Diflucan: instructions for use of capsules, solution and powder. Diflucan, solution for infusion. Is Diflucan hormonal or not?

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pharmachologic effect

An antifungal drug of the triazole series, it is a powerful selective inhibitor of sterol synthesis in fungal cells.

Fluconazole has been shown to be active in vitro and in clinical infections against most of the following microorganisms: Candida alhicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

Fluconazole has been shown to be active in vitro against the following microorganisms, but its clinical significance is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

When administered orally and administered intravenously, fluconazole showed activity in various models of fungal infections in animals. The activity of the drug in opportunistic mycoses has been demonstrated, incl. caused by Candida spp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychoptyton spp. The activity of fluconazole has also been established in models of endemic mycoses in animals, including infections caused by Blastomyces dermatitidis, Coccidioides immitis (including intracranial infections) and Histoplasma capsulatum in animals with normal and reduced immunity.

Fluconazole has high specificity for fungal enzymes dependent on cytochrome P450. Treatment with fluconazole 50 mg/day for up to 28 days does not affect plasma testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole at a dose of 200-400 mg/day did not have a clinically significant effect on the levels of endogenous steroids and their response to ACTH stimulation 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 that is the target of fluconazole (lanosteryl 14-α-demethylase), decreased access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene, encoding the target enzyme, lead to a modification of the target and a decrease in affinity for azoles. An increase in the expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates the need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.

The second significant mechanism of resistance is the active removal of fluconazole from the intracellular space through the activation of two types of transporters involved in the active removal (efflux) of drugs from the fungal cell. These transporters include the main messenger, encoded by the MDR (multidrug resistance) genes, and the ATP-binding cassette transporter superfamily, encoded by the CDR genes (genes for the resistance of Candida spp. to azole antimycotics).

Overexpression of the MDR gene leads to resistance to fluconazole, while overexpression of CDR genes can lead to resistance to various azoles.

Resistance to Candida glabrata is usually mediated by overexpression of the CDR gene, resulting in resistance to many azoles. For those strains in which the MIC is determined to be intermediate (16-32 μg/ml), it is recommended to use the maximum dose of fluconazole.

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

Pharmacokinetics

The pharmacokinetics of fluconazole are similar when administered intravenously and when administered orally.

Suction

After oral administration, fluconazole is well absorbed, its plasma levels (and total bioavailability) exceed 90% of fluconazole plasma levels when administered intravenously. Concomitant food intake does not affect oral absorption. Cmax is achieved 0.5-1.5 hours after taking fluconazole on an empty stomach. The concentration in blood plasma is proportional to the dose.

Distribution

90% C ss is achieved by the 4-5th day after the start of therapy (with repeated doses 1 time per day).

Administration of a loading dose (on the 1st day), 2 times higher than the average daily dose, allows you to achieve a C ss of 90% by the 2nd day.

V d approaches the total water content in the body. Plasma protein binding is low (11-12%).

Fluconazole penetrates well into all body fluids. Levels of fluconazole in saliva and sputum are similar to its concentrations in plasma.

In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid are approximately 80% of plasma levels.

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are reached that exceed serum concentrations. Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg 1 time / day, the concentration of fluconazole after 12 days was 73 mcg/g, and 7 days after stopping treatment - only 5.8 mcg/g. When used at a dose of 150 mg 1 time/week. the concentration of fluconazole in the stratum corneum on the 7th day was 23.4 mcg/g, and 7 days after taking the second dose – 7.1 mcg/g.

Concentration of fluconazole in nails after 4 months of use at a dose of 150 mg once a week. was 4.05 µg/g in healthy and 1.8 µg/g in affected nails; 6 months after completion of therapy, fluconazole was still detectable in the nails.

When comparing concentrations in saliva and blood plasma after a single dose of fluconazole at a dose of 100 mg in the form of a capsule and an oral suspension (rinsing and keeping in the mouth for 2 minutes and swallowing), it was found that the C max of fluconazole in saliva after taking the suspension was observed after 5 min and was 182 times higher than Cmax in saliva after taking the capsule (reached after 4 hours). After approximately 4 hours, fluconazole concentrations in saliva were similar. The mean AUC 0-96 in saliva was significantly higher with the suspension than with the capsule. There were no significant differences in the rate of excretion from saliva or pharmacokinetic parameters in blood plasma when using fluconazole in the form of two release forms.

Metabolism and excretion

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. Fluconazole clearance is proportional to QC. No circulating metabolites were detected.

T1/2 from plasma is about 30 hours. Long T1/2 from plasma allows you to take fluconazole once for vaginal candidiasis and 1 time / day or 1 time / week. for other indications.

Pharmacokinetics in special clinical situations

Table. Pharmacokinetic parameters of fluconazole in children

* - indicator recorded on the last day.

In preterm infants (approximately 28 weeks of development), fluconazole was administered IV at a dose of 6 mg/kg every 3rd day for a maximum of 5 doses while the infants remained in the NICU. The average T1/2 was 74 hours (range 44-185 hours) on day 1, decreasing on the 7th day to an average of 53 hours (range 30-131 hours) and on the 13th day on average up to 47 hours (within 27-68 hours).

AUC values were 271 mcg×h/mL (range 173-385 mcg×h/mL) on day 1, then increased to 490 mcg×h/mL (range 292-734 mcg×h/mL) on day 7 day and decreased to an average of 360 μg×h/ml (range 167-566 μg×h/ml) by the 13th day.

Vd was 1183 ml/kg (range 1070-1470 ml/kg) on day 1, then increased to an average of 1184 ml/kg (range 510-2130 ml/kg) on day 7 and up to 1328 ml/kg (range 1040-1680 ml/kg) on the 13th day.

U elderly patients (65 years and older) with a single use of fluconazole at a dose of 50 mg orally (in some cases with simultaneous use of a diuretic), it was found that C max was achieved 1.3 hours after administration and was 1.54 μg/ml, average AUC values 76.4 ± 20.3 μg × h/ml, average T 1/2 was 46.2 hours.

The values of these pharmacokinetic parameters are higher than in young patients. The simultaneous use of diuretics did not cause a significant change in AUC and Cmax. CC (74 ml/min), the percentage of the drug excreted unchanged in the urine (0-24 hours, 22%) and renal clearance of fluconazole (0.124 ml/min/kg) are lower in elderly patients compared to young patients. Higher values of pharmacokinetic parameters in elderly patients taking fluconazole are likely associated with decreased renal function characteristic of old age.

Cryptococcosis, including cryptococcal meningitis and infections of other sites (for example, lungs, skin), incl. in patients with a normal immune response and in patients with AIDS, organ transplant recipients and patients with other forms of immunodeficiency; maintenance therapy to prevent relapses of cryptococcosis in patients with AIDS;

Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, incl. in patients with malignant tumors who are in the ICU and receiving cytotoxic or immunosuppressive drugs, as well as in patients with other factors predisposing to the development of candidiasis;

Candidiasis of the mucous membranes, including the mucous membranes of the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic candidiasis of the oral cavity (associated with wearing dentures), incl. in patients with normal and suppressed immune function; prevention of relapse of oropharyngeal candidiasis in patients with AIDS;

Genital candidiasis; acute or recurrent vaginal candidiasis; prevention to reduce the frequency of relapses of vaginal candidiasis (3 or more episodes per year); candidal balanitis;

Prevention of fungal infections in patients with malignant tumors who are predisposed to the development of such infections as a result of cytotoxic chemotherapy or radiation therapy;

Mycoses of the skin, including mycoses of the feet, body, groin area, pityriasis versicolor, onychomycosis and skin candidal infections;

Deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

Concomitant use of terfenadine during repeated use of fluconazole at a dose of 400 mg/day or more;

Concomitant use with drugs that increase the QT interval and are metabolized by the CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine;

Sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption (for powder for suspension);

Galactose intolerance, lactase deficiency and glucose/galactose malabsorption (for capsules);

Children under 3 years of age (for capsules);

Hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole.

WITH caution the drug is prescribed for abnormal liver function tests, for impaired renal function, for the appearance of a rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, with simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day, with potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

Most frequently encountered side effects, which were registered in clinical and post-marketing (*) studies of the drug Diflucan ®.

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

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia*, vomiting*, dry mouth, constipation, hepatotoxicity (in some cases with fatal), increased bilirubin concentration, serum activity of ALT and AST, alkaline phosphatase, liver dysfunction*, hepatitis*, hepatocellular necrosis*, jaundice*, cholestasis, hepatocellular damage.

From the outside of cardio-vascular system*: increase in QT interval on ECG, arrhythmia, incl. ventricular tachysystolic type "pirouette".

From the skin: rash, alopecia*, exfoliative skin diseases*, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, increased sweating, drug rash.

From the hematopoietic system*: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Metabolism*: increased levels of cholesterol and triglycerides in plasma, hypokalemia.

From the outside musculoskeletal system: myalgia.

Allergic reactions*: anaphylactic reactions (including angioedema, facial swelling, urticaria, itching).

Others: weakness, asthenia, increased fatigue, fever, vertigo.

In some patients, especially with serious diseases (AIDS, malignant neoplasms), changes in blood counts, kidney and liver function were observed during treatment with Diflucan ® and similar drugs, but the clinical significance of these changes and their relationship with treatment have not been established.

The drug is usually very well tolerated.

Overdose

In one case of fluconazole overdose, a 42-year-old patient infected with HIV developed hallucinations and paranoid behavior after taking 8200 mg of fluconazole. The patient was hospitalized, his condition returned to normal within 48 hours.

Treatment: in case of overdose, symptomatic therapy is carried out (including supportive measures and gastric lavage).

Fluconazole is excreted primarily in the urine, so forced diuresis is likely to accelerate its elimination. A hemodialysis session lasting 3 hours reduces plasma fluconazole levels by approximately 50%.

special instructions

There have been reports of cases of superinfection caused by strains of Candida other than Candida aibicans, which are often naturally resistant to fluconazole (eg, 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, incl. with a fatal outcome, mainly in patients with serious concomitant diseases. There was no obvious dependence of the hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effects of fluconazole were usually reversible; its signs disappeared after cessation of therapy. Patients whose liver function tests are impaired during treatment with fluconazole should be monitored for signs of more serious liver damage. When clinical signs or symptoms of liver damage that may be associated with fluconazole, the drug should be discontinued.

During treatment with fluconazole, patients have rarely developed exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. People with AIDS are more likely to develop severe skin reactions when taking many drugs. If a patient receiving treatment for a superficial fungal infection develops a rash that can be associated with the use of fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme develop.

As with other azoles, fluconazole can rarely cause anaphylactic reactions.

Concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be carried out under close supervision.

Like other azoles, fluconazole may cause prolongation of the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation/flutter were observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalances and concomitant therapy that contributes to the development of such disorders. Therefore, fluconazole should be used with caution in such patients with potentially proarrhythmic conditions.

Patients with liver, heart and kidney diseases are advised to consult a doctor before using Diflucan ®. When using Diflucan ® 150 mg for vaginal candidiasis, patients should be warned that improvement in symptoms is usually observed after 24 hours, but sometimes takes several days for complete resolution. If symptoms persist for several days, you should consult a doctor.

Evidence of the effectiveness of fluconazole in the treatment of other types of endemic mycoses such as paracoccidioidomycosis, sporotrichosis and histoplasmosis is limited, preventing specific dosing recommendations.

Impact on the ability to drive vehicles and operate machinery

Experience with the use of the drug Diflucan ® indicates that deterioration in the ability to drive a car and operate machinery associated with the use of the drug is unlikely.

For renal failure

Patients with renal failure(QC<50 мл/мин)

In case of liver dysfunction

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, incl. with a fatal outcome, mainly in patients with serious concomitant diseases. There was no obvious dependence of the incidence of hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effects of fluconazole were usually reversible; its signs disappeared after cessation of therapy. Patients whose liver function tests are impaired during treatment with fluconazole should be monitored for signs of more serious liver damage. If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued.

Elderly

U elderly patients

Use during pregnancy and breastfeeding

Adequate and controlled studies of the safety of the drug in pregnant women have not been conducted. Cases of multiple congenital malformations have been described in newborns whose mothers received high-dose fluconazole therapy (400-800 mg/day) for coccidioidomycosis for 3 or more months. The following developmental disorders were noted: brachycephaly, impaired development of the facial part of the skull, impaired formation of the cranial vault, cleft palate, curvature of the femurs, thinning and elongation of the ribs, arthrogryposis and congenital heart defects. Currently, there is no evidence of a connection between the listed congenital disorders and the use of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

The use of fluconazole during pregnancy should be avoided, except in cases of severe and potentially life-threatening fungal infections when the expected benefit of treatment outweighs the possible risk to the fetus. That's why women of childbearing age Reliable contraception should be used.

Fluconazole is found in breast milk in concentrations close to plasma levels, therefore the use of Diflucan ® during lactation (breastfeeding) is not recommended.

Drug interactions

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

Concomitant use of fluconazole with the following drugs are contraindicated

Cisapride: with the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. ventricular tachysystolic arrhythmia of the "pirouette" type. The use of fluconazole at a dose of 200 mg 1 time / day and cisapride at a dose of 20 mg 4 times / day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine: With the simultaneous use of azole antifungals and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

Astemizole: simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by isoenzymes of the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. With an increase in the concentration of astemizole in the blood plasma, a prolongation of the QT interval and, in some cases, the development of ventricular tachysystolic arrhythmia "pirouette" is possible. The simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: Although appropriate in vitro or in vivo studies have not been conducted, the simultaneous use of fluconazole and pimozide may lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide can lead to a prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the "pirouette" type. The simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Although adequate in vitro or in vivo studies have not been conducted, concomitant 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 (TdP).
The simultaneous use of quinidine and fluconazole is contraindicated.

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

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

Drugs affecting fluconazole

Hydrochlorothiazide: repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in the blood plasma by 40%. An effect of this severity does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but the doctor should take this into account.

Rifampicin: simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and a decrease in T 1/2 of fluconazole by 20%. In patients concomitantly taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs Affected by Fluconazole

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

Alfentanil: there is a decrease in clearance and Vd, an increase in T 1/2 of alfentanil. This may be due to inhibition of the CYP3A4 isoenzyme by fluconazole. Alfentanil dosage adjustment may be required.

Amitriptyline, nortriptyline: increase in effect. The concentration of 5-nortriptyline and/or S-amitriptyline can be determined at the beginning of combination therapy with fluconazole and one week after initiation. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: In studies in mice (including those with immunosuppression), the following results were noted: a small additive antifungal effect in systemic infection caused by Candida albicans, lack of interaction in intracranial infection caused by Cryptococcus neoformans and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is unclear.

Anticoagulants: like other antifungal agents - azole derivatives, fluconazole, when used simultaneously with warfarin, increases the prothrombin time (by 12%), and therefore the development of bleeding (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena) is possible. In patients receiving coumarin anticoagulants, prothrombin time must be constantly monitored. The advisability of adjusting the warfarin dose should also be assessed.

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

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

When taking triazolam simultaneously in a single dose, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-32% and T1/2 by 25-50% due to inhibition of triazolam metabolism. Triazolam dose adjustment may be necessary.

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

Calcium channel blockers: Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the CYP3A4 isoenzyme. Fluconazole increases the systemic exposure of calcium channel antagonists. Monitoring for the development of side effects is recommended.

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

Cyclophosphamide: with simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is observed. This combination is acceptable given the risk of increased bilirubin and creatinine concentrations.

Fentanyl: There has been a report of one death possibly related to the concomitant use of fentanyl and fluconazole. The disturbances are believed to be related to fentanyl intoxication. Fluconazole has been shown to significantly prolong the clearance time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to depression of respiratory function.

Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of the CYP3A4 isoenzyme.

HMG-CoA reductase inhibitors: When fluconazole is used concomitantly with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If simultaneous therapy with these drugs is necessary, patients should be monitored to identify symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. If there is a significant increase in creatinine kinase concentrations or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular blood pressure monitoring is necessary.

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

NSAIDs: The max and AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, the C max and AUC of the pharmacologically active isomer increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg). With simultaneous use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg, the Cmax and AUC of celecoxib increase by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

Although there are no targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). NSAID dose adjustment may be necessary.

When using NSAIDs and fluconazole concomitantly, patients should be under close medical supervision to identify and monitor NSAID-related adverse reactions and toxicities.

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

Phenytoin: simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentrations. If simultaneous use of both drugs is necessary, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic plasma concentrations.

Prednisone: There is a report of the development of acute adrenal insufficiency in a patient after liver transplantation while fluconazole was discontinued after a 3-month course of therapy. Presumably, cessation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased metabolism of prednisone.
Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to assess the condition of the adrenal cortex.

Rifabutin: simultaneous use of fluconazole and rifabutin can lead to an increase in plasma concentrations of the latter by up to 80%. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin.
Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

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

Sirolimus: an increase in the concentration of sirolimus in the blood plasma, presumably due to inhibition of the metabolism of sirolimus through inhibition of the CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Sulfonylureas: fluconazole, when taken simultaneously, leads to an increase in half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus can be prescribed fluconazole and sulfonylureas for oral administration simultaneously, but the possibility of hypoglycemia should be taken into account; in addition, regular monitoring of blood glucose levels and, if necessary, dose adjustment of sulfonylureas are necessary.

Tacrolimus: simultaneous use of fluconazole and tacrolimus (orally) leads to an increase in serum concentrations of the latter up to 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine through the CYP3A4 isoenzyme. No significant changes in the pharmacokinetics of the drugs were observed when tacrolimus was used intravenously. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole simultaneously require careful monitoring. 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 rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of developing theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.

Tofacitinib: Tofacitinib exposure increases when co-administered with drugs that are both moderate CYP3A4 inhibitors and strong CYP2C19 inhibitors (for example, fluconazole). A dose adjustment of tofacitinib may be necessary.

Vinca alkaloid: Although targeted studies are lacking, it is suggested that fluconazole may increase plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) and thus lead to neurotoxicity, possibly due to inhibition of CYP3A4.

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

Zidovudine: with simultaneous use with fluconazole, an increase in Cmax and AUC of zidovudine was observed 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 therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was established.

Patients receiving this combination should be monitored for side effects of zidovudine.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): simultaneous use of voriconazole (400 mg 2 times / day on the first day, then 200 mg 2 times / day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg / day for 4 days) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively. It has been shown that this effect persists when the dose is reduced and/or the frequency of administration of any of the drugs is reduced. Concomitant use of voriconazole and fluconazole is not recommended.

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

The listed interaction was established with repeated use of fluconazole; Drug interactions resulting from a single dose of fluconazole are unknown. Doctors should note that interactions with other drugs have not been specifically studied, but are possible.

Pharmaceutical interactions

Diflucan ® - solution for intravenous administration is compatible with the following solutions: 20% glucose solution, Ringer's solution, Hartmann's solution, potassium chloride solution in glucose, 4.2% sodium bicarbonate solution, aminofusin, isotonic saline solution. Diflucan ® can be administered into the infusion system together with one of the solutions listed above. Although cases of specific incompatibility of fluconazole with other drugs have not been described, it is nevertheless not recommended to mix it with any other drugs before infusion.

Treatment can be started pending results of cultures and other laboratory tests. However, therapy will need to be modified accordingly when the results of these studies become known.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. For vaginal candidiasis, in most cases, a single dose of the drug is effective. For infections requiring repeated administration of the antifungal drug, treatment should be continued until clinical or laboratory signs of the fungal infection disappear. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require supportive care to prevent recurrence of infection.

For adults at cryptococcal meningitis and cryptococcal infections for other localizations, an average of 400 mg is prescribed on the first day, and then treatment is continued at a dose of 200-400 mg 1 time/day. The duration of treatment for cryptococcal infections depends on the presence of clinical and mycological effect; For cryptococcal meningitis, treatment is usually continued for at least 6-8 weeks.

For prevention of relapse of cryptococcal meningitis in patients with AIDS After completing the full course of primary treatment, fluconazole therapy at a dose of 200 mg/day can be continued for a very long period.

At candidemia, disseminated candidiasis and other invasive candidal infections, the dose averages 400 mg on the first day, and then 200 mg/day. Depending on the severity of the clinical effect, the dose can be increased to 400 mg/day. The duration of therapy depends on clinical effectiveness.

At oropharyngeal candidiasis the drug is prescribed on average 50-100 mg 1 time/day for 7-14 days. If necessary, in patients with a pronounced decrease in immunity, treatment can be continued for a longer time. For atrophic candidiasis of the oral cavity associated with wearing dentures, the drug is prescribed at an average dose of 50 mg 1 time / day for 14 days in combination with local antiseptics for treating the denture.

At other candidal infections of the mucous membranes(except for genital candidiasis), such as esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the effective dose averages 50-100 mg/day with a treatment duration of 14-30 days.

For prevention of relapses of oropharyngeal candidiasis in patients with AIDS after completing the full course of primary therapy, fluconazole can be prescribed 150 mg once a week.

At vaginal candidiasis Fluconazole is taken orally once at a dose of 150 mg.

For reducing the frequency of relapses of vaginal candidiasis the drug can be used in a dose of 150 mg 1 time/month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use. The use of the drug in a single dose in children under 18 years of age and patients over 60 years of age without a doctor’s prescription is not recommended.

At balanitis caused by Candida spp., fluconazole is prescribed as a single dose of 150 mg orally.

For prevention of candidiasis The recommended dose of fluconazole is 50-400 mg 1 time/day, depending on the degree of risk of developing a fungal infection. If there is a high risk of generalized infection, for example in patients with severe or long-lasting neutropenia, the recommended dose is 400 mg 1 time / day. Diflucan ® is prescribed several days before the expected development of neutropenia and after the number of neutrophils increases to more than 1000/μl, treatment is continued for another 7 days.

At skin infections, including mycoses of the feet, smooth skin, groin area and candidal infections, the recommended dose is 150 mg 1 time/week. or 50 mg 1 time/day. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy may be required (up to 6 weeks).

At pityriasis versicolor The recommended dose is 300 mg 1 time/week. within 2 weeks; some patients require a third dose of 300 mg/week, while for some patients a single dose of 300-400 mg is sufficient. An alternative treatment regimen is the use of the drug 50 mg 1 time / day for 2-4 weeks.

At onychomycosis The recommended dose is 150 mg 1 time/week. Treatment should be continued until the infected nail is replaced (the uninfected nail regrows). Regrowth of fingernails and toenails usually takes 3-6 months and 6-12 months, respectively. However, growth rate can vary widely between individuals and also depending on age. After successful treatment of long-standing chronic infections, a change in the shape of the nails is sometimes observed.

At deep endemic mycoses It may be necessary to use the drug at a dose of 200-400 mg/day for up to 2 years. The duration of therapy is determined individually; it is 11-24 months for coccidioidomycosis, 2-17 months for paracoccidioidomycosis, 1-16 months for sporotrichosis, and 3-17 months for histoplasmosis.

U children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. The daily dose for children should not exceed that for adults. Diflucan ® is used daily 1 time/day.

At candidiasis of the mucous membranes The recommended dose of Diflucan ® is 3 mg/kg/day. On the first day, a loading dose of 6 mg/kg may be prescribed in order to more quickly achieve constant equilibrium concentrations.

For treatment generalized candidiasis and cryptococcal infection The recommended dose is 6-12 mg/kg/day depending on the severity of the disease.

For suppression of relapse of cryptococcal meningitis in children with AIDS The recommended dose of Diflucan ® is 6 mg/kg/day.

For prevention of fungal infections in patients with reduced immunity in whom the risk of developing infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day depending on the severity and duration of persistence of induced neutropenia.

When using the drug in children aged 4 weeks or less It should be borne in mind that fluconazole is excreted slowly in newborns.

IN first 2 weeks of life the drug is prescribed in the same dose (in mg/kg) as for older children, but with an interval of 72 hours.

Babies aged 3 and 4 weeks the same dose is administered at intervals of 48 hours.

U elderly patients in the absence of signs of renal failure, the drug is prescribed in an average dose. Elderly patients with renal failure (KR)<50 мл/мин) correction of the dosage regimen is required.

Fluconazole is excreted mainly in the urine unchanged. With a single dose, no dose change is required. U patients (including children) with impaired renal function with repeated use of the drug, a loading dose of 50 mg to 400 mg should initially be administered, after which the daily dose (depending on the indications) is determined according to the following table.

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 (depending on QC) dose of the drug.

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

Rules for using the drug

Fluconazole can be taken orally (in the form of capsules and suspensions) or administered intravenously (in the form of a solution for intravenous administration) by infusion at a rate of no more than 10 ml/min; the choice of route of administration depends on the clinical condition of the patient. When transferring a patient from intravenous administration to oral administration of the drug or vice versa, no change in the daily dose is required.

Capsules should be swallowed whole.

When preparing a suspension for oral administration, add 24 ml of water to the contents of one bottle and shake thoroughly. The suspension should be shaken before each use.

The drug solution for intravenous administration contains 0.9% sodium chloride solution; Each 200 mg (100 ml bottle) contains 15 mmol Na + and Cl -. Therefore, in patients who require sodium or fluid restriction, the rate of fluid administration must be considered.

Storage conditions and shelf life

Capsules should be stored at a temperature not exceeding 30°C. Shelf life – 5 years. The powder for preparing a suspension for oral administration should be stored at a temperature not exceeding 30°C. Shelf life – 3 years. The finished suspension should be stored at a temperature not exceeding 30°C; do not freeze. The shelf life of the finished suspension is 14 days. The solution for intravenous administration should be stored at a temperature not exceeding 30°C; do not freeze. Shelf life – 5 years. The drug should be stored out of the reach of children.

Release from pharmacies

The drug is available by prescription. The drug in the form of 150 mg capsules is approved for use as an over-the-counter product (only for the treatment of vaginal candidiasis, previously confirmed by a doctor).

Currently, the drug Diflucan is one of the most effective antifungal agents. It is most often prescribed to treat thrush. Moreover, the symptoms of the disease can be eliminated with a single use of the medicine. However, in any case, a doctor should prescribe this drug, taking into account the clinical picture of the pathology.

Diflucan tablets are part of a new class of triazole antifungal drugs. They are considered a powerful method of combating fungal microorganisms of various natures. The active substance of the drug is fluconazole, which has antibiotic properties. By suppressing the life processes of fungi, the drug leads to their death.

It is important to note that the medicine does not affect the balance of hormones. The effectiveness of the drug was tested on different models of fungal pathologies. This medicine is considered to be most effective for opportunistic mycoses. These include diseases caused by Candida spp.

What does Diflucan help with?

The instructions for use of Diflucan contain the following indications for the use of the drug:

Cryptococcosis. This category includes cryptococcal meningitis, as well as infections in other locations, such as the lungs or skin.
Generalized form of candidiasis. This group includes disseminated candidiasis, candidemia and other types of invasive infections.
Mucosal candidiasis. This category includes the mucous membranes of the pharynx, esophagus, and mouth.
Genital and vaginal candidiasis. Diflucan for thrush in women is also used to prevent the disease in case of more than 3 exacerbations per year.
Skin mycoses. The drug is used for fungal infections of the feet, groin area, and body. Indications include pityriasis versicolor, skin infections and onychomycosis.
Deep endemic mycoses.

Instructions for use of Diflucan, dosage

Diflucan 150 mg capsules must be swallowed whole. The daily volume is determined depending on the type of fungal infection and age category. Typically, therapy is prescribed before laboratory test results are obtained. However, a specific scheme is selected based on research results.

Diflucan for thrush is used 1 time in a volume of 150 mg. If a woman suffers from frequent relapses of the pathology, the medicine is used in the same dosage once a month for prevention purposes. The duration of use ranges from 4 months to a year - it depends on the characteristics of the body. In some cases, doctors prescribe Diflucan suppositories.

If balanitis caused by fungal microorganisms Candida is observed, Diflucan is also prescribed once in a volume of 150 mg. For other candidal infections, the scheme is somewhat different. So, on the first day it is recommended to use 400 mg of the drug, then the volume is reduced to 200 mg once a day. If the desired effect cannot be achieved, the dosage is again increased to 400 mg.

Features of the use of diflucan directly depend on the type of pathology:

Cryptococcal infections - on the first day you need to take 400 mg of the drug, then 200-400 mg are required.
Infectious skin lesions - it is recommended to take 150 mg once a week or 50 mg every day. Therapy lasts 2-4 weeks.
Pityriasis versicolor - different treatment regimens are used. Sometimes the medicine is prescribed once a week in an amount of 300 mg. This treatment lasts 14 days. In accordance with the second regimen, the drug is used once a day in a volume of 50 mg. In this situation, therapy continues for 2-4 weeks.
Onychomycosis - weekly use of 150 mg is prescribed until a healthy nail appears completely. It usually takes 3-6 months to grow on the arms, and up to a year on the legs.
Oropharyngeal candidiasis - prescribe daily use of the drug for 1-2 weeks. Dosage – 50-100 mg per day. The atrophic form of oral candidiasis requires the use of Diflucan for 2 weeks. In this case, the dosage of the drug is 50 mg per day.

For other types of candidal lesions of the mucous membranes, the medicine is used in a volume of 50-100 mg per day. Treatment should last 14-30 days.

Diflucan contraindications

This medicine has many contraindications. These include the following:

liver pathologies;
high sensitivity to ingredients;
allergic reactions to fluconazole;
the use of drugs that affect the heart rhythm - these include astemizole, cisapride;
complex pathologies of the cardiovascular system, accompanied by rhythm disturbances;
electrolyte imbalance.

In some cases, Diflucan causes unwanted side effects. They manifest themselves in the form of nausea, dizziness, pain in the stomach, headaches, flatulence, and diarrhea. Some people suffer from swelling, seizures, leukopenia, exanthema, or impaired taste. If unwanted side effects occur, the drug must be replaced. Cheap analogs of Diflucan are fluconazole, mycoflucan.

Overdose

An overdose of this drug leads to increased side effects. If the recommended amount is seriously exceeded, the person is at risk of experiencing delusions and hallucinations. In such a situation, hospitalization is required. As first aid, it is recommended to drink activated carbon.

In a hospital setting, the victim undergoes gastric lavage. Since the active component is excreted primarily through the kidneys, hemodialysis is sometimes used to eliminate the symptoms of overdose.

special instructions

Treatment with Diflucan is continued until clinical and hematological remission occurs. Premature cessation of therapy provokes relapses. In order for it to bring the desired results, the following rules should be followed:

The drug can be used in the absence of laboratory test results. After receiving them, the doctor must make adjustments to fungicidal therapy.
During treatment, you need to keep your kidney and liver function under control, as well as monitor your blood counts. If any violations occur, it is recommended to stop using the product.
The hepatotoxic effect of the drug is reversible. Symptoms of liver damage usually disappear after stopping treatment.
If patients with immunosuppression develop skin rashes, they should be carefully examined. If the reactions progress, treatment is stopped because there is a risk of developing Lyell's or Stevens-Johnson syndrome.
During therapy, it is necessary to monitor the prothrombin index when combining the drug with coumarin anticoagulants.

Diflucan is considered a fairly effective remedy that can cope with most fungal infections. To get the desired result, it is very important to strictly adhere to the doctor’s recommendations and take into account all contraindications to the use of the medicine.

PHARMACHOLOGIC EFFECT

Antifungal drug. Fluconazole, a representative of the class of triazole antifungal agents, is a powerful selective inhibitor of sterol synthesis in fungal cells.

When administered orally and administered intravenously, fluconazole showed activity in various models of fungal infections in animals. The activity of the drug in opportunistic mycoses has been demonstrated, incl. caused by Candida spp., including generalized candidiasis in animals with reduced immunity; Cryptococcus neoformans, including intracranial infections; Microsporum spp. and Trychoptyton spp. The activity of fluconazole has also been established in models of endemic mycoses in animals, including infections caused by Blastomyces dermatitidis, Coccidioides immitis, including intracranial infections, and Histoplasma capsulatum in animals with normal and reduced immunity.

Fluconazole has high specificity for fungal enzymes dependent on cytochrome P450. Treatment with fluconazole 50 mg/day for up to 28 days did not affect plasma testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole at a dose of 200-400 mg/day did not have a clinically significant effect on the levels of endogenous steroids and their response to ACTH stimulation in healthy male volunteers.

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

There have been reports of cases of superinfection caused by Candida strains other than Candida albicans, which are often not sensitive to fluconazole (for example, Candida krusei). In such cases, alternative antifungal therapy may be required.

PHARMACOKINETICS

The pharmacokinetics of fluconazole are similar when administered intravenously and when administered orally.

Suction

Distribution

90% of the equilibrium concentration is achieved by the 4-5th day after the start of therapy (with repeated doses 1 time per day).

Administration of a loading dose (on the 1st day), 2 times higher than the average daily dose, allows you to achieve a C ss of 90% by the 2nd day. The apparent V d approaches the total water content in the body. Plasma protein binding is low (11-12%).

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

In the stratum corneum, epidermis-dermis and sweat fluid, high concentrations are reached that exceed serum concentrations. Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg 1 time / day, the concentration of fluconazole after 12 days was 73 mcg/g, and 7 days after stopping treatment - only 5.8 mcg/g. When used at a dose of 150 mg 1 time/week. the concentration of fluconazole in the stratum corneum on the 7th day was 23.4 mcg/g, and 7 days after taking the second dose - 7.1 mcg/g.

Metabolism and excretion

Long T1/2 from blood plasma allows you to take fluconazole once for vaginal candidiasis and 1 time / day or 1 time / week. for other indications.

Pharmacokinetics in special clinical situations

In children The following pharmacokinetic parameters were identified:

* - indicator recorded on the last day.

Vd was 1183 ml/kg (range 1070-1470 ml/kg) on day 1, then increased to an average of 1184 ml/kg (range 510-2130 ml/kg) on day 7 and up to 1328 ml/kg (range 1040-1680 ml/kg) on the 13th day.

U elderly patients (65 years and older) with a single use of fluconazole at a dose of 50 mg orally (in some cases with simultaneous use of a diuretic), it was found that C max was achieved 1.3 hours after administration and was 1.54 μg/ml, average AUC values 76.4 ± 20.3 μg × h/ml, average T 1/2 was 46.2 hours.

INDICATIONS

— cryptococcosis, including cryptococcal meningitis and infections of other localizations (for example, lungs, skin), incl. in patients with a normal immune response and in patients with AIDS, organ transplant recipients and patients with other forms of immunodeficiency; maintenance therapy to prevent relapses of cryptococcosis in patients with AIDS;

- generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, incl. in patients with malignant tumors who are in the ICU and receiving cytotoxic or immunosuppressive drugs, as well as in patients with other factors predisposing to the development of candidiasis;

- candidiasis of the mucous membranes, including the mucous membranes of the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic candidiasis of the oral cavity (associated with wearing dentures), incl. in patients with normal and suppressed immune function; prevention of relapse of oropharyngeal candidiasis in patients with AIDS;

- genital candidiasis; acute or recurrent vaginal candidiasis; prevention to reduce the frequency of relapses of vaginal candidiasis (3 or more episodes per year); candidal balanitis;

- prevention of fungal infections in patients with malignant tumors who are predisposed to the development of such infections as a result of cytotoxic chemotherapy or radiation therapy;

— mycoses of the skin, including mycoses of the feet, body, groin area, pityriasis versicolor, onychomycosis and skin candidal infections;

— deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

DOSING REGIME

Treatment can be started pending results of cultures and other laboratory tests. However, therapy will need to be modified accordingly when the results of these studies become known.

For prevention of relapses of oropharyngeal candidiasis in patients with AIDS after completing the full course of primary therapy, fluconazole can be prescribed 150 mg once a week.

At vaginal candidiasis Fluconazole is taken orally once at a dose of 150 mg.

At balanitis caused by Candida, fluconazole is prescribed as a single dose of 150 mg orally.

At skin infections, including mycoses of the feet, smooth skin, groin area and candidiasis infections, the recommended dose is 150 mg 1 time/week. or 50 mg 1 time/day. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy may be required (up to 6 weeks).

For treatment generalized candidiasis and cryptococcal infection The recommended dose is 6-12 mg/kg/day depending on the severity of the disease.

When using the drug in children aged 4 weeks or less It should be borne in mind that fluconazole is excreted slowly in newborns. IN first 2 weeks of life the drug is prescribed in the same dose (in mg/kg) as for older children, but with an interval of 72 hours. Babies aged 3 and 4 weeks the same dose is administered at intervals of 48 hours.

U elderly patients in the absence of signs of renal failure, the drug is prescribed in an average dose.

Patients with renal failure (KR<50 мл/мин) correction of the dosage regimen is required.

Capsules should be swallowed whole.

When preparing a suspension for oral administration, add 24 ml of water to the contents of one bottle and shake thoroughly. The suspension should be shaken before each use.

SIDE EFFECT

The most common side effects were those that were recorded in clinical and post-marketing (*) studies of Diflucan ® .

From the central nervous system and peripheral nervous system: headache, dizziness*, convulsions*, change in taste*.

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia*, vomiting*, hepatotoxicity (including rare cases with fatal outcome), increased levels of alkaline phosphatase, bilirubin, serum aminotransferase levels (ALT and AST), liver dysfunction*, hepatitis*, hepatocellular necrosis*, jaundice*.

From the cardiovascular system*: increased QT interval on ECG, ventricular fibrillation/flutter.

Dermatological reactions: rash, alopecia*, exfoliative skin diseases*, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the hematopoietic system*: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

Metabolism*: increased levels of cholesterol and triglycerides in plasma, hypokalemia.

Allergic reactions*: anaphylactic reactions (including angioedema, facial swelling, urticaria, itching).

CONTRAINDICATIONS

- simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg/day or more;

- simultaneous use of cisapride;

- hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole.

WITH caution the drug is prescribed for abnormal liver function tests during the use of fluconazole, when a rash appears during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, with simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day, with potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

PREGNANCY AND LACTATION

Fluconazole is found in breast milk in concentrations close to plasma levels, therefore the use of Diflucan ® during lactation (breastfeeding) is not recommended.

SPECIAL INSTRUCTIONS

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, incl. with a fatal outcome, mainly in patients with serious concomitant diseases. There was no obvious dependence of the hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effects of fluconazole were usually reversible; its signs disappeared after cessation of therapy. Patients whose liver function tests are impaired during treatment with fluconazole should be monitored for signs of more serious liver damage. If clinical signs or symptoms of liver damage that may be associated with fluconazole appear, the drug should be discontinued.

As with other azoles, fluconazole can rarely cause anaphylactic reactions.

Concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be carried out under close supervision.

Impact on the ability to drive vehicles and operate machinery

Experience with the use of the drug Diflucan ® indicates that deterioration in the ability to drive a car and operate machinery associated with the use of the drug is unlikely.

OVERDOSE

Treatment: Symptomatic therapy (including supportive measures and gastric lavage) can provide an adequate effect.

DRUG INTERACTIONS

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

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

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

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

Oral contraceptives: with simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily administration of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole once a week - AUC of ethinyl estradiol and norethindrone increased by 24% and 13%, respectively. Thus, repeated use of fluconazole at the indicated 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 phenytoin concentrations. If concomitant use of both drugs is necessary, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.

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

Rifampicin: simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T 1/2 of fluconazole by 20%. In patients simultaneously taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Sulfonylureas: fluconazole, when taken simultaneously, leads to an increase in half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). In patients with diabetes mellitus, fluconazole and oral sulfonylureas can be prescribed together, but the possibility of hypoglycemia should be taken into account.

Tacrolimus: simultaneous use of fluconazole and tacrolimus leads to increased serum concentrations of the latter. Cases of nephrotoxicity have been described. Patients receiving tacrolimus and fluconazole concomitantly should be monitored closely.

Terfenadine: With the simultaneous use of azole antifungals and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

Zidovudine: with simultaneous use with fluconazole, an increase in zidovudine concentrations is observed, which is likely due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was established.

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

The simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by isoenzymes of the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. When prescribing fluconazole simultaneously, in the absence of reliable information, caution must be exercised. Patients should be monitored carefully.

The listed interaction was established with repeated use of fluconazole; There are no known drug interactions resulting from a single dose of fluconazole.

It should be borne in mind that interactions with other drugs have not been specifically studied, but they are possible.

Pharmaceutical interactions

STORAGE CONDITIONS AND EXPIRATION DATES

Capsules should be stored at a temperature not exceeding 30°C. Shelf life - 5 years.

The powder for preparing a suspension for oral administration should be stored at a temperature not exceeding 30°C. Shelf life - 3 years. The finished suspension should be stored at a temperature not exceeding 30°C; do not freeze. The shelf life of the finished suspension is 14 days.

The solution for intravenous administration should be stored at a temperature not exceeding 30°C; do not freeze. Shelf life - 5 years.

The drug should be stored out of the reach of children.

Characteristics of the drug

Release form: tablets, solution, powder

Indications for use:fungal infections, thrush, lichen

Side effects:headaches, swelling, nausea, allergic reactions

Contraindications:pregnancy, breastfeeding

Price: 500-1000 rub.

Fungal infections that occur against the background of a weakened immune system can affect almost all organs and systems of people of different ages. Diflucan is a modern antifungal agent that effectively copes with almost all types of pathogenic microorganisms.

When using Diflucan, side effects are rare, and the variety of release forms allows it to be used by people of all ages.

What is the peculiarity of using the drug in the treatment of fungal infections, what is its composition, what similar products are on sale - you will find the answer to all these and other equally important questions in this article.

Specifics of action and release forms

The main component of the product is fluconazole, which prevents the formation of microbial cell membranes, inhibiting the synthesis of sterol. Therefore, the fungus stops reproducing, and its living cells die.

Diflucan therapy is effective against yeast, yeast-like and mold fungi. The drug is almost completely absorbed by the digestive tract, and its concentration in the blood reaches 90% within 30-90 minutes after administration.

Note! Taking the drug in all its forms does not affect changes in hormonal levels.

The medicine can be used both before and after meals, since food intake does not affect the level of bioavailability. The active substance is characterized by excellent penetration into the skin, mucous membranes, all organs and tissues, while it is evenly concentrated in them.

Considering that the product is excreted from the body for quite a long time, this makes it possible to use it once a day. Cases have been recorded where a lasting effect was achieved after one dose of the medicine.

The active component acts in the body during the day and is then excreted unchanged by the kidneys.

Let's consider the drug release forms offered by the manufacturer:

Diflucan tablets (capsules). The white powder with a slight yellowish tint is contained in a capsule of the same color with a blue cap. Each capsule has a black logo. The dosage of fluconazole in 1 tablet can be 50, 100 or 150 mg. They are packaged in 1 or 7 pieces in a blister.
The solution is a colorless and transparent liquid that is used to administer the drug intravenously. There are 2 mg of active substance per 1 ml of solution. It is sold in glass bottles of 50, 100, 200 ml.
The powder is used to prepare a suspension, 1 ml of which contains 10 ml of fluconazole. The powder is sold in 5 ml plastic bottles.

Considering that women often use Diflucan for thrush, they are concerned about the question: is the drug available for sale in the form of suppositories. To date, this form of the drug is not available, but sometimes, on the recommendation of a doctor, suppositories are prepared from a Diflucan solution independently. To do this, a sterile cotton swab is soaked in 25 ml of solution and inserted deep into the vagina overnight.

Features of use

The product has indications for use in the treatment of many infections caused by fungus:

In addition, the drug is indicated for use by people with weakened immune systems for preventive purposes:

after radiation and chemotherapy;
patients with HIV;
people undergoing long-term drug treatment with antibiotics or drugs containing hormones.

The product not only prevents the possibility of complications such as fungal infections, but also helps the body cope with them. Therefore, it is prescribed in the complex treatment of infectious diseases of the respiratory and genitourinary organs.

The instructions for use of Diflucan prescribe the dosage for the treatment of certain diseases. However, it is better to use the product according to the regimen prescribed by the attending physician, since in this case the individual characteristics of the patient’s body and the severity of the disease are taken into account.

Disease	Dosage	Notes
Vaginal candidiasis and balanitis	Single dose of capsule with a dosage of 150 mg	The capsule should be drunk without chewing. After treatment, for prevention, the drug in the same dosage is used once a month.
Invasive candidal and cryptococcal infections, intestinal candidiasis	The beginning of treatment involves taking 400 mg of the drug per day. Afterwards, the dosage is reduced to 200 mg.	The duration of therapy is 1-2 months.
Candidiasis of the mucous membranes	50 to 100 mg per day.	Therapy is carried out from two weeks to a month. For candidiasis caused by the use of dentures, a two-week treatment is prescribed.
Fungal skin infections and mycoses of the feet	50 mg of the drug daily for a month. For mycoses of the feet up to 2 months.	This regimen can be replaced and taken once a week, but at a dosage of 300 mg. Treatment is carried out for 2 weeks.
Onychomycosis	150 mg of the drug once a week	Diflucan for nail fungus is used until the nail infected with the fungus is completely replaced by a healthy one.

For patients with deep endemic mycosis, drug therapy is prescribed from 200 to 400 mg daily for two years.

For preventive purposes, the dosage of the drug is calculated based on the patient’s body weight (3-12 mg per 1 kg).

Treatment of children and pregnant women

For the treatment of mucous membranes, the dosage is calculated at 3 mg per 1 kg of child weight. In advanced stages of the disease, it is allowed to use an increased dose of the drug on the first day to achieve a better therapeutic effect.

For the treatment of cryptococcal infections, as well as generalized candidiasis in children, Diflucan is used at a rate of 6 to 12 mg per 1 kg of body weight. In case of prophylactic use, the dose should be reduced to 6 mg per 1 kg of body.

For newborns, the drug is used in the same dosage as for older children. However, the frequency of taking the medicine varies.

For example, in newborns up to two weeks, the drug is used no more often than every 72 hours, and after this period the drug is administered every 2 days.

For infants, as well as children and adults with severe fungal infections, the drug is administered intravenously.

Note! The administration of Diflucan intravenously should only be carried out in a medical facility by qualified personnel.

The solution is administered very slowly, no more than 10 ml per minute.

For children from 2 to 7 years old, it is advisable to use the drug in the form of a suspension, which has an orange flavor. The syrup is easier to dose and convenient for treating children.

The effect of the drug in the early stages is especially unfavorable, since studies have documented various congenital pathologies in infants whose mothers were treated with this drug during pregnancy. Pregnant women can use the drug only if the manifestations of fungal infections threaten their lives.

If a woman did not know that she was pregnant and took the medicine, she must inform her doctor about this.

When breastfeeding, Diflucan therapy is also contraindicated, since fluconazole, which is part of the drug, passes into breast milk. In the event that treatment of fungal infections must be carried out immediately, breastfeeding should be temporarily suspended, using formula milk to feed the baby.

Important information

Like many other medicines, Diflucan has contraindications for use:

The drug is used with extreme caution in the following cases:

liver diseases;
skin rash that appeared during therapy;
diseases of the heart and vascular system.

Note! Combining Diflucan and alcohol is strictly prohibited, since this interaction poses a danger to human life. It is impossible to predict how the body will react to the simultaneous use of Diflucan and alcohol.

Numerous consumer reviews indicate that the drug is well tolerated and side effects are rare.

However, the instructions for use indicate their possible manifestations:

In case of overdose, hallucinations and paranoid behavior are observed. In this case, you need to rinse the stomach, stimulate the process of copious urination and immediately seek medical help.

Treatment of thrush in women and men

We have already told you how to take Diflucan for thrush. However, this insidious disease has a number of specific features that need to be discussed in more detail.

Thrush bothers women with its obvious and unpleasant symptoms: burning, itching, copious curd-like discharge from the vagina. And as soon as they disappear after a few days of treatment, many women believe that therapy can be stopped. You can find out more about the symptoms and characteristics of thrush.

Such actions lead to the fact that after a very short time the microorganisms begin their active activity again. Moreover, they become immune to the composition of the drug, and it is more difficult to cure them: candidiasis enters the chronic stage.

In addition, the characteristics of the female reproductive system lead to sharp hormonal changes during menstruation. Due to this fact, the immune system weakens, and the symptoms of thrush begin to appear more strongly.

However, it is not recommended to use anti-candidiasis medications during menstruation. Treatment should begin after they are completed.

An important point is the joint therapy of sexual partners. Although thrush is not an STI, the fungus is highly contagious, so both partners should be treated.

Diflucan for men is indicated for use both for preventive purposes (if there are no external manifestations of thrush, and the sexual partner is being treated for candidal colpitis) and for the treatment of balanitis (with pronounced symptoms).

In the first case, a man only needs to take 150 mg of the medicine once.

Treatment of balanitis with Diflucan should be carried out comprehensively, combining it with topical medications (creams or ointments), always taking into account their compatibility.

Note! Only the attending physician should prescribe a detailed treatment regimen, since it will depend on the form and severity of candidiasis, individual characteristics and age of the patient. You also need to take into account the compatibility of the selected medications.

Interaction with other drugs

When treating with Diflucan, it is important to consider how compatible the components of the drug are with other medications used during therapy.

Thus, taking oral contraceptives in combination with Diflucan leads to their increased levels in the blood.

Taking Rifampicin provokes rapid elimination of Diflucan, therefore, despite their compatibility, the dose of the latter should be increased.

The combined use of Diflucan and Theophylline, on the contrary, helps to increase the plasma content of the latter, so the dosage also requires adjustment.

Rifampicin Theophylline

Note! The simultaneous use of Diflucan and Terfenadine, Cisapride is strictly prohibited, since their combined effect disrupts the heart rhythm and can cause the death of the patient!

The effect of similar products and their cost

Diflucan has analogues that have a similar composition or are similar in their action. These include the following medicines:

Particular attention should be paid to the Russian analogue of the drug, which is called Fluconazole. The principle of its operation is similar, the main component is the same, and the price is much lower.

Drugs with a similar effect are prescribed if Fluconazole does not help for some reason. Most often this occurs due to interrupted or incorrect treatment, when the pathogen becomes persistently addicted to the active substance.

Note! You should not change the treatment method on your own or start therapy with other medications. Analogs have many contraindications and features in use. Therefore, only the attending physician should decide on replacing the medication.

The cost of the drug varies depending on the dosage and release form.

So, the average price of the drug in Russia looks like this:

Consumer Opinions

Positive reviews about the drug are left not only by doctors and pharmacists, but also by patients. Many people who have encountered manifestations of fungal infections have found the answer to what to do for its successful treatment with Diflucan

Olga, 38 years old: I have been suffering from thrush for a long time. I tried almost all medications. The doctor prescribed Diflucan. I started drinking capsules and making candles from the solution. The result is amazing! I recommend.

Daria, 26 years old: I got a fungus on my feet after visiting the pool. By that time, I had just finished a course of antibiotics, so my immunity was weaker than ever. I was surprised when the doctor prescribed Diflucan, because I thought that it only treated thrush. I was treated for more than a month, everything went away. True, I suffered from insomnia, which went away after stopping treatment.

Ira, 21 years old: I learned about Diflucan from reviews of friends. Why doesn't he help? The medicine dealt with my thrush quickly: 1 capsule – and no problems!

active substance: fluconazole; 1 ml of solution contains 2 mg of fluconazole;

Excipients: sodium chloride, water for injection.

Dosage form

Solution for infusion.

Pharmacotherapeutic group

Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Indications

Treatment of diseases in adults such as:

cryptococcal meningitis;
coccidioidosis;
invasive candidiasis;
candidiasis of the mucous membranes, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic candidiasis of the skin and mucous membranes;
chronic atrophic candidiasis (candidiasis caused by the use of dentures) when local therapy is ineffective.

Prevention of diseases in adults such as:

relapse of cryptococcal meningitis in patients at high risk of developing it;
relapse of oropharyngeal or esophageal candidiasis in patients with HIV at high risk of developing it;
prevention of candidal infections in patients with prolonged neutropenia (for example, patients with malignant blood diseases who are receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation).

Diflucan ® is used in children from birth for the treatment of candidiasis of the mucous membranes (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and for the prevention of candidal infections in patients with reduced immunity. The drug can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children at high risk of developing it.

Therapy with Diflucan ® can be started before receiving the results of cultural and other laboratory tests; Once results are obtained, antibiotic therapy should be adjusted accordingly.

Contraindications

Hypersensitivity to fluconazole, other azole compounds or to any of the excipients of the drug.

Concomitant use of fluconazole and terfenadine in patients using fluconazole repeatedly at doses of 400 mg/day or higher (according to the results of a multiple-use interaction study).

Concomitant use of fluconazole and other drugs that prolong the QT interval and are metabolized by the enzyme SURZA4 (for example, cisapride, astemizole, pimozide, quinidine and erythromycin).

Directions for use and doses

The dose of fluconazole depends on the type and severity of the fungal infection.

If repeated use of the drug is necessary, treatment of infections should be continued until clinical and laboratory manifestations of fungal infection activity disappear. Insufficient duration of treatment may lead to the resumption of the active infectious process.

Diflucan is used, depending on the dosage form, orally or intravenously by infusion. The method of administration of the drug depends on the clinical condition of the patient. There is no need to change the daily dose of the drug when changing the route of its administration from oral to intravenous and vice versa.

The solution for infusion should be administered at a rate not exceeding 10 ml/min.

Drug compatibility.

Diflucan ® is compatible with such solutions as:

5% and 20% glucose solution;
Ringer's solution;
Hartmann's solution;
solution of potassium chloride in glucose;
4.2% and 5% sodium bicarbonate solution;
3.5% solution of aminosine;
0.9% sodium chloride solution;
dialaflex (6.36% solution for intraperitoneal dialysis).

Diflucan ® can be administered into the infusion system together with one of the solutions listed above. Although cases of nonspecific incompatibility of the drug with other drugs have not been described, it is not recommended to mix Diflucan ® with other drugs before infusion.

The solution for intravenous infusion is intended for single use only. Dilution should be carried out under aseptic conditions. The solution must be checked for the presence of foreign particles and discoloration. The solution should only be used when it is clear and free of foreign particles. Unused remains of the drug must be destroyed.

Adults.

Cryptococcosis.

treatment of cryptococcal meningitis: the recommended loading dose is 400 mg on the first day, the maintenance dose is 200-400 mg/day. The duration of treatment is usually at least 6-8 weeks. For life-threatening infections, the daily dose can be increased to 800 mg.
maintenance therapy to prevent relapse of cryptococcal meningitis in patients at high risk of developing it: the recommended dose of the drug is 200 mg/day for an unlimited time.

Coccidioidosis. The recommended dose is 200-400 mg/day. The duration of treatment is 11-24 months or longer depending on the patient's condition. For the treatment of some forms of infection, and especially for the treatment of meningitis, a dose of 800 mg/day may be appropriate.

Invasive candidiasis. The loading dose is 800 mg on the first day, the maintenance dose is 400 mg/day. Typically, the recommended duration of treatment for candidemia is 2 weeks after the first negative blood culture results and resolution of signs and symptoms of candidemia.

Candidiasis of the mucous membranes.

Oropharyngeal candidiasis: loading dose is 200-400 mg on the first day, maintenance dose is 100-200 mg/day. The duration of treatment is 7-21 days (until remission is achieved), but can be increased for patients with severe immunodeficiency.
esophageal candidiasis: loading dose is 200-400 mg on the first day, maintenance dose is 100-200 mg/day. The duration of treatment is 14-30 days (until remission is achieved), but can be increased for patients with severe immunodeficiency.
candiduria: the recommended dose is 200-400 mg/day for 7-21 days. For patients with severe immunodeficiency, the duration of treatment can be increased.
chronic atrophic candidiasis: the recommended dose is 50 mg/day for 14 days.
chronic candidiasis of the skin and mucous membranes: the recommended dose is 50-100 mg/day. The duration of treatment is up to 28 days, but can be increased depending on the severity and type of infection or decreased immunity.

Prevention of relapse of mucosal candidiasis in patients with HIV who are at high risk of developing it.

oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100-200 mg/day or 200 mg 3 times a week. The duration of treatment is unlimited for immunosuppressed patients.

Prevention of candidal infections in patients with prolonged neutropenia. The recommended dose is 200-400 mg. Treatment should begin several days before the expected development of neutropenia and continue for 7 days after the neutrophil count increases to more than 1000/mm 3.

Elderly patients.

The dose should be adjusted depending on the state of renal function (see below).

Patients with renal failure.

Fluconazole is excreted from the body mainly in the urine unchanged. For one-time use, there is no need to adjust the dose of the drug. For patients (including children) with impaired renal function, if multiple doses of the drug are required on the first day of treatment, an initial dose of 50-400 mg should be used, depending on the indication. After this, the daily dose (depending on the indication) should be calculated according to the following table:

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis. On a day when dialysis is not performed, the patient should receive a dose adjusted based on creatinine clearance.

Patients with impaired liver function.

Fluconazole should be used with caution in patients with impaired liver function, since there is insufficient information on the use of fluconazole in this category of patients.

Children.

The maximum daily dose of 400 mg should not be exceeded.

As with similar infections in adults, the duration of treatment depends on the clinical and mycological response. Diflucan ® is used once a day.

The dosage of the drug for children with impaired renal function is given above. The pharmacokinetics of the drug have not been studied in children with renal failure (see below for information on use in newborns, who often have primary renal immaturity).

Children aged 12 years and older.

Depending on weight and pubertal development, the doctor should evaluate which dose of the drug (for adults or for children) is optimal for the patient. Clinical data indicate that the clearance of fluconazole is higher in children compared to adults. Doses of 100, 200 and 400 mg in adults and doses of 3, 6 and 12 mg/kg in children result in comparable systemic exposure.

Children aged 28 days to 11 years.

Candidiasis of the mucous membranes: the initial dose is 6 mg/kg/day, the maintenance dose is 3 mg/kg/day. The initial dose can be used on the first day in order to more quickly achieve equilibrium concentration.

Invasive candidiasis, cryptococcal meningitis: the dose of the drug is 6-12 mg/kg/day, depending on the severity of the disease.

Maintenance therapy to prevent relapse of cryptococcal meningitis in children at high risk of developing it: the dose of the drug is 6 mg/kg/day, depending on the severity of the disease.

Prevention of candidiasis in patients with immunodeficiency: the dose of the drug is 3-12 mg/kg/day, depending on the severity and duration of induced neutropenia (see doses for adults).

Children aged from birth to 27 days.

In newborns, fluconazole is excreted slowly from the body. The pharmacokinetic data on which the doses for term neonates below are based are given in the Pharmacokinetics section.

Term neonates 0 to 14 days of age: Doses similar to those above for children 28 days to 11 years of age should be administered every 72 hours. The maximum dose should not be exceeded, which is 12 mg/kg every 72 hours.
Term neonates 15 to 27 days of age: Doses similar to those above for children 28 days to 11 years of age should be administered every 48 hours. The maximum dose should not be exceeded, which is 12 mg/kg every 48 hours.

Adverse reactions

The following adverse reactions were frequently (> 1/10) reported: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood alkaline phosphatase.

To assess the frequency of adverse reactions, the following classification is used: very often (≥ 1/10), often (from ≥ 1/100 to< 1/10), нечасто (от ≥ 1/1000 до < 1/100), редко (от ≥ 1/10000 до < 1/1000), очень редко (< 1/10000) и частота неизвестна (невозможно оценить на основании имеющихся данных).

Disorders of the blood and lymphatic system.

Uncommon: anemia.

Rarely: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders.

Rarely: anaphylaxis.

Metabolic and nutritional disorders.

Uncommon: decreased appetite.

Rarely: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Mental disorders.

Uncommon: insomnia, drowsiness.

Nervous system disorders.

Often: headache.

Uncommon: convulsions, dizziness, paresthesia, taste disturbances.

Rarely: tremor.

Disorders of the hearing and vestibular apparatus.

Uncommon: vertigo.

Heart disorders.

Rarely: paroxysmal ventricular tachycardia of the “pirouette” type, prolongation of the QT interval.

Gastrointestinal disorders.

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders.

Often: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase.

Rarely: cholestasis, jaundice, increased bilirubin levels.

Rarely: liver failure, hepatocellular necrosis, hepatitis, hepatocellular lesions.

Disorders of the skin and subcutaneous tissue.

Common: rash.

Uncommon: itching, drug-induced dermatitis, urticaria, increased sweating.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioedema, facial edema, alopecia.

Disorders of the musculoskeletal system and connective tissue.

Uncommon: myalgia.

General disorders and reactions at the injection site.

Uncommon: increased fatigue, malaise, asthenia, fever.

Children. The frequency and nature of adverse reactions and abnormal laboratory test results during clinical trials in children are comparable to those in adults.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is important. This allows continuous monitoring of the balance between the benefits and risks associated with the use of this medicine. Healthcare professionals are asked to report any suspected adverse reactions as required by local regulations.

Overdose

A fluconazole overdose has been reported; hallucinations and paranoid behavior have been reported simultaneously.

In case of overdose, it is necessary to carry out symptomatic supportive therapy and, if necessary, rinse the stomach.

Fluconazole is largely excreted in the urine; forced diuresis may accelerate drug elimination. A hemodialysis session lasting 3 hours reduces the level of fluconazole in the blood plasma by approximately 50%.

Use during pregnancy or breastfeeding

Data obtained with single or repeated use of fluconazole in usual doses (< 200 мг/сутки) нескольким сотням беременных женщин в течение I триместра беременности, не продемонстрировали нежелательных эффектов на плод. Сообщалось о многочисленных врожденных патологиях у новорожденных (включая брадифрению, дисплазию ушной раковины, чрезмерное увеличение переднего родничка, искривление бедра, плечоликтьовий синостоз), матери которых принимали высокие дозы флуконазола (400-800 мг/сут) в течение по крайней мере трех или более месяцев для лечения кокцидиоїдозу. Связь между применением флуконазола и этими случаями не определен.

Animal studies have demonstrated reproductive toxicity.

Usual doses of fluconazole and short-term courses of treatment with fluconazole should not be used during pregnancy unless absolutely necessary.

High doses of fluconazole and/or long courses of fluconazole treatment should not be used during pregnancy, except for the treatment of potentially life-threatening infections.

Fluconazole passes into breast milk and reaches lower concentrations than in plasma. Breastfeeding can be continued after a single dose of the usual dose of fluconazole, which is 200 mg or less.

Children

The drug is used for children from birth.

Features of application

Dermatophytosis. A study of fluconazole for the treatment of dermatophytosis in children found that fluconazole was no more effective than griseofulvin and had an overall efficacy rate of less than 20%. Therefore, Diflucan ® should not be used to treat dermatophytosis.

Cryptococcosis. There is insufficient evidence of the effectiveness of fluconazole for the treatment of cryptococcosis of other sites (for example, pulmonary cryptococcosis and cutaneous cryptococcosis), so there are no recommendations regarding the dosage regimen for the treatment of such diseases.

Deep endemic mycoses. There is insufficient evidence of the effectiveness of fluconazole for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis and cutaneous lymphatic sporotrichosis, so there are no recommendations regarding the dosage regimen for the treatment of such diseases.

Renal system. In patients with impaired renal function, the drug should be used with caution (see section " Directions for use and doses»).

Hepatobiliary system. In patients with impaired liver function, the drug should be used with caution. The use of fluconazole has been associated with rare cases of severe hepatotoxicity, including deaths, mainly in patients with severe underlying diseases. In cases where the development of hepatotoxicity was associated with the use of fluconazole, there was no clear dependence on the total daily dose of the drug, duration of therapy, gender or age of the patient. Fluconazole-induced hepatotoxicity is usually reversible and disappears after discontinuation of therapy.

Patients who develop abnormal liver function tests while receiving fluconazole should be closely monitored for the development of more severe liver damage.

Patients should be informed of symptoms that may indicate a serious effect on the liver (severe asthenia, anorexia, persistent nausea, vomiting and jaundice). In this case, use of the drug should be stopped immediately and consult a doctor.

The cardiovascular system. Some azoles, including fluconazole, are associated with prolongation of the QT interval on the electrocardiogram. Very rare cases of QT prolongation and torsade de pointes (TdP) have been reported with the use of Diflucan. These reports involved patients with severe illness with a combination of multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs that affect the QT interval.

Diflucan ® should be used with caution in patients at risk of developing arrhythmias. Concomitant use with drugs that prolong the QTc interval and are metabolized by the cytochrome P450 enzyme CYP3A4 is contraindicated.

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.

Dermatological reactions. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely reported during the use of fluconazole. Patients with AIDS are more likely to develop severe skin reactions when taking many medications. If a patient with a superficial fungal infection develops a rash that can be associated with the use of fluconazole, further use of the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, the patient should be closely monitored and fluconazole should be discontinued if bullous rashes or erythema multiforme develop.

Hypersensitivity. In rare cases, anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is an inhibitor of the CYP2C19 enzyme. The condition of patients who are simultaneously using Diflucan ® and drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19 and CYP3A4 should be monitored.

Terfenadine. The patient's condition should be carefully monitored when terfenadine and fluconazole are used concomitantly at a dose of less than 400 mg per day.

Excipients. 1 ml of the drug contains 9 mg of sodium chloride (equivalent to 0.154 mmol sodium). This should be taken into account in patients on a sodium-controlled diet.

The ability to influence the reaction rate when driving a vehicle or working with other mechanisms

No studies have been conducted on the effect of Diflucan ® on the ability to drive vehicles or operate other machinery.

Patients should be informed about the possibility of developing dizziness or lightheadedness when using Diflucan ® . If such symptoms develop, it is not recommended to drive vehicles or operate other machinery.

Interaction with other drugs and other types of interactions

The combined use of fluconazole and the following drugs is contraindicated.

Cisapride: the development of adverse reactions from the heart, including paroxysmal ventricular tachycardia of the "pirouette" type, has been reported in patients who simultaneously used fluconazole and cisapride. A controlled study demonstrated that concomitant use of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in plasma cisapride levels and prolongation of the QT interval. The simultaneous use of fluconazole and cisapride is contraindicated (see section " Contraindications").

Terfenadine: Drug interaction studies have been conducted to address the incidence of severe cardiac arrhythmias associated with prolongation of the QTc interval in patients using azole antifungal drugs concomitantly with terfenadine. In one study, fluconazole 200 mg daily did not prolong the QTc interval. Another study using fluconazole at doses of 400 mg and 800 mg/day demonstrated that the use of fluconazole at doses of 400 mg/day or higher significantly increased plasma levels of terfenadine when these drugs were coadministered. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section " Contraindications"). When using fluconazole in doses below 400 mg/day concomitantly with terfenadine, the patient's condition should be carefully monitored.

Astemizole: Concomitant use of fluconazole and astemizole may reduce the clearance of astemizole. The resulting increase in the concentration of astemizole in the blood plasma can lead to a prolongation of the QT interval and, in rare cases, to paroxysmal ventricular tachycardia of the “pirouette” type. The simultaneous use of fluconazole and astemizole is contraindicated.

Pimozide and quinidine: Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of the metabolism of pimozide or quinidine, although appropriate studies in vitro And in vivo were not carried out. An increase in the concentration of pimozide or quinidine in the blood plasma can cause a prolongation of the QT interval and in rare cases lead to the development of paroxysmal ventricular tachycardia of the "pirouette" type. The simultaneous use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin: simultaneous use of erythromycin and fluconazole may potentially lead to an increased risk of cardiotoxicity (QT interval prolongation, torsade de pointes (TdP) ) and, as a consequence, to sudden cardiac death. The use of a combination of these drugs is contraindicated.

Halofantrine fluconazole may cause increased plasma concentrations of halofantrine due to inhibition of CYP3A4. The simultaneous use of these drugs may potentially lead to an increased risk of cardiotoxicity (QT prolongation, torsade de pointes) and, as a result, sudden cardiac death. The use of a combination of these drugs should be avoided.

The combined use of fluconazole and the following drugs requires caution and dose adjustment.

Effect of other drugs on fluconazole.

Interaction studies have shown that concomitant ingestion of food, cimetidine, antacids, or further whole body irradiation for bone marrow transplantation does not have a clinically significant effect on the absorption of oral fluconazole.

Rifampicin: Concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and reduced the half-life of fluconazole by 20%. Therefore, an increase in the fluconazole dose should be considered in patients receiving rifampicin.

Effect of fluconazole on other drugs.

Fluconazole is a potent inhibitor of cytochrome P450 isoenzyme 2C9 (CYP) and a moderate inhibitor of CYP3A4. Fluconazole is a CYP2C19 inhibitor. In addition to the observed/documented interactions described below, when used concomitantly with fluconazole, there is a risk of increased plasma concentrations of other compounds that are metabolized by CYP2C9, CYP2C19 and CYP3A4. Therefore, such combinations of drugs should be used with caution; In this case, it is necessary to carefully monitor the condition of patients. The inhibitory effect of fluconazole on enzymes persists for 4-5 days after its use due to its long half-life.

Alfentanil: During concomitant use of alfentanil at a dose of 20 mcg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in AUC 10 was observed, possibly due to inhibition of CYP3A4. Alfentanil dose adjustment may be necessary.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. It is recommended to measure 5-nortriptyline and/or S-amitriptyline concentrations at the start of combination therapy and after 1 week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: Concomitant administration of fluconazole and amphotericin B to immunocompetent infected mice and immunocompromised infected mice resulted in the following results: small additive antifungal effect in systemic infection C. albicans, lack of interaction with intracranial infection Cryptococcus neoformans and antagonism of two drugs in systemic infection Aspergillus fumigatus. The clinical significance of the results obtained from these studies is unknown.

Anticoagulants: As with the use of other azole antifungals, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria and melena) in combination with prolongation of prothrombin time have been reported with the simultaneous use of fluconazole and warfarin. With simultaneous use of fluconazole and warfarin, a twofold increase in prothrombin time was observed, probably due to inhibition of the metabolism of warfarin through CYP2C9. Prothrombin time should be carefully monitored in patients receiving concomitant coumarin anticoagulants. Warfarin dose adjustment may be necessary.

Short-acting benzodiazepines, eg midazolam, triazolam: administration of fluconazole after oral administration of midazolam resulted in a significant increase in midazolam concentrations and enhanced psychomotor effects. Co-administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in an increase in AUC and half-life of 3.7-fold and 2.2-fold, respectively. The use of fluconazole at a dose of 200 mg/day and triazolam 0.25 mg orally resulted in an increase in AUC and half-life by 4.4 and 2.3 times, respectively. With the simultaneous use of fluconazole and triazolam, potentiation and prolongation of the effects of triazolam were observed.

If benzodiazepine therapy should be prescribed concomitantly to a patient being treated with fluconazole, the dose of benzodiazepines should be reduced and the patient's condition should be monitored appropriately.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and causes an increase in the level of carbamazepine in the blood serum by 30%. There is a risk of developing toxicity from carbamazepine. It may be necessary to adjust the dose of carbamazepine depending on the level of its concentration and the effect of the drug.

Calcium channel blockers: Some calcium antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by the enzyme CYP3A4. Fluconazole may potentially increase the systemic exposure of calcium channel blockers. Close monitoring for the development of adverse reactions is recommended.

Celecoxib: with simultaneous use of fluconazole (200 mg per day) and celecoxib (200 mg), the Cmax and AUC of celecoxib increased by 68% and 134%, respectively. When using celecoxib and fluconazole simultaneously, it may be necessary to halve the dose of celecoxib.

Cyclophosphamide: simultaneous use of cyclophosphamide and fluconazole leads to an increase in the level of bilirubin and creatinine in the blood serum. These drugs can be used together, despite the risk of increasing serum bilirubin and creatinine concentrations.

Fentanyl: One fatal case of fentanyl toxicity has been reported due to a possible interaction between fentanyl and fluconazole. Additionally, in a study of 12 healthy volunteers, it was demonstrated that fluconazole significantly delayed the elimination of fentanyl. Increased concentrations of fentanyl may lead to respiratory depression, so the patient's condition should be carefully monitored. A dose adjustment of fentanyl may be necessary.

Inhibitors HMG-CoA reductase: simultaneous use of fluconazole and HMG-CoA reductase inhibitors that are metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors that are metabolized by CYP2C9 (fluvastatin), increases the risk of developing myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, the patient should be carefully monitored for the occurrence of symptoms of myopathy and rhabdomyolysis and creatine kinase levels should be monitored. In the case of a significant increase in creatininease levels, as well as when myopathy/rhabdomyolysis is diagnosed or suspected, the use of HMG-CoA reductase inhibitors should be discontinued.

Immunosuppressants (eg cyclosporine, everolimus, sirolimus and tacrolimus).

Cyclosporine: fluconazole significantly increases the concentration and AUC of cyclosporine. With simultaneous use of fluconazole at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an increase in the AUC of cyclosporine by 1.8 times was observed. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration.

Everolimus: although research in vitro And in vivo have not been performed, fluconazole may increase serum concentrations of everolimus through inhibition of SURZA4.

Sirolimus fluconazole increases the plasma concentration of sirolimus, probably by inhibiting the metabolism of sirolimus by the enzyme CYP3A4 and P-glycoprotein. These drugs can be used together, provided the sirolimus dose is adjusted based on drug concentrations and effects.

Tacrolimus: Fluconazole may increase serum concentrations of tacrolimus up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. When tacrolimus was administered intravenously, no significant changes in pharmacokinetics were observed. Elevated levels of tacrolimus are associated with nephrotoxicity. The dose of oral tacrolimus should be reduced depending on the concentration of tacrolimus.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure in patients is recommended.

Methadone: Fluconazole may increase serum concentrations of methadone. When methadone and fluconazole are used concomitantly, methadone dosage adjustment may be required.

Non-steroidal anti-inflammatory drugs: when used concomitantly with fluconazole, the Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared with the corresponding values when using flurbiprofen alone. Similarly, when fluconazole was coadministered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared with those when racemic ibuprofen was used alone.

Although specific studies have not been conducted, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). It is recommended to periodically monitor for adverse reactions and toxicities associated with NSAIDs. NSAID dose adjustment may be required.

Phenytoin: Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous repeated use of 200 mg of fluconazole and 250 mg of phenytoin intravenously leads to an increase in AUC 24 phenytoin by 75% and C min by 128%. When these drugs are used concomitantly, serum phenytoin concentrations should be monitored to avoid the development of phenytoin toxicity.

Prednisone: A case was reported in which a liver transplant patient who was treated with prednisone developed acute adrenal insufficiency that occurred after stopping a three-month course of fluconazole therapy. Discontinuation of fluconazole likely resulted in increased CYP3A4 activity, resulting in increased metabolism of prednisone. Patients who use fluconazole and prednisone concomitantly for long periods of time should be closely monitored to prevent the development of adrenal insufficiency after discontinuation of fluconazole.

Rifabutin: fluconazole increases the concentration of rifabutin in the blood serum, which leads to an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the simultaneous use of fluconazole and rifabutin. When using this combination of drugs, symptoms of rifabutin toxicity should be taken into account.

Saquinavir: fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of the hepatic metabolism of saquinavir by CYP3A4 and via inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more severe. Dose adjustments of saquinavir may be necessary.

Sulfonylurea derivatives: When used concomitantly, fluconazole prolongs the half-life of oral sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide) when administered to healthy volunteers. It is recommended to frequently monitor blood sugar and reduce the dose of sulfonylureas accordingly when used concomitantly with fluconazole.

Theophylline: In a placebo-controlled drug interaction study, fluconazole 200 mg for 14 days resulted in an 18% reduction in mean plasma theophylline clearance. Patients using high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity occur.

Vinca alkaloids: Although studies have not been conducted, fluconazole, possibly due to inhibition of CYP3A4, may cause increased plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: it was reported that in a patient who simultaneously used trans-retinoic acid (the acid form of vitamin A) and fluconazole, adverse reactions from the central nervous system in the form of pseudotumor cerebri were observed; this effect disappeared after fluconazole was discontinued. These drugs can be used simultaneously, but be aware of the risk of adverse reactions from the central nervous system.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and SUZA4): concomitant use of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on the first day, then 200 mg every 24 hours for 4 days) in 8 healthy male volunteers resulted in an increase in voriconazole Cmax and AUC to an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether reducing the dose and/or frequency of voriconazole or fluconazole until this effect is eliminated. When using voriconazole after fluconazole, monitoring should be performed for voriconazole-associated side effects.

Zidovudine: fluconazole increases the Cmax and AUC of zidovudine by 84% and 74%, respectively, which is due to a decrease in the clearance of zidovudine by approximately 45% when administered orally. The half-life of zidovudine was also prolonged by approximately 128% following the use of a combination of fluconazole and zidovudine. Patients using this combination of drugs should be monitored for the development of adverse reactions associated with the use of zidovudine. A dose reduction of zidovudine may be considered.

Azithromycin: In an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effects of azithromycin and fluconazole on each other's pharmacokinetics were assessed when administered simultaneously at single oral doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were identified.

Oral contraceptives: There were 2 pharmacokinetic studies of repeated use of fluconazole and a combined oral contraceptive. When using fluconazole at a dose of 50 mg, there was no effect on hormone levels, while when using fluconazole at a dose of 200 mg per day, an increase in the AUC of ethinyl estradiol by 40% and levonorgestrel by 24% was observed. This indicates that repeated use of fluconazole at the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Ivacaftor: Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) enhancer, increased ivacaftor exposure by 3-fold and hydroxymethylivacaftor (M1) exposure by 1.9-fold. For patients receiving concomitant use of moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Fluconazole, an antifungal agent of the triazole class, is a powerful and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol. The primary mechanism of its action is the inhibition of fungal 14 alpha-lanosterol demethylation mediated by cytochrome P450, which is an integral step in the biosynthesis of fungal ergosterol. Accumulation of 14 alpha-methyl sterols correlates with subsequent loss of ergosterol by the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.

The use of fluconazole at a dose of 50 mg per day for 28 days does not affect the level of testosterone in the blood plasma in men or the level of endogenous steroids in women of reproductive age. Fluconazole at a dose of 200-400 mg per day does not have a clinically significant effect on the level of endogenous steroids or on the response to ACTH stimulation in healthy male volunteers.

An interaction study with antipyrine demonstrated that single or repeated use of 50 mg fluconazole does not affect the metabolism of antipyrine.

Sensitivity in vitro.

Fluconazole in vitro demonstrates antifungal activity against species Candida, which occur most often (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata demonstrates a wide range of sensitivity to fluconazole, whereas C. krusei is resistant to it.

Also fluconazole in vitro demonstrates activity both against Cryptococcus neoformans And Cryptococcus gattii, and against endemic molds Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum And Paracoccidioides brasiliensis.

Relationship between pharmacokinetic and pharmacodynamic properties .

Based on animal studies, there is a correlation between minimum inhibitory concentrations and efficacy against experimental models of mycoses caused by species Candida. According to the results of clinical studies, there is a linear relationship between AUC and the dose of fluconazole (approximately 1:1). There is also a direct but insufficient relationship between AUC or dose and positive clinical response to treatment of oral candidiasis and, to a lesser extent, candidemia. Likewise, treatment of infections caused by strains for which fluconazole exhibits a high minimum inhibitory concentration is less satisfactory.

Mechanism of resistance.

Microorganisms of the genus Candida demonstrate multiple mechanisms of resistance to azole antifungals. Fluconazole exhibits a high minimum inhibitory concentration against fungal strains that have one or more resistance mechanisms, which negatively impacts efficacy in vivo and in clinical practice. Cases of superinfection have been reported Candida spp., other than C. albicans species that are often insensitive to fluconazole (eg Candida krusei). Alternative antifungal agents should be used to treat such cases.

Control points (according to the European Committee for Antimicrobial Susceptibility Testing).

Based on pharmacokinetic/pharmacodynamic information, sensitivity studies in vitro and clinical responses, breakpoints for fluconazole were determined for microorganisms of the genus Candida. They were categorized into non-species-specific breakpoints, which were determined largely based on pharmacokinetic/pharmacodynamic information and independent of species-specific allocation based on minimum inhibitory concentration, and species-specific breakpoints, which most often associated with infections in humans. These checkpoints are listed below.

- sensitivity studies are not recommended, since this type is not the goal of drug therapy;

IE - There is insufficient evidence as to whether this type is a target for drug therapy.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar when administered intravenously and orally.

Absorption.

Fluconazole is well absorbed when administered orally, and the drug plasma level and systemic bioavailability exceed 90% of the fluconazole plasma level, which is achieved when the drug is administered intravenously. Concomitant consumption of food does not affect the absorption of the drug when administered orally. Peak plasma concentrations are achieved 0.5-1.5 hours after taking the drug. The concentration of the drug in the blood plasma is proportional to the dose. A steady-state concentration of 90% is achieved on the second day of treatment when a loading dose twice the usual daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to the total fluid content of the body. Plasma protein binding is low (11-12%).

Fluconazole penetrates well into all body fluids tested. The level of fluconazole in saliva and sputum is similar to the drug concentration in blood plasma. The level of fluconazole in saliva and sputum is similar to the drug concentration in blood plasma. In patients with fungal meningitis, the level of fluconazole in the cerebrospinal fluid reaches 80% of the concentration in the blood plasma.

High concentrations of fluconazole in the skin, which exceed serum concentrations, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When using a dose of 50 mg once daily, the fluconazole concentration after 12 days of treatment was 73 mcg/g, and 7 days after completion of treatment the concentration was still 5.8 mcg/g. When using a dose of 150 mg once a week, the concentration of fluconazole on the 7th day of treatment was 23.4 mcg/g; 7 days after the next dose, the concentration was still 7.1 μg/g.

The concentration of fluconazole in nails after 4 months of use of 150 mg once a week was 4.05 mcg/g in healthy volunteers and 1.8 mcg/g in nail diseases; fluconazole was determined in nail samples 6 months after completion of therapy.

Biotransformation.

Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted in the urine in an altered form. Fluconazole is a selective inhibitor of the CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of the CYP2C19 isoenzyme.

Excretion.

The half-life of fluconazole from blood plasma is about 30 hours. Most of the drug is excreted by the kidneys, with 80% of the administered dose found unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites were detected.

The long half-life of the drug from blood plasma makes it possible to use the drug once for vaginal candidiasis, as well as use the drug once a week for other indications.

Kidney failure.

In patients with severe renal failure (glomerular filtration rate< 20 мл/мин) период полувыведения увеличивается с 30 часов до 98 часов. Поэтому этой категории пациентов необходимо снизить дозу флуконазола. Флуконазол удаляется путем гемодиализа, в меньшей степени - путем интраперитонеального диализа. Сеанс гемодиализа продолжительностью 3 часа снижает уровень флуконазола в плазме крови приблизительно на 50 %.

Children.

Pharmacokinetic data were assessed in 113 children in 5 studies: 2 single-dose studies, 2 multiple-dose studies and 1 preterm neonatal study.

Following administration of 2-8 mg/kg fluconazole to children aged 9 months to 15 years, the AUC was approximately 38 mcg * hour/ml per 1 mg/kg dose. After repeated dosing, the mean plasma half-life of fluconazole varied between 15 and 18 hours; the volume of distribution was 880 ml/kg. The longer plasma half-life was approximately 24 hours after a single dose of fluconazole. This figure is comparable to the plasma half-life of fluconazole after a single dose of 3 mg/kg intravenously in children aged 11 days to 11 months. The volume of distribution in patients in this age group was approximately 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 preterm infants at approximately 28 weeks' gestation. The mean age of the child at first dose was 24 hours (range 9 to 36 hours); the average birth weight was 900 g (range 750 to 1100 g). For 7 patients the study protocol was completed. A maximum of 5 intravenous injections of fluconazole at a dose of 6 mg/kg were administered every 72 hours. The mean half-life was 74 hours (44-185) on day 1, then decreased to 53 hours (30-131) on day 7 and 47 (27-68) on day 13. The area under the curve (μg*hour/ml) was 271 (173-385) on the first day, increased to 490 (292-734) on the 7th day, then decreased to 360 (167-566) on the 13th day. The volume of distribution (ml/kg) was 1183 (1070-1470) on day 1, increasing to 1184 (510-2130) on day 7 and 1328 (1040-1680) on day 13.

Elderly patients.

Pharmacokinetic studies were conducted in 22 patients (over 65 years of age) who received 50 mg of fluconazole orally. 10 of the participants were simultaneously using diuretics. C max was 1.54 μg/ml and was achieved within 1.3 hours after fluconazole administration. The mean AUC was 76.4 ± 20.3 μg*hour/ml. The average half-life is 46.2 hours. These pharmacokinetic parameters are higher compared to those in healthy younger volunteers. Concomitant use of diuretics did not have a significant effect on Cmax and AUC. Also, creatinine clearance (74 ml/min), the percentage of fluconazole excreted unchanged in urine (0-24 hours, 22%) and renal clearance of fluconazole (0.124 ml/min/kg) in patients of this age group were lower than similar indicators for younger volunteers. Therefore, changes in pharmacokinetics in elderly patients apparently depend on parameters of renal function.

Basic physical and chemical properties

a clear, colorless solution without visible particles, which meets the requirements of the standards for parenteral solutions, in transparent bottles made of neutral glass.

Incompatibility

No particular incompatibility of the drug was noted. Do not mix the drug with other medications in the same container, except those indicated in the section " Directions for use and doses».

Best before date

Storage conditions

Does not require special storage conditions. Keep out of the reach of children. Do not freeze.

Detailed information on storage.

The product should be used immediately after opening the package. Any unused infusion solution should be discarded.

From a microbiological point of view, the diluted product should be used immediately. If the product is not used immediately, the user is responsible for the period and conditions of its storage during use; Typically, such storage of the drug should last no more than 24 hours at a temperature of 2 to 8 °C, unless dissolution was carried out under controlled and validated aseptic conditions.

Package

50 ml or 100 ml solution in bottles, 1 bottle in a cardboard package.

Vacation category

On prescription.

Manufacturer

Fareva Amboise / Fareva Amboise.

Location

Zone Industriale, 29 route des Industries, 37530 Pose-sur-Sis, France /

Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.