the repeated growth of the nails on the fingers and toes, it usually takes 3-6 months and 6-12 months, respectively. However, the growth rate can vary widely among different people, and also depending on age. After successful treatment of long-lasting chronic infections, the shape of the nails is sometimes observed.

For the prevention of candidiasis in patients with malignant tumors, the recommended dose of fluconazole is 200-400 mg once a day, depending on the degree of risk of fungal infection. For patients at high risk of generalized infection, for example, with marked or prolonged persistent ytropenia, the recommended dose is 400 mg once daily. Fluconazole apply a few days before the expected development of neutropenia and, after increasing the number of neutrophils more than 1000 in mm3, treatment is continued for another 7 days.

Use in children

As with similar infections in adults, the duration of treatment depends on the clinical and picological effect.For children, the daily dose of the drug should not exceed that for adults.

Fluconazole is used daily once a day.

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

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

For the prevention of fungal infections in children with suppressed immunity, the risk of infection is associated with neutropenia, which develops as a result of cytotoxic chemotherapy or radiation therapy, the drug is used but 3-12 mg / kg / day, depending on the severity and duration of preservation of induced neutropenia (cm dose for adults, for children with kidney failure - see the dose for patients with renal insufficiency).

If it is not possible to use the medicinal form of the drug correctly in children Fluconazole in the form of capsules should consider the possibility of replacement with other dosage forms of the drug (powder for the preparation of a suspension for oral administration or solution for intravenous administration) in equivalent doses.

Application in the elderly

In the absence of signs of renal insufficiency fluconazole used in the 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 failure. 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 administered a shock dose of 50 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	100%
<50 (without dialysis)	50%
regular dialysis	100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis session. On the day when dialysis is not performed, patients should receive a reduced dose (depending on the creatinine clearance) of the drug.

In children with impaired function of the nights, the daily dose of the drug should be reduced (in the same proportional relationship as in adults), in accordance with the degree of renal failure.

Side effects:

Classification of the incidence of side effects according to the recommendations of the World Health Organization (WHO): very often> 1/10;

often from> 1/100 to <1/10;

infrequently from> 1/1000 to <1/100;

rarely from> 1/10000 to <1/1000;

very rarely <1/10000, including individual messages;

hThe frequency is unknown - according to the available data, it is not possible to establish the frequency of occurrence.

Impaired nervous system: often - headache; infrequently - dizziness, convulsions, drowsiness; rarely a tremor.

Impaired sensory organs: infrequently - vertigo.

Disorders from the gastrointestinal tract: often - abdominal pain, diarrhea, nausea, vomiting; infrequent - dryness of the oral mucosa, a decrease in appetite.

Disorders from the liver and bile ducts:

often - increased activity of "liver" transaminases, increased activity of alkaline phosphatase;

infrequently - increased bilirubin concentration, congestion of the biliary tract, jaundice;

rarely - hepatic insufficiency, hepatocellular necrosis, hepatitis, hepatotoxicity, in some cases with a fatal outcome, a violation of liver function, gsatocellular injury.

Disturbances from the skin: often - a rash;

infrequently - increased sweating, drug rash;

rarely - alopecia, exfoliative skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

Immune system disorders:

rarely anaphylaxis (including angioedema, facial edema, hives, itching).

Violations from the blood and lymphatic system: infrequently - anemia:

rare-leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Disorders from the cardiovascular system:

often - increasing the interval Q G on the ECG, arrhythmia ventricular tachysystolic type "pirouette" (torsade de pointes).

Disorders from the metabolism and nutrition:

rarely - an increase in the concentration of cholesterol and triglycerides in the blood plasma, gnpokalemia.

Disturbances from the musculoskeletal and connective tissue:

infrequently - myalgia.

Other:

infrequently - weakness, asthenia, increased fatigue, fever, increased sweating.

In some patients, especially those suffering from serious diseases, such as AIDS or cancer, flukonazole and similar drugs have been treated with changes in blood counts, kidney and liver function, but the clinical significance of these changes and their relationship to treatment have not been established.

Overdose:

Symptoms: nausea, vomiting, diarrhea. In severe cases, convulsions, hallucinations, paranoid behavior can occur.

Treatment: symptomatic, gastric lavage. As fluconazole excreted by the kidneys, it is recommended forced diuresis. Hemodialysis within 3 hours reduces the concentration in the plasma by 2 times.

Interaction:

A single or multiple administration of flucoazole at a dose of 50 mg does not affect the metabolism of phenazone when they are taken concomitantly.

The simultaneous use of flucoazole with the following drugs is contraindicated: Cisapride: with the simultaneous use of flucoazole and cisapride, unwanted heart reactions are possible, including torsade de pointes ventricular tachysystolic type arrhythmia.Application flukoiazola 200 mg 1 time per day and cisapride at a dose of 20 mg four times a day resulting in a marked increase in plasma concentrations of cisapride and increase QT interval on the electrocardiogram. Simultaneous administration of cisapride and flucoidazole is contraindicated.

Terfenadine: with the simultaneous use of azole antifungal agents and herfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When receiving flukoiazola a dose of 200 mg / day, increasing the QT interval is not set, however, the use flukoiazola in doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Aspemizol: simultaneous application flukoiazola astemizole with other drugs or whose metabolism is carried isozymes of cytochrome P450, can be accompanied by an increase in plasma concentrations of these agents. Increased concentration of astemizole in the plasma can lead to a lengthening of QT interval, and in some cases to the development of ventricular arrhythmias tachysystolic type "pirouette" (torsade de pointes).Simultaneous use of astemizole and flucoidazole is contraindicated.

Piozide: 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 the plasma concentration of pimozide can lead to an elongation of the QT interval and in some c; to the development of arrhythmia of ventricular tachysystolic type "pirouette" (torsade de primes). 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 prolongation of the QT interval and, in some cases, with the development of torsade de pointes, a ventricular tachysystolic type arrhythmia. Simultaneous use of quinidine and fluconazole is contraindicated.

Erythromycin: simultaneous use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the QT interval, the development of ventricular arrhythmic tachysystolic type "pirouette") and, as a result, sudden cardiac death.The simultaneous use of fluconazole and erythromycin is contraindicated.

Care should be taken and it is possible to adjust the dose with the simultaneous administration of the following drugs and fluconazole:

Hydrochlorothiazide: multiple application of hydrochlorothiazide simultaneously

with fluconazole leads to an increase in the concentration of fluconazole in blood plasma by%. The effect of this degree of expression does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the doctor should take this into account.

Rifampicin: simultaneous application of fluconazole and rifampicin results in AUC gustation of 25% and duration of half-life of fluconazole by 20%. patients simultaneously taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Fluconazole is a potent inhibitor of the CYP2C9 and CYP2C19 isoenzyme cytochrome P450 and a moderate inhibitor of the CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of elevated concentrations in the blood plasma and other drugs metabolized by the CYP2C9, CYP2CI9 and CYP3A4 isoenzymes while being administered with fluconazole.In this regard, caution should be exercised when using these drugs at the same time, and if necessary, such combinations should be carefully monitored by patients. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to a prolonged half-life.

Alfentanip: 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 enzyme CYP3A4 by fluconazole. Alfventanyl dosage adjustment may be required. Amitriptysish, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured in the first phase of combined therapy with fluconazole and a week after initiation. If necessary, adjust the dose of amitriptyline / nortriptyline. Amphotericin B: a small additive antifungal effect in systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans, and antagonism in systemic infection caused by A.fumigatus. The clinical significance of these results is not clear.

Anticoagulants: like other antifungal agents (azole derivatives), fluconazole with simultaneous application with warfarin increases prothrombin time (by 12%), which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). In patients receiving

coumarin anticoagulants, it is necessary to constantly monitor prothrombin time during therapy and for 8 days after simultaneous use. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

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

Benzodiazepines (short-acting): after ingestion of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects. When concomitant therapy with benzodiazepines, patients taking fluconazole, should be monitored to assess the appropriateness of an appropriate dose reduction for benzodiazepine.

With the simultaneous administration of a single dose of triazolam, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-50% and half-life by 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.

Corbamazepine: fluconazole It inhibits the metabolism of carbamazepine and increases the plasma concentration of carbamazepine by 30%. It is necessary to consider the risk of development of toxicity of carbamazepine. It is necessary to evaluate the need for correcting the dose of carbamazepine as a function of concentration / effect.

Calcium channel blockers: some calcium channel antagonists (nifedipine, ieradipine, amlodipine, broke 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 plasma 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. With simultaneous use with fluconazole, as with other antifungal azole agents, it is possible to develop ventricular tachasmystolic type "pirouette", so joint application is not recommended.

Inhibitors of HMG-CoA reductase: with simultaneous application of fluconazole

with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. In case of need for simultaneous therapy with 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.

Losartan: 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 II receptors. Regular monitoring of blood pressure is necessary. Memadoir. fluconazole can increase the plasma concentration of methadone. Methadone dose adjustment may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs): C max and AUC of flurbiprofen increase by 23% and 81%, respectively. Similarly, Cmax and AUC of the pharmacologically active isomer [5 - (+) - ibuprofen] increased by 15% and 82%, respectively, with simultaneous application of fluconazole with racemic ibuprofen (400 mg).

With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib at a dose of 200 mg of Cmax and AUC of celecoxib are increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.

Despite the lack of targeted research, fluconazole can increase the systemic exposure of other NSAIDs, megabolized 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 hormone concentrations, whereas with the daily intake of 200 mg of fluconazole, AUC of eugeniel estradiol and levonorgestrel increase by 40% and 24% respectively, and with 300 mg of fluconazole Once a week, the AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively.Thus, the repeated use of fluconazole at these doses is unlikely to affect the effectiveness of the combined oral contraceptive. Phenytoin: simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If simultaneous use of both drugs is necessary, the concentration of phenytoin should be monitored and its dose adjusted accordingly to ensure therapeutic concentration in the blood plasma.

Prednisone: There is a report on the development of acute adrenal insufficiency in the patient after liver transplantation on the background of the cancellation of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the isoenzyme CYP3A4, which led to an increased metabolism of prednisone.

Patients receiving combination therapy with prednisone and fluconazole should be carefully monitored when fluconazole is withdrawn to evaluate the condition of the adrenal cortex.

Rifabutin: simultaneous application of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients simultaneously receiving rifabutin and fluconazole, must be carefully observed.

Saquinavir: AUC increases by approximately 50%, C max 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 is presumably associated with inhibition of the metabolism of sirolimus through oppression of the isoenzyme

CYP3A4 and P-glycoprotein. This combination can be applied with appropriate dose correction of sirolimus depending on the effect / concentration.

Sulfonylureas. with simultaneous admission fluconazole leads to an increase in the half-life of oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be assigned joint usefluconazole and oral sulfonylureas, but the possibility of developing hypoglycemia should be considered. In addition, regular monitoring of glucose concentration in the blood and, if necessary, correction of the dose of sulfonylurea preparations.

Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in plasma concentration of the latter by a factor of 5 due to inhibition of tacrolimus metabolism occurring in the intestine via the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of nephrotoxicity are described. Patients who simultaneously take inward 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.

Theophelli: with simultaneous application with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. In the administration of fluconazole to patients receiving theophylline in high doses, or to patients with an increased risk of developing the toxic effect of theophylline,it is necessary to observe the appearance of symptoms of an overdose of theophylline and, if necessary, adjust the therapy accordingly.

Vinca alkaloids: Despite the lack of targeted research,

it is assumed that fluconazole can increase the concentration of drugs containing vinca alkaloids (for example, vincristine and vinblasgin) in the blood plasma and, thus, lead to neurotoxicity, which may possibly be due to the inhibition of the isoenzyme CYP3A4.

Vitamin A: there is a report of one case of the development of an undesirable reaction from the central nervous system (CNS) in the form of pseudo-brainwave with the simultaneous use of all-transretinic acid and fluconazole, which disappeared after the discontinuation of fluconazole. The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the CNS. Zidovudine: with simultaneous application with fluconazole, there is an increase in Stach 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, a significant increase in zidovudine AUC (20%) was found in HIV-infected patients with AIDS-related complex.

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

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4): simultaneous application of voriconazole (400 mg twice a day on the first day, then 200 mg twice daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per mesh for 4 days) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively. It was shown that this effect persists with a reduction in the dose and / or a decrease in the frequency of administration of any of the drugs. Simultaneous use of voriconazole and fluconazole is not recommended.

Investigations of the interaction of oral forms of fluconazole with its simultaneous administration with food, cimetidine, antacids, and after total body irradiation for the preparation of bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.

The listed interactions are established at repeated application fluconazole. Interactions with drugs as a result of a single ampule of fluconazole are not known.

Doctors should take into account that interaction with other drugs has not been explored, but it is possible.

Tofacitinib: exposure to tofacitinib increases with its combined use of drugs that are both moderate inhibitors of the CYPZA4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (eg, fluconazole). It may be necessary to correct the dose of tofacitinib.

Special instructions:

Treatment can be started in the absence of seeding results or other laboratory tests, but if appropriate, a correction of fungicidal therapy is recommended.

Because the fluconazole is excreted mainly by the kidneys, caution should be exercised in patients with renal insufficiency. With long-term treatment with fuukonazole, dosing should be done taking into account the CK.

Caution should be exercised in appointing fluconazole to patients with impaired liver function.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, its signs disappeared after the cessation of therapy. Patients who are in violation of liver function during therapy should be monitored in order to identify signs of more serious liver damage. If there are clinical signs and symptoms of liver damage that may be associated with the use of fluconazole, the drug should be discontinued.

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. HIV-infected patients 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 invasive / systemic fungal infections, they should be carefully monitored and canceled fluconazole when there are bullous changes or erythema multiforme. Required to control prothrombin time in patients simultaneously receiving fluconazole and anticoagulants of the coumarin series.

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

Like others azoles, fluconazole may cause an increase in the interval QT on the ECG. When

application of fluconazole increase in QT interval and flicker or flutter

ventricles very rarely seen in patients from heavy diseases

with multiple risk factors, such as organic heart disease, electrolyte imbalance and contributing to the development of such disorders, concomitanttherapy. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole with caution. Patients with liver, heart and kidney disease before using the drug are advised to consult a doctor. When fluconazole 150 mg is used for vaginal candidiasis, the patient should be warned that an improvement in ci of the symptoms is usually observed after 24 hours, but to completely disappear, it sometimes takes several days. If symptoms persist for several days, consult a doctor.

With simultaneous therapy with drugs with a narrow therapeutic profile, metabolized isoenzymes CYP2C9, CYP2CI9, CYP3A4, caution is recommended.

Treatment should continue until the appearance of clinical and microbiological remission. Premature termination of treatment leads to relapse.

The azorubin dye, which is part of the drug, can cause allergic reactions, including bronchial asthma. Allergic reactions are more common in patients with intolerance to acetylsalicylic acid.

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

Experience with fluconazole indicates that a disruption in the ability to drive vehicles and mechanisms associated with the use of the drug is unlikely. However, in the event that the patient experiences dizziness, complicity at the time of taking the drug, you should refrain from engaging in potentially hazardous activities.

Form release / dosage:Capsules 50 mg and 150 mg

Packaging:

For a dosage of 50 mg

7 capsules in a planar cell packaging made of a polyvinylchloride film and foil, or in a jar of low-density polyethylene.

1 contour mesh package or one jar along with instructions for use in a pack of cardboard.

For a dosage of 150 mg

1, 2 or 3 capsules in a contoured cell pack of a polyvinyl chloride film and aluminum foil or in a bank of low density polyethylene.

1, 2 or 3 contourcell packs of 1 capsule, 1 circuit cell package 2 capsules, I contour pack of 3 capsules or one can together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:3 years.

Do not use after expiry date.

Terms of leave from pharmacies:Without recipe

Registration number:P N003242 / 01

Date of registration:09.12.2009

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp14.10.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)