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

Excipients: lactose monohydrate (milk sugar) 24.6 mg or 73.8 mg; Povidone (polyvinylpyrrolidone) 0.6 mg or 1.8 mg; potato starch 2,4 mg or 7.2 mg; silicon dioxide colloid (aerosil) 1.6 mg or 4.8 mg; magnesium stearate 0.8 mg or 2.4 mg;

composition of hard gelatin capsules No. 2 (for a dosage of 150 mg): gelatin, water, titanium dioxide, iron oxide yellow, indigo carmine;

composition of hard gelatin capsules № 4 (for a dosage of 50 mg): gelatin, water, titanium dioxide.

Description:

Hard gelatin capsules № 4 (for a dosage of 50 mg) white with white caps, the contents of the capsules: granules and white or white powder with a slightly yellowish tinge.

Hard gelatin capsules № 2 (for a dosage of 150 mg) white with green lids; contents of capsules: granules and powder white or white with a slightly yellowish hue of color.

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 in vitro and in clinical infections against most of the following microorganisms: Candida albicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

Fluconazole activity was demonstrated in vitro for the following microorganisms, however, the clinical significance of this is unknown: Candida dubliniensis, Candida guilliermondii, Candida parapsilosis, Candida kefyr, Candida lusitaniae.

Ingestion fluconazole shows activity on various models of fungal infections in animals. The activity of the drug was demonstrated for opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in animals with depressed immunity), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychophyton spp.

The activity of fluconazole on the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Coccidioides immitis (including intracranial infections) and Histoplasma capsulatum 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 gene ERG11, which encodes the target enzyme, lead to a modification of the target and a decrease in the affinity for azoles. Increased gene expression ERG11 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 removal of fluconazole from the intracellular space by activating the two types of transporter involved in the active excretion of drugs from the fungal cell. These transports include the main mediator, encoded by genes MDR (multiple drug resistance), and the superfamily of the ATP-binding transport cassette, 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 to Candida glabrata is usually mediated by the overexpression of the gene 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

The pharmacokinetics of fluconazole is similar for intravenous administration and ingestion. After oral administration fluconazole is well absorbed, its concentrations in the blood plasma (and total bioavailability) exceed 90% of those in intravenous administration. Simultaneous food intake does not affect the absorption of fluconazole.

Distribution

The concentration in the blood plasma is proportional to the dose and reaches a maximum (C_mOh) 0.5-1.5 hours after fasting fluconazole, and the half-life is about 30 hours. 90% of the equilibrium concentration is reached by the fourth or fifth day after the start of therapy (with repeated administration of the drug once a day). The maximum concentration of fluconazole in saliva when taking the capsule is reached after 4 hours. The introduction of a shock dose (on day 1), which is twice the usual daily dose, makes it possible to achieve 90% of the equilibrium concentration by the second day. The volume of distribution approximates the total water content in the body. Binding to blood 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, fluconazole concentrations in the cerebrospinal fluid are about 80% of its plasma concentrations.

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.

Metabolism and excretion

The drug is excreted mainly through the kidneys; approximately 80% of the administered dose is detected in the urine unchanged. The clearance of fluconazole is proportional to the creatinine clearance. No circulating metabolites were detected.

A prolonged half-life from plasma allows fluconazole once for vaginal candidiasis and 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)	*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 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, C_mOh was achieved 1.3 hours after administration and was 1.54 μg / ml, the mean values AUC - 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 AUC and C_mOh.

Creatinine clearance (74 ml / min), the percentage of fluconazole excreted through the kidneys unchanged (0-24 h, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients is lower than in younger patients .

Indications:

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

- cryptococcal meningitis;

- coccidioidomycosis;

- invasive candidiasis;

- mucous candidiasis, incl. Oropharyngeal candidiasis of the oral cavity, 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, incl. dermatofytii trunk, inguinal dermatophytosis, multi-colored lichen and skin candidiasis infections when systemic treatment is indicated;

- nail dermatophytosis (onychomycosis), when treatment with other drugs is not acceptable.

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

- recurrence of cryptococcal meningitis in patients with high risk of meningitis;

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

- to reduce the frequency of vaginal candidiasis (4 or more episodes per year);

- for the prevention of candidal infections in patients with prolonged neutropenia (such as patients with hemoblastoses 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 prevention of candidal infections in patients with weakened immune system;

- fluconazole is used as a maintenance therapy to prevent the recurrence of cryptococcal meningitis in children with a high risk of recurrence.

Contraindications:

- Hypersensitivity to fluconazole or a close structure of azole compounds;

- 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 interval QT and metabolized by isoenzyme CYP3 A4, such as cisapride, astemizole, erythromycin, pimozide and quinidine (see the section "Interaction with other medicinal products");

- Children under 3 years old (for this dosage form);

- lactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Carefully:

- Impaired 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, electrolyte imbalance and concomitant therapy contributing to the development of such disorders).

Pregnancy and lactation:

Controlled clinical studies on the use of fluconazole in pregnant women have not been conducted.

Several cases of multiple congenital malformations in newborns whose mothers received high-dose fluconazole (400-800 mg / day) for most or all of the first trimester have been described. 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.

During pregnancy, fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment 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 use in women during breastfeeding is not recommended.

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 an intravenous to an oral intake 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.

Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require supportive therapy to prevent recurrence of the infection.

Application in adults

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

To prevent the recurrence of cryptococcal meningitis in patients with a high risk of recurrence after 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 may require the use of 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,therapy can last up to 2 years; it is 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 usually 800 mg on the first day, the subsequent dose of 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

With oropharyngeal candidiasis a saturated dose of 200-400 mg on the first day, the subsequent dose: 100-200 mg once a day for 7-21 days. If necessary, patients with marked suppression of immune function treatment can continue for a longer time.

At a chronic atrophic candidiasis of an 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.

When 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 immune system function, longer periods of therapy can be used.

With chronic mucocutaneous candidiasis apply 50-100 mg / day to 28 days of treatment. Depending on the severity of the treatment of infection or the concomitant damage to the immune system, longer periods of therapy can be used.

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

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

To prevent recurrence of esophageal candidiasis in HIV-infected patients at high risk of recurrenceat 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.

With acute vaginal candidiasis, candida balanitis fluconazole apply once inside at 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 the 1 st, 4 th and 7 th days), then maintain a dose of 150 mg once a week. The maintenance dose can be applied up to 6 months.

Treatment of dermatomycosis

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

With multi-colored lichen 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 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, 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 an increase in the number of neutrophils more than 1000 in mm³ treatment continues for another 7 days.

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. Fluconazole apply once a day.

When candidiasis of mucous membranes the recommended dose of fluconazole is 3 mg / kg / sug. 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.

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 depressed immunity, at which the risk of infection is associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, the drug is used at 3-12 mg / kg / day, depending on the severity and duration of preservation of induced neutropenia (see dose for adults, for children 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 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 administered a shock dose of 50 mg to 400 mg, after a 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.

Side effects:

Drug tolerance is usually good.

Disturbances from the organs of hematopoiesis and lymphatic system:

rarely - anemia, leukopenia including neutropenia and agranulocytosis, thrombocytopenia.

Immune system disorders:

infrequently - anaphylaxis (including angioedema, edema of the face, urticaria, itching).

Disorders from the metabolism and nutrition:

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

Disturbances from the nervous system:

infrequently - headache, dizziness, rarely - convulsions, taste change, paresthesia, insomnia, drowsiness, tremor.

Heart Disease:

rarely - increasing the interval QT on an electrocardiogram, an arrhythmia ventricular tahisistolic type "pirouette" (torsade de pointes) (see section "Special instructions").

Disorders from the gastrointestinal tract:

infrequently - abdominal pain, diarrhea / constipation, flatulence, nausea, dyspepsia, vomiting, dryness of the oral mucosa.

Disturbances from the liver and bile ducts:

rarely - hepatotoxicity, in some cases fatal, increased bilirubin concentration, serum activity of aminotransferases (alanine aminotransferase (ALT) and aspartate aminotransferase (ACT)), alkaline phosphatase, a violation of liver function, hepatitis, hepatocellular necrosis, jaundice, cholestasis, hepatocellular injury.

Disturbances from the skin and subcutaneous tissues:

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

Disturbances from musculoskeletal and connective tissue:

very rarely - myalgia.

General disorders and disorders at the site of administration:

very rarely - weakness, asthenia, fatigue, fever, excessive sweating, vertigo.

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

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic (supporting measures and gastric lavage), Fluconazole is excreted mainly through the kidneys, therefore forced diuresis, probably, can accelerate the excretion of the drug.The hemodialysis session lasting 3 hours reduces the level of fluconazole in the blood plasma by approximately 50%.

Interaction:

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

The simultaneous use of fluconazole with the following drugs is contraindicated:

Cisapride: with the simultaneous use of fluconazole and cisapride, unwanted reactions from the heart are possible, including arrhythmia of the ventricular tachysystolic type "pirouette" (torsade de pointes). The use of fluconazole at a dose of 200 mg 1 time per day and cisapride in a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the interval QT on the ECG. Simultaneous administration of cisapride and fluconazole is contraindicated.

Terfenadine: with the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias can occur as a result of an increase in the interval QT. When taking fluconazole at a dose of 200 mg / day increasing the interval QT is not established, however, the use of fluconazole at doses of 400 mg / day and higher causes a significant increase in the concentration of terfenadine in the blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated (see.section "Contraindications"). Treatment with fluconazole in doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemizole: the simultaneous use of fluconazole with 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 interval QT and in some cases, to the development of ventricular arrhythmia of tachysystolic type "pirouette" (torsade de pointes). Simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: Despite the fact that no relevant studies have been carried out in vitro or in vivo, simultaneous application of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. In turn, an increase in the plasma concentrations of pimozide can lead to lengthening of the interval QT and in some cases, the development of ventricular arrhythmia of tachysystolic type "pirouette" (torsade de pointes). Simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Despite the fact that no relevant studies have been carried out in vitro or in vivo, simultaneous application of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with lengthening the interval QT and in some cases with the development of ventricular arrhythmia of tachysystolic type "pirouette" (torsade de pointes). Simultaneous use of quinidine and fluconazole is contraindicated.

Erythromycin: simultaneous application of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (lengthening of the interval QT, torsade de pointes) and, as a result, sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.

Tofacitinib: The exposure to tofacitinib increases with its combined use with drugs that are both moderate inhibitors of the isoenzyme CYP3A4 and potent inhibitors of isoenzyme CYP2C19 (for example fluconazole). It may be necessary to correct the dose of tofacitinib.

Care should be taken and, perhaps, adjust the dose with the simultaneous use of the following drugs and fluconazole:

Drugs affecting fluconazole:

Hydrochlorothiazide: the repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in the blood plasma by 40%. The effect of such a degree of expression does not require a change in the dosage regimen of fluconazole in patients receiving both diuretics at the same time, but the doctor should take this into account.

Rifampicin: simultaneous application of fluconazole and rifampicin leads to a decrease AUC by 25% and the duration of the half-life of fluconazole by 20%. 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 isoenzyme CYP2C9 and CYP2C19 cytochrome P450 and moderate inhibitor of isoenzyme CYP3A4. In addition, in addition to the effects listed below, there is a risk of increasing plasma concentrations of blood and other drugs metabolized by isoenzymes CYP2C9 and CYP2C19 and CYP3A4 with simultaneous admission 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.

Alfentanil: there is a decrease in clearance and volume of distribution, an increase in the half-life of alfentanil. Perhaps this is due to inhibition of the isoenzyme CYP3A4 with fluconazole. Alfventanyl dosage adjustment may be required.

Amitriptyline, nortriptyline: increase in effect. The concentration of 5-nortryptiline and / or Samitriptyline can be measured at the beginning of a combination therapy with fluconazole and a week after the start of treatment. 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 FROM. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans, and antagonism with systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.

Anticoagulants: as well as 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 and fluconazole, it is necessary to constantly monitor prothrombin time during therapy and within 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 expressed pharmacokinetic interaction between both drugs is not established.

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

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

Carbamazepine: fluconazole It inhibits the metabolism of carbamazepine and increases the serum 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, isradipine, amlodipine, verapamil and felodipine) are metabolized by 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. With simultaneous use with fluconazole, as with other antifungal azole agents, the possibility of arrhythmia of the ventricular tachysystolic type "pirouette" increases. Their joint use is not recommended.

Inhibitors of HMG-CoA reductase: with simultaneous application of fluconazole with inhibitors of HMG-CoA reductase, metabolized by isoenzyme CYP3A4 (such as atorvastatin and simvastatin) or isoenzyme CYP2D6 (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-31 74), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular monitoring of blood pressure is necessary.

Methadone: fluconazole may increase the plasma concentration of methadone. Methadone dose adjustment may be necessary.

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

With the simultaneous use of fluconazole at a dose of 200 mg / sug and celecokeib at a dose of 200 mg C_mOh and AUC celecoxib 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 isoenzyme CYP2C9 (e.g., 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 AUC ethinyl estradiol and levonorgestrel increased by 40% and 24%, respectively, and when 300 mg of fluconazole is administered once a week AUC 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 application 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 with a fluconazole withdrawal after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3 A4 isoenzyme, 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_mOh - by 55%, saquinavir clearance is reduced by approximately 50% due to inhibition of hepatic isoenzyme metabolism CYP3A4 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 oppression of the isoenzyme CYP3 A4 and P-glycoprotein. This combination can be applied with appropriate correction of the dose of sirolimus depending on the effect / concentration.

Sulfonylurea preparations: fluconazole, while receiving, increases the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, tolbutamide and glipizide). Patients suffering from diabetes, you can assign the combined use of fluconazole and oral sulfonylureas, but it should take into account the possibility of hypoglycemia also requires regular monitoring of glucose levels in blood and, if necessary, dose adjustment of sulfonylureas.

Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter by a factor of 5 due to inhibition of the metabolism of tacrolimus occurring in the intestine through isoenzyme CYP3 A4. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of nephrotoxicity are described. Patients simultaneously taking tacrolimus inside and fluconazole, should be carefully observed. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Theophylline: when used simultaneously 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 in patients at increased risk of developing the toxic effect of theophylline, the symptoms of an overdose of theophylline should be monitored and, if necessary, adjusted accordingly.

Vinca alkaloid: Despite the lack of targeted research, it is assumed that fluconazole can increase the concentration of vinca alkaloids (eg, vincristine and vinblastine) in the blood plasma and, thus, lead to neurotoxicity, which may possibly be due to oppression of the isoenzyme CYP3A4.

Vitamin A: there is a report of one case of development of undesirable reactions from the central nervous system (CNS) in the form of a pseudotumor of the brain with simultaneous application of all transretinic acid and fluconazole that disappeared after the withdrawal of fluconazole. The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the CNS.

Zidovudine: when used simultaneously with fluconazole, there is an increase in Stach and AUC 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 with AIDS and ARC (AIDS-related complex), a significant increase AUC zidovudine (20%).

Nevirapine: simultaneous application of fluconazole and nevirapine resulted in an increase in the effect of nevirapine by approximately 100%. In the case of simultaneous use of these drugs, accompanied by a risk of increased exposure to nevirapine, care must be taken and patients carefully monitored. Clinically significant effects of nevirapine on fluconazole was not noted.

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 a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) leads to an increase in the concentration and AUC 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 above interactions were established with repeated application of fluconazole; interactions with drugs as a result of a single administration of fluconazole are not known. Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible.

Special instructions:

There have been reports of cases of superinfection caused by Candida albicans strains Candida, 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. If the patient develops a superficial fungal infection, a rash that can be associated with 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 carried out under close supervision (see the section "Interaction with other medicinal products").

Like other azoles, fluconazole may cause an increase in the interval QT on the ECG. When using fluconazole, the increase in the interval QT and fibrillation or fluttering of the ventricles was very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant 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 improvement of symptoms is usually observed after 24 hours, but for their complete disappearance it sometimes takes several days. If symptoms persist for several days, consult a doctor.

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

When taking fluconazole, it is possible to develop side effects (dizziness, convulsions), so caution should be exercised when driving vehicles and performing work that requires increased concentration of attention.

Form release / dosage:

Capsules, 50 mg and 150 mg.

Packaging:

1, 4, 7 or 10 capsules per contour cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

By 1, 2, 7, 10, 14, 20, 28 or 50 capsules in cans of polymer.

Each can, or 1, 2 contour squares per 1 capsule, or 1 circuit cell pack of 4 capsules, or 1, 2, 4 contour packs of 7 capsules or 1, 3, 5, 10 contour packs of 10 capsules together with instructions for use put in a pack of cardboard box.

Storage conditions:

In a dry, the 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 the product after the expiry date printed on the package.

Terms of leave from pharmacies:Without recipe

Registration number:LP-003423

Date of registration:21.01.2016

Expiration Date:21.01.2021

The owner of the registration certificate:MEDISORB, CJSC MEDISORB, CJSC Russia

Manufacturer: & nbsp

MEDISORB, CJSC Russia

Information update date: & nbsp04.08.2016

Illustrated instructions

Instructions

Fluconazole (Fluconazole )