Diflucan in Bulgaria. Diflucan: instructions for use

Antifungal drug.
Preparation: DIFLUCAN®

The active substance of the drug: fluconazole
ATX encoding: J02AC01
CFG: Antifungal drug
Registration number: P No. 013546/02
Date of registration: 06.11.07
The owner of the reg. Award: PFIZER PGM (France)

Diflucan release form, drug packaging and composition.

Capsules hard gelatin, №4, with a turquoise cap and a white body, marked with the logo "Pfizer" and "FLU-50" in black; the contents of the capsules are powder from white to pale yellow.

1 caps.
fluconazole
50 mg

Capsules hard gelatin, No. 2, with a white cap and body, marked with the logo "Pfizer" and "FLU-100" in black; the contents of the capsules are powder from white to pale yellow.

1 caps.
fluconazole
100 mg

Excipients: lactose, corn starch, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate.

The composition of the capsule shell: titanium dioxide (E171), gelatin.
Ink composition: shellac glaze, iron oxide black (E172), N-butyl alcohol, industrial methylated alcohol 74OP, soy lecithin, antifoam component DC1510.

7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.

Capsules hard gelatin, No. 1, with a turquoise cap and body, marked with the logo "Pfizer" and "FLU-150" in black; the contents of the capsules are powder from white to pale yellow.

1 caps.
fluconazole
150 mg

Excipients: lactose, corn starch, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate.

The composition of the capsule shell: titanium dioxide (E171), gelatin, patent blue dye (E131).
Ink composition: shellac glaze, iron oxide black (E172), N-butyl alcohol, industrial methylated alcohol 74OP, soy lecithin, antifoam component DC1510.

1 PC. - blisters (1) - packs of cardboard.

5 ml of finished susp.
fluconazole
50 mg

Powder for suspension for oral administration, white or almost white, free from visible impurities.

5 ml of finished susp.
fluconazole
200 mg

Excipients: anhydrous citric acid, sodium benzoate, xanthan gum, titanium dioxide (E171), sucrose, anhydrous colloidal silicon dioxide, sodium citrate dihydrate, orange flavor *.

* contains orange essential oil, maltodextrin and water.

Plastic bottles (1) complete with a measuring spoon - packs of cardboard.

1 ml
1 vial
fluconazole
2 mg
50 mg

25 ml - colorless glass bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, colorless.

1 ml
1 vial
fluconazole
2 mg
100 mg

Excipients: sodium chloride, water for injection.

50 ml - colorless glass bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, colorless.

1 ml
1 vial
fluconazole
2 mg
200 mg

Excipients: sodium chloride, water for injection.

100 ml - colorless glass bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, colorless.

1 ml
1 vial
fluconazole
2 mg
400 mg

Excipients: sodium chloride, water for injection.

200 ml - colorless glass bottles (1) - packs of cardboard.

The description of the drug is based on the officially approved instructions for use.

Pharmacological action Diflucan

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

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

Fluconazole has a high specificity for cytochrome P450-dependent fungal enzymes. Fluconazole therapy at 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 had no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

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

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

Pharmacokinetics of the drug.

fluconazole is similar when administered intravenously and when taken orally.

Suction

After oral administration, fluconazole is well absorbed, with plasma levels (and overall bioavailability) exceeding 90% of fluconazole plasma levels when administered intravenously. Simultaneous ingestion of food does not affect absorption when taken orally. Cmax is achieved 0.5-1.5 hours after taking fluconazole on an empty stomach. Plasma concentration is dose proportional.

Distribution

90% of the equilibrium concentration is achieved by the 4-5th day of treatment with the drug (when taken 1 time / day).

The introduction of a loading dose (on the 1st day), 2 times the average daily dose, allows you to accelerate the onset of Css 90% by the 2nd day. The apparent Vd approaches the total body water content. Protein binding is low (11-12%).

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

In the stratum corneum, epidermis-dermis and sweat fluid, high concentrations are achieved that exceed serum levels. 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 after 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 μg / g, and 7 days after the second dose - 7.1 μg / g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg 1 time / 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 detected in the nails.

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 CC. No circulating metabolites were found.

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.

Salivary and plasma concentrations were compared after a single dose of fluconazole at a dose of 100 mg in the form of a suspension for oral administration (rinsing and remaining in the mouth for 2 minutes and swallowing) and capsules. Cmax of fluconazole in saliva after taking the suspension was observed after 5 minutes and was 182 times higher than the maximum concentration in saliva after taking the capsule (reached after 4 hours). Approximately after 4 h, the concentrations of fluconazole in saliva were the same. The mean AUC0-96 in saliva was significantly higher with the suspension than with the capsules. Significant differences in the rate of excretion from saliva or pharmacokinetics in plasma when using the two forms of release have not been identified.

Pharmacokinetics of the drug.

in special clinical situations

The following pharmacokinetic parameters have been identified in children:
Age
Dose
T1/2 (h)
AUC (µg x h/ml)
11 days-11 months
once in / in 3 mg / kg
23
110.1
9 months-13 years
once orally 2 mg/kg
25.0
94.7
once orally 8 mg/kg
19.5
362.5
5-15 years old
repeatedly orally 2 mg/kg
17.4*
67.4*
repeatedly orally 4 mg/kg
15.2*
139.1*
repeatedly orally 8 mg/kg
17.6*
196.1*
Average age 7 years
repeatedly in/in 3 mg/kg
15.5
41.6

* - indicator marked on the last day.

Premature infants (approximately 28 weeks of development) received fluconazole IV at a dose of 6 mg/kg every 3rd day up to a maximum of 5 doses while the infants remained in the intensive care unit. The average T1 / 2 was 74 hours (within 44-185 hours) on the 1st day, with a decrease on the 7th day to an average of 53 hours (within 30-131 hours) and on the 13th day to an average of 47 hours (within 27-68 hours).

AUC values were 271 µg x h/mL (range 173-385 µg x h/mL) on Day 1, then increased to 490 µg x h/mL (range 292-734 µg x h/mL) by 7 - day and decreased to an average of 360 mcg x h / ml (within 167-566 mcg x 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 to 1329 ml /kg (within 1040-1680 ml/kg) on the 13th day.

In elderly patients (65 years and older) with a single dose of fluconazole at a dose of 50 mg orally (in some cases with the simultaneous use of a diuretic), it was found that Cmax was reached 1.3 hours after administration and was 1.54 μg / ml, the average AUC values were 76.4 ± 20.3 mcg.h / ml, the average T1 / 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 pronounced change in AUC and Cmax. Creatinine clearance (74 ml / min), the percentage of the drug excreted in the urine unchanged (0-24 h, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients are lower than in young patients. The higher values of pharmacokinetic parameters in elderly patients taking fluconazole are probably associated with reduced renal function, which is characteristic of the elderly.

Indications for use:

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

Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, incl. in patients with malignant tumors in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis;

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 recurrence of oropharyngeal candidiasis in AIDS patients;

genital candidiasis; acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrence 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, inguinal region, pityriasis versicolor, onychomycosis and skin candidal infections;

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

Dosage and method of application of the drug.

Treatment can begin before culture and other results are available. laboratory research. However, therapy should be changed accordingly when the results of these studies become known.

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

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

For the prevention of recurrence of cryptococcal meningitis in AIDS patients after completion of the full course primary treatment therapy with fluconazole at a dose of 200 mg / day can be continued for a very long time.

With candidemia, disseminated candidiasis and other invasive candidal infections, the dose is an average of 400 mg on the first day, and then 200 mg / day. Depending on the severity of the clinical effect, the dose may be increased to 400 mg / day. The duration of therapy depends on clinical efficacy.

With 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. With atrophic candidiasis of the oral cavity associated with the wearing of dentures, the drug is prescribed at an average dose of 50 mg 1 time / day for 14 days in combination with local antiseptics for processing a prosthesis.

For other candidal infections of the mucous membranes (with the exception of genital candidiasis), such as esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is an average of 50-100 mg / day with a duration of treatment of 14-30 days.

To prevent recurrence of oropharyngeal candidiasis in patients with AIDS, after completing the full course of primary therapy, fluconazole can be prescribed 150 mg 1 time / week.

With vaginal candidiasis, fluconazole is taken once orally at a dose of 150 mg.

To reduce the frequency of recurrence of vaginal candidiasis, the drug can be used at 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 the age of 18 years and patients over 60 years of age without a doctor's prescription is not recommended.

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

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg 1 time / day, depending on the risk of developing a fungal infection. In the presence of 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. Fluconazole is prescribed a few days before the expected appearance of neutropenia, and after an increase in the number of neutrophils more than 1000/µl, treatment is continued for another 7 days.

For skin infections, including mycoses of the feet, smooth skin, inguinal region 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 (up to 6 weeks) may be required.

With 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 the drug at a 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.

With onychomycosis, the recommended dose is 150 mg 1 time / week. Treatment should be continued until replacement of the infected nail (growth of an uninfected nail). Re-growth of fingernails and toenails usually takes 3-6 months and 6-12 months, respectively. However, the growth rate can vary over a wide range different people and also depending on age. After successful treatment of long-standing chronic infections, a change in the shape of the nails is sometimes observed.

With 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.

In children, as in 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. Fluconazole is used daily 1 time / day.

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

For the prevention of fungal infections in patients with reduced immunity, in whom the risk of infection is associated with neutropenia that develops 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 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 the first 2 weeks of life, the drug is prescribed at the same dose (in mg / kg) as for older children, but with an interval of 72 hours. For children aged 3 and 4 weeks of life, the same dose is administered with an interval of 48 hours.

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

Patients with kidney failure(QC<50 мл/мин) требуется коррекция режима дозирования.

Fluconazole is excreted mainly in the urine unchanged. With a single dose, a dose change is not required. In patients (including children) with impaired renal function with repeated use of the drug, a loading dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indications) is determined according to the following table.
Creatinine clearance (ml/min)
Recommended dose percentage
>50
100%
50 (without dialysis)
50%
Patients on permanent dialysis
100% after each dialysis session

Fluconazole can be taken orally (in the form of capsules and suspension) or administered intravenously (in the form of a solution for intravenous administration) by infusion at a rate of not more than 10 ml / min; the choice of the route of administration depends on the clinical condition of the patient. When transferring a patient from intravenous administration to taking the drug orally, or vice versa, changes in the daily dose are not required.

Capsules should be swallowed whole.

When preparing a suspension for oral administration, 24 ml of water should be added to the contents of one vial and shaken thoroughly. Shake the suspension before each use.

The solution of the drug for intravenous administration contains 0.9% sodium chloride solution; each 200 mg (100 ml vial) contains 15 mmol Na + and Cl -, therefore, in patients who require restriction of sodium or fluid intake, it is necessary to consider the rate of fluid administration.

Side effects of Diflucan:

The most common side effects reported in clinical and post-marketing (*) studies of fluconazole.

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

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

From the side of cardio-vascular system*: ECG QT prolongation, ventricular fibrillation/flutter.

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

On the part of the hematopoietic system *: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

On the part of metabolism*: increased plasma cholesterol and triglyceride levels, hypokalemia.

Allergic reactions *: anaphylactic reactions (including angioedema, swelling of the face, urticaria, itching).

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

Contraindications to the drug:

Simultaneous use of cisapride;

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

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

With caution, the drug is prescribed for violations of liver function indicators against the background of the use of fluconazole, with the appearance of a rash against the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, while using 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).

Use during pregnancy and lactation.

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. Therefore, women of childbearing age should use reliable contraception.

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

Special instructions for the use of Diflucan.

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, sex and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after cessation of therapy. Patients who experience abnormal liver function tests during treatment with fluconazole should be monitored for signs of more severe 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 in rare cases developed exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more likely to develop severe skin reactions with many drugs. If a rash appears in a patient receiving treatment for a superficial fungal infection, which can be associated with the use of fluconazole, the drug should be discontinued. If a rash occurs in patients with invasive / systemic fungal infections, they should be carefully monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme appear.

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

The simultaneous use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored.

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation / flutter tachycardia was noted very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders. Therefore, such patients with potentially proarrhythmic conditions should use fluconazole with caution.

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

Influence on the ability to drive vehicles and control mechanisms

Experience with the use of fluconazole indicates that the deterioration in the ability to drive a car and mechanisms associated with the use of the drug is unlikely.

Drug overdose:

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

Treatment: adequate effect can give symptomatic therapy(including supportive measures and gastric lavage).

Fluconazole is excreted primarily in the urine, so forced diuresis could probably hasten its elimination. A 3-hour hemodialysis session reduces plasma levels of fluconazole by approximately 50%.

Interaction of Diflucan with other drugs.

Anticoagulants: like other antifungal agents - azole derivatives, fluconazole, when used simultaneously with warfarin, increases 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, it is necessary to constantly monitor the prothrombin time.

Azithromycin: with the simultaneous use of oral 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 it is administered intravenously. If concomitant benzodiazepine therapy is required, patients taking fluconazole should be monitored for an appropriate dose reduction of the benzodiazepine.

Cisapride: with the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. flickering / flutter of the ventricles (pirouette-type 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 pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Co-administration 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 the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporine in bone marrow recipients was observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.

Hydrochlorothiazide: Repeated use of hydrochlorothiazide concomitantly with fluconazole results in an increase in plasma concentration of fluconazole by 40%. The effect of this degree of severity does not require a change in the dosing regimen of fluconazole in patients receiving diuretics at the same time, but this should be taken into account.

Oral contraceptives: with the 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 200 mg of fluconazole AUC of ethinylestradiol and levonorgestrel increased by 40% and 24%, respectively, and when taking 300 mg of fluconazole once a week, the AUC of ethinylestradiol 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: The simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If it is necessary to use both drugs simultaneously, the concentration of phenytoin should be monitored and its dose adjusted accordingly in order to ensure therapeutic serum concentrations.

Rifabutin: the simultaneous use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described. Patients simultaneously receiving rifabutin and fluconazole should be carefully monitored.

Rifampicin: The simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T1 / 2 fluconazole by 20%. In patients concomitantly 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 T1 / 2 of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Sick diabetes fluconazole and oral sulfonylurea preparations can be co-administered, but the possibility of hypoglycemia should be considered.

Tacrolimus: The simultaneous use of fluconazole and tacrolimus leads to an increase in serum concentrations of the latter. Cases of nephrotoxicity have been described. Patients taking tacrolimus and fluconazole concomitantly should be closely monitored.

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 was not 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. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole at doses less than 400 mg/day in combination with terfenadine should be carefully monitored.

Theophylline: when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline, or to patients with an increased risk of developing the toxic effects of theophylline, the appearance of symptoms of theophylline overdose should be observed and, if necessary, therapy should be adjusted accordingly.

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

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

The simultaneous use of fluconazole with astemizole or other drugs, the metabolism of which is carried out by isoenzymes of the cytochrome P450 system, may be accompanied by an increase in the serum concentrations of these agents. With the simultaneous appointment of fluconazole, in the absence of reliable information, care must be taken. Patients should be carefully observed.

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

These interactions have been established with repeated use of fluconazole; interactions with medicines as a result of a single dose of fluconazole are unknown.

It should be borne in mind that the interaction with other drugs has not been specifically studied, but it is possible.

Pharmaceutical interaction

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, aminofusine, isotonic saline.

Conditions of sale in pharmacies.

The drug is dispensed by prescription. The drug in the form of capsules of 150 mg is approved for use as an over-the-counter drug.

Terms of storage conditions of the drug Diflucan.

The drug should be stored out of the reach of children at a temperature not exceeding 30 ° C.

The shelf life of capsules and solution for intravenous administration is 5 years. The shelf life of the powder for the preparation of a suspension for oral administration is 3 years. The shelf life of the finished suspension is 14 days; the solution and suspension should not be allowed to freeze.

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

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 susceptible), 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 intravenously, fluconazole was active in various models of fungal infections in animals. The activity of the drug in opportunistic mycoses, incl. caused by Candida spp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychoptyton spp. Fluconazole activity 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 a high specificity for cytochrome P450 dependent fungal enzymes. Therapy with fluconazole 50 mg/day for up to 28 days does not affect plasma testosterone levels in men or steroid levels in women of childbearing age. Fluconazole at a dose of 200-400 mg/day had no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

Mechanisms of development of resistance to fluconazole

Fluconazole resistance can develop in the following cases: a qualitative or quantitative change in the enzyme that is the target of fluconazole (lanosteril 14-α-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene encoding the target enzyme lead to a modification of the target and a decrease in 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 a 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 genes (multiple drug resistance) and the ATP-binding cassette transporter superfamily encoded by the CDR genes (candida spp. resistance genes to azole antimycotics).

Overexpression of the MDR gene leads to resistance to fluconazole, while overexpression of the 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 defined as intermediate (16-32 μg / ml), it is recommended to use the maximum dose of fluconazole.

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

Pharmacokinetics

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

Suction

After oral administration, fluconazole is well absorbed, its plasma levels (and overall bioavailability) exceed 90% of fluconazole plasma levels when administered intravenously. Simultaneous ingestion of food does not affect absorption when taken orally. C max is achieved 0.5-1.5 hours after taking fluconazole on an empty stomach. Plasma concentration is dose proportional.

Distribution

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

The introduction of a loading dose (on the 1st day), 2 times the average daily dose, allows you to reach C ss 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. The levels of fluconazole in saliva and sputum are similar to its plasma concentrations.

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

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are achieved that exceed serum levels. 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 after 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 μg / g, and 7 days after the second dose - 7.1 μg / g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg 1 time / 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 detected in the nails.

When comparing the 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 suspension for oral administration (rinsing and keeping in the mouth for 2 minutes and swallowing), it was found that Cmax of fluconazole in saliva after taking the suspension was observed through 5 min and 182 times higher than Cmax in saliva after taking the capsule (reached after 4 hours). Approximately after 4 h, the concentrations of fluconazole in saliva were the same. The mean AUC 0-96 in saliva was significantly higher with the suspension than with the capsules. There were no significant differences in the rate of excretion from saliva or pharmacokinetics in blood plasma when using fluconazole in the form of two forms of release.

Metabolism and excretion

T 1/2 from plasma is about 30 hours. Long T 1/2 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 marked on the last day.

Premature infants (approximately 28 weeks of development) received fluconazole IV at 6 mg/kg every 3rd day for a maximum of 5 doses while the infants remained in the ICU. The average T 1/2 was 74 hours (within 44-185 hours) on the 1st day, with a decrease on the 7th day to an average of 53 hours (within 30-131 hours) and on the 13th day on average up to 47 hours (within 27-68 hours).

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

V d 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 (within 1040-1680 ml/kg) on the 13th day.

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

The values of these pharmacokinetic parameters are higher than in young patients. The simultaneous use of diuretics did not cause a pronounced change in AUC and C max . CC (74 ml / min), the percentage of the drug excreted in the urine unchanged (0-24 h, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients is lower than in young patients. The higher values of pharmacokinetic parameters in elderly patients taking fluconazole are probably associated with reduced renal function, which is characteristic of the elderly.

Release form

Capsules hard gelatin, №4, with a turquoise cap and a white body, marked with the logo "Pfizer" and "FLU-50" in black; the contents of the capsules are powder from white to pale yellow.

Excipients: lactose - 49.708 mg, corn starch - 16.5 mg, colloidal silicon dioxide - 0.117 mg, magnesium stearate - 1.058 mg, sodium lauryl sulfate - 0.117 mg.

The composition of the capsule shell: titanium dioxide (E171) - 4.47%, patented blue dye (E131) - 0.03%, gelatin - up to 100%.
Ink composition: shellac glaze - 63%, black iron oxide (E172) - 25%, N-butyl alcohol - 8.995%, industrial methylated spirit 74OP - 2%, soy lecithin - 1%, antifoam component DC1510 - 0.005%.

7 pcs. - blisters (1) - packs of cardboard.

Dosage

Treatment can be started before culture and other laboratory results are available. However, therapy should be changed accordingly when the results of these studies become known.

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

To prevent the recurrence of cryptococcal meningitis in AIDS patients after completion of the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can be continued for a very long time.

For other candidal infections of the mucous membranes (with the exception of genital candidiasis), for example, esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the effective dose is an average of 50-100 mg / day with a duration of treatment of 14-30 days.

To prevent recurrence of oropharyngeal candidiasis in patients with AIDS, after completing the full course of primary therapy, fluconazole can be prescribed 150 mg 1 time / week.

With vaginal candidiasis, fluconazole is taken once orally at a dose of 150 mg.

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

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg 1 time / day, depending on the risk of developing a fungal infection. In the presence of 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 a few days before the expected development of neutropenia and after an increase in the number of neutrophils more than 1000/µl, treatment is continued for another 7 days.

With onychomycosis, the recommended dose is 150 mg 1 time / week. Treatment should be continued until replacement of the infected nail (growth of an uninfected nail). Re-growth of fingernails and toenails usually takes 3-6 months and 6-12 months, respectively. However, the rate of growth can vary widely from person to person and also according to age. After successful treatment of long-standing chronic infections, a change in the shape of the nails is sometimes observed.

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

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

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

For children aged 3 and 4 weeks of life, the same dose is administered with an interval of 48 hours.

In elderly patients in the absence of signs of renal failure, the drug is prescribed in an average dose. Elderly patients with renal insufficiency (CK<50 мл/мин) требуется коррекция режима дозирования.

Fluconazole is excreted mainly in the urine unchanged. With a single dose, a dose change is not required. In 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 hepatic impairment. In this regard, caution should be exercised when using the drug Diflucan ® in this category of patients.

Rules for the use of the drug

Capsules should be swallowed whole.

When preparing a suspension for oral administration, 24 ml of water should be added to the contents of one vial and shaken thoroughly. Shake the suspension before each use.

The solution of the drug for intravenous administration contains 0.9% sodium chloride solution; each 200 mg (100 ml bottle) contains 15 mmol Na + and Cl - . Therefore, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration.

Overdose

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 could probably hasten its elimination. A 3-hour hemodialysis session reduces plasma levels of fluconazole by approximately 50%.

Interaction

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

The concomitant use of fluconazole with the following drugs is 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 pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Co-administration 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 blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole at doses less than 400 mg/day in combination with terfenadine should be carefully monitored.

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

Pimozide: Although no appropriate in vitro or in vivo studies have 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: Despite the fact that no relevant studies have been conducted in vitro or in vivo, the simultaneous use of fluconazole and quinidine can also lead to inhibition of the metabolism of quinidine. The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of ventricular tachysystolic arrhythmia of the "pirouette" type.
The simultaneous use of quinidine and fluconazole is contraindicated.

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

Caution should be exercised and possibly dose adjustments should be made when the following drugs are co-administered with fluconazole

Drugs that affect fluconazole

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

Rifampicin: The 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 CYP2C9 and CYP2C19 isoenzymes and a moderate inhibitor of CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations
and other drugs metabolized by CYP2C9, CYP2C19 and CYP3A4 isoenzymes while taking fluconazole. In this regard, caution should be exercised with the simultaneous use of these drugs, and, if necessary, similar combinations. Patients should be under close medical supervision. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.

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

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

Amphotericin B: in studies in mice (including immunosuppressed), the following results were noted: a small additive antifungal effect in systemic infection caused by Candida albicans, no interaction in intracranial infection caused by Cryptococcus neoformans, and antagonism in systemic infection caused by A . fumigatus. The clinical significance of these results is not clear.

Azithromycin: with the simultaneous use of oral 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 it is administered intravenously. If concomitant benzodiazepine therapy is required, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate dose reduction of the benzodiazepine.

With the simultaneous administration of triazolam in a single dose, fluconazole increases triazolam AUC by approximately 50%, C max by 25-32% and T 1/2 by 25-50% due to inhibition of triazolam metabolism. Dose adjustment of triazolam 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 considered. The need to adjust the dose of carbamazepine depending on the concentration / effect should be evaluated.

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. It is recommended to control the development of side effects.

Cyclosporine: In patients with a transplanted kidney, the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporine in bone marrow recipients was observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to control the concentration of cyclosporine in the blood.

Cyclophosphamide: With the simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is noted. This combination is acceptable, taking into account the risk of increasing the concentrations of bilirubin and creatinine.

Fentanyl: There has been a report of one death possibly related to the concomitant use of fentanyl and fluconazole. It is assumed that the violations are associated with fentanyl intoxication. Fluconazole has been shown to significantly prolong the elimination time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to respiratory depression.

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

HMG-CoA reductase inhibitors: With the simultaneous use of fluconazole with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or by the CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If concomitant therapy with these drugs is necessary, patients should be observed to detect symptoms of myopathy and rhabdomyolysis. It is necessary to control the concentration of creatinine kinase. In the event of a significant increase in the concentration of creatinine kinase 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 required.

Methadone: fluconazole may increase the plasma concentration of methadone. You may need to adjust your methadone dose.

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

Despite the lack of targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (eg, naproxen, lornoxicam, meloxicam, diclofenac). You may need to adjust the dose of NSAIDs.

With the simultaneous use of NSAIDs and fluconazole, patients should be under close medical supervision in order to identify and monitor adverse reactions and manifestations of toxicity associated with NSAIDs.

Oral contraceptives: with the 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 ethinylestradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole 1 time/week AUC of ethinylestradiol and norethindrone increases 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.

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

Rifabutin: the simultaneous use of fluconazole and rifabutin can lead to an increase in the plasma concentration of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described.
Patients simultaneously receiving rifabutin and fluconazole should be carefully monitored.

Saquinavir: AUC increases by approximately 50%, C max 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: increased plasma concentrations of sirolimus, presumably due to inhibition of sirolimus metabolism 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 concomitantly, leads to an increase in the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be given simultaneously fluconazole and sulfonylurea drugs for oral administration, but the possibility of developing hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylurea drugs is necessary.

Tacrolimus: The simultaneous use of fluconazole and tacrolimus (oral) leads to an increase in serum concentrations of the latter up to 5 times due to inhibition of the metabolism of tacrolimus that occurs in the intestine through the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs were not observed with the use of tacrolimus in / in. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole at the same time require careful monitoring. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Tofacitinib: Exposure to tofacitinib is increased when co-administered with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). Dose adjustment of tofacitinib may be necessary.

Vinca alkaloid: Despite the lack of targeted studies, it is assumed that fluconazole can increase the concentration of vinca alkaloids (for example, vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may possibly be associated with inhibition of the CYP3A4 isoenzyme.

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

Zidovudine: when used simultaneously with fluconazole, there is an increase in Cmax and AUC of zidovudine by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg / day for 15 days, patients with AIDS and ARC (AIDS-related complex) showed a significant increase in AUC of zidovudine (20%).

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

Voriconazole (an 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) resulted in an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively. This effect has been shown to persist with dose reduction and/or reduction in the frequency of administration of any of the drugs. Co-administration of voriconazole and fluconazole is not recommended.

Studies of the interaction of oral forms of fluconazole when taken simultaneously with food, cimetidine, antacids, and also after total body irradiation in preparation for bone marrow transplantation have shown 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; interaction with drugs as a result of a single dose of fluconazole is unknown. Physicians should be aware that interactions with other drugs have not been specifically studied, but they are possible.

Pharmaceutical interaction

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

Side effects

The most frequently reported side effects were reported in clinical and post-marketing (*) studies of Diflucan ® .

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

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

From the side of the cardiovascular system *: an increase in the QT interval on the 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.

On the part of metabolism*: increased plasma cholesterol and triglyceride levels, hypokalemia.

From the musculoskeletal system: myalgia.

Allergic reactions *: anaphylactic reactions (including angioedema, swelling of the face, urticaria, itching).

Other: weakness, asthenia, fatigue, fever, vertigo.

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

Tolerability of the drug is usually very good.

Indications

cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), incl. in patients with a normal immune response and in AIDS patients, recipients of transplanted organs and patients with other forms of immunodeficiency; maintenance therapy to prevent recurrence of cryptococcosis in AIDS patients;
generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, incl. in patients with malignant tumors in the ICU and receiving cytotoxic or immunosuppressive agents, 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 recurrence of oropharyngeal candidiasis in AIDS patients;
genital candidiasis; acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrence of vaginal candidiasis (3 or more episodes per year); candidal balanitis;
prevention of fungal infections in patients with malignant tumors 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, inguinal region, pityriasis versicolor, onychomycosis and skin candidal infections;
deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

Contraindications

simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg / day or more;
simultaneous use with drugs that increase the QT interval and are metabolized using the CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine;
sucrase / isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption (for suspension powder);
galactose intolerance, lactase deficiency and malabsorption of glucose / galactose (for capsules);
children's age up to 3 years (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 violations of liver function, with impaired renal function, with the appearance of a rash against the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, while using 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).

Application features

Use during pregnancy and lactation

Adequate and well-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 have been noted: brachycephaly, impaired development of the facial part of the skull, impaired formation of the cranial vault, cleft palate, curvature of the femur, thinning and lengthening of the ribs, arthrogryposis and congenital heart defects. Currently, there is no evidence of an association of the listed congenital disorders with the use of fluconazole in low doses (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

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

Application for violations of liver function

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 frequency of development of hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, sex and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after cessation of therapy. Patients who experience abnormal liver function tests during treatment with fluconazole should be monitored for signs of more severe liver damage. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued.

Application for violations of kidney function

Patients with renal insufficiency (KK<50 мл/мин) требуется коррекция режима дозирования.

Use in children

Use in elderly patients

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

special instructions

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

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, 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, sex and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after cessation of therapy. Patients who experience abnormal liver function tests during treatment with fluconazole should be monitored for signs of more severe liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole, the drug should be discontinued.

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

The simultaneous use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored.

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

Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using Diflucan ®. When using the drug Diflucan ® 150 mg for vaginal candidiasis, patients should be warned that the improvement of symptoms is usually observed after 24 hours, but sometimes it takes several days for their complete disappearance. 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, which does not allow for specific dosing recommendations.

Influence on the ability to drive vehicles and control mechanisms

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

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antifungal drug

pharmachologic effect

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

When administered orally and intravenously, fluconazole was active in various models of fungal infections in animals. The activity of the drug in opportunistic mycoses, incl. caused by Candida spp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychoptyton spp. Fluconazole activity 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.

Mechanisms of development of resistance to fluconazole

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

Pharmacokinetics

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

Suction

Distribution

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

The introduction of a loading dose (on the 1st day), 2 times the average daily dose, allows you to reach C ss 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. The levels of fluconazole in saliva and sputum are similar to its plasma concentrations.

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

Metabolism and excretion

T 1/2 from plasma is about 30 hours. Long T 1/2 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 marked on the last day.

V d 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 (within 1040-1680 ml/kg) on the 13th day.

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

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

genital candidiasis; acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrence 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, inguinal region, pityriasis versicolor, onychomycosis and skin candidal infections;

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

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

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

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

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

Children's age up to 3 years (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 violations of liver function indicators, with impaired renal function, with the appearance of a rash against the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, while using 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).

The most frequently reported side effects were reported in clinical and post-marketing (*) studies of Diflucan ® .

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

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia*, vomiting*, dry mouth, constipation, hepatotoxicity (sometimes fatal), elevated bilirubin, serum ALT and AST, alkaline phosphatase, abnormal liver function* , hepatitis*, hepatocellular necrosis*, jaundice*, cholestasis, hepatocellular damage.

From the side of the cardiovascular system*: an increase in the QT interval on the ECG, arrhythmia, incl. ventricular tachysystolic type "pirouette".

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

From the side of metabolism*: increased plasma cholesterol and triglyceride levels, hypokalemia.

From the musculoskeletal system: myalgia.

Allergic reactions*: anaphylactic reactions (including angioedema, swelling of the face, urticaria, itching).

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

Tolerability of the drug is usually very good.

Overdose

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 could probably hasten its elimination. A 3-hour hemodialysis session reduces plasma levels of fluconazole by approximately 50%.

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, sex and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after cessation of therapy. Patients who experience abnormal liver function tests during treatment with fluconazole should be monitored for signs of more severe liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole, the drug should be discontinued.

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

The simultaneous use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored.

Influence on the ability to drive vehicles and control mechanisms

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

With kidney failure

Patients with renal insufficiency (KK<50 мл/мин)

In violation of the functions of the liver

Elderly

At elderly patients

Use during pregnancy and lactation

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 at concentrations close to plasma, so the use of Diflucan ® during lactation (breastfeeding) is not recommended.

drug interaction

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

Simultaneous 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 pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Co-administration 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 blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole at doses less than 400 mg/day in combination with terfenadine should be carefully monitored.

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

Pimozide: despite the fact that no relevant in vitro or in vivo studies have 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: despite the fact that no relevant in vitro or in vivo studies have been conducted, the simultaneous use of fluconazole and quinidine can also lead to inhibition of the metabolism of quinidine. The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of ventricular tachysystolic arrhythmia of the "pirouette" type.
The simultaneous use of quinidine and fluconazole is contraindicated.

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

Caution should be exercised and possibly dose adjustments should be made when the following drugs are co-administered with fluconazole

Drugs that affect fluconazole

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

Rifampicin: the 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

Alfentanil: there is a decrease in clearance and V d , an increase in T 1/2 alfentanil. This may be due to the inhibition of the CYP3A4 isoenzyme by fluconazole. Dose adjustment of alfentanil 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 a week after the start. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: in studies on mice (including those with immunosuppression), the following results were noted: a small additive antifungal effect in systemic infection caused by Candida albicans, no interaction in intracranial infection caused by Cryptococcus neoformans, and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.

Anticoagulants: like other antifungal agents - azole derivatives, fluconazole, when used simultaneously with warfarin, increases 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, it is necessary to constantly monitor the prothrombin time. The advisability of adjusting the warfarin dose should also be assessed.

Azithromycin: with simultaneous use of oral 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 it is administered intravenously. If concomitant benzodiazepine therapy is required, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate dose reduction of the benzodiazepine.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the plasma concentration of carbamazepine by 30%. The risk of carbamazepine toxicity must be considered. The need to adjust the dose of carbamazepine depending on the concentration / effect should be evaluated.

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. It is recommended to control the development of side effects.

Cyclosporine: in patients with a transplanted kidney, the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporine in bone marrow recipients was observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to control the concentration of cyclosporine in the blood.

Cyclophosphamide: with the simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is noted. This combination is acceptable, taking into account the risk of increasing the concentrations of bilirubin and creatinine.

Fentanyl: there is a report of one fatal outcome, possibly associated with the simultaneous use of fentanyl and fluconazole. It is assumed that the violations are associated with fentanyl intoxication. Fluconazole has been shown to significantly prolong the elimination time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to respiratory depression.

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

HMG-CoA reductase inhibitors: with the simultaneous use of fluconazole 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 concomitant therapy with these drugs is necessary, patients should be observed to detect symptoms of myopathy and rhabdomyolysis. It is necessary to control the concentration of creatinine kinase. In the event of a significant increase in the concentration of creatinine kinase 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 required.

Methadone: fluconazole may increase the plasma concentration of methadone. You may need to adjust your methadone dose.

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

Oral contraceptives: with the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, a significant effect on hormone levels has not been established, whereas with a 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 / day weeks AUC of ethinylestradiol and norethindrone increases 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: the simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If it is necessary to use both drugs simultaneously, the concentration of phenytoin should be monitored and its dose adjusted accordingly in order to ensure therapeutic plasma concentrations.

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

Rifabutin: the simultaneous use of fluconazole and rifabutin can lead to an increase in the plasma concentration of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described.
Patients simultaneously receiving rifabutin and fluconazole should be carefully monitored.

Saquinavir: AUC increases by approximately 50%, Cmax - 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 T 1/2 of oral sulfonylurea preparations (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be given simultaneously fluconazole and sulfonylurea drugs for oral administration, but the possibility of developing hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylurea drugs is necessary.

Tacrolimus: the 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, which occurs in the intestine through the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs were not observed with the use of tacrolimus in / in. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole at the same time 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 plasma clearance rate of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline, or to patients with an increased risk of developing the toxic effects of theophylline, the appearance of symptoms of theophylline overdose should be observed and, if necessary, therapy should be adjusted accordingly.

Tofacitinib: exposure to tofacitinib is increased when co-administered with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). Dose adjustment of tofacitinib may be necessary.

Vinca alkaloid: despite the lack of targeted studies, it is assumed that fluconazole can increase the concentration of vinca alkaloids (for example, vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may possibly be associated with inhibition of the CYP3A4 isoenzyme.

Vitamin A: there is a report of one case of the development of adverse reactions from the side of the central nervous system in the form of a pseudotumor of the brain with the simultaneous use of all-trans retinoic acid and fluconazole, which disappeared after fluconazole was discontinued. The use of this combination is possible, but one should be aware of the possibility of unwanted reactions from the central nervous system.

Zidovudine: when used simultaneously with fluconazole, there is an increase in C max and AUC of zidovudine by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg / day for 15 days, patients with AIDS and ARC (AIDS-related complex) showed a significant increase in AUC of zidovudine (20%).

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

Voriconazole (an inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): the 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. This effect has been shown to persist with dose reduction and/or reduction in the frequency of administration of any of the drugs. Co-administration of voriconazole and fluconazole is not recommended.

Pharmaceutical interaction

Treatment can be started before culture and other laboratory results are available. However, therapy should be changed accordingly when the results of these studies become known.

Adults at cryptococcal meningitis and cryptococcal infections other localization on the first day, an average of 400 mg is prescribed, 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 a clinical and mycological effect; in cryptococcal meningitis, treatment is usually continued for at least 6-8 weeks.

For prevention of recurrence of cryptococcal meningitis in patients with AIDS after completion of the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can be continued for a very long time.

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 may be increased to 400 mg / day. The duration of therapy depends on clinical efficacy.

At oropharyngeal candidiasis the drug is prescribed an average of 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. With atrophic candidiasis of the oral cavity associated with the wearing of dentures, the drug is prescribed at an average dose of 50 mg 1 time / day for 14 days in combination with local antiseptic agents for the treatment of the prosthesis.

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

For prevention of recurrence of oropharyngeal candidiasis in patients with AIDS after completion of the full course of primary therapy, fluconazole can be prescribed 150 mg 1 time / week.

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

For reducing the frequency of recurrence of vaginal candidiasis the drug can be used at 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 the age of 18 years and patients over 60 years of age without a doctor's prescription is not recommended.

At balanitis caused by Candida spp., fluconazole is prescribed once at a 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. In the presence of 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 a few days before the expected development of neutropenia and after an increase in the number of neutrophils more than 1000/µl, treatment is continued for another 7 days.

At skin infections, including athlete's foot, smooth skin, groin and candida 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 (up to 6 weeks) may be required.

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 the drug at a 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 replacement of the infected nail (growth of an uninfected nail). Re-growth of fingernails and toenails usually takes 3-6 months and 6-12 months, respectively. However, the rate of growth can vary widely from person to person and also according to age. After successful treatment of long-standing chronic infections, a change in the shape of the nails is sometimes observed.

At deep endemic mycoses may require the use of 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.

At 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 mucosal candidiasis the recommended dose of Diflucan ® is 3 mg/kg/day. On the first day, a loading dose of 6 mg/kg may be given 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 recurrence of cryptococcal meningitis in children with AIDS The recommended dose of Diflucan ® is 6 mg/kg/day.

For prevention of fungal infections in immunocompromised patients in which the risk of infection is associated with neutropenia, which develops 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 induced neutropenia.

When using the drug for 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 at the same dose (in mg / kg) as for older children, but with an interval of 72 hours.

Children aged 3 and 4 weeks of life the same dose is administered 48 hours apart.

At elderly patients in the absence of signs of renal failure, the drug is prescribed in an average dose. Elderly patients with renal insufficiency (CK<50 мл/мин) dosage adjustment is required.

Fluconazole is excreted mainly in the urine unchanged. With a single dose, a dose change is not required. At 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.

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

Rules for the use of the drug

Capsules should be swallowed whole.

When preparing a suspension for oral administration, 24 ml of water should be added to the contents of one vial and shaken thoroughly. Shake the suspension before each use.

Storage conditions and shelf life

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

Vacation from pharmacies

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

To effectively combat nail fungus, you need to choose an effective remedy. Proven effectiveness will reduce the likelihood of relapse, and the correct composition is a guarantee of the rapid destruction of the infection. Diflucan is one of those drugs that have won respect not only from patients, but also from doctors. This will be confirmed by numerous reviews with photos - after treatment with this drug, the nails began to look the same as before infection.

Release form and composition

Diflucan is available in three varieties:

capsules (50 mg - package contains 7 capsules, 150 mg - package contains 1 capsule, 4 or all 12);
solution (bottles of 50 and 100 ml);
ready suspension, powder.

The main substance of all forms of the drug is fluconazole, and there is much more of it in capsules. Accordingly, auxiliary components are lactose, silicon dioxide and corn starch.

The solution contains sodium chloride, as well as purified water.

Diflucan - solution for intravenous administration

Auxiliary substances of the suspension are sucrose and sodium benzoate. Also citric acid (anhydrous); together, these components quickly eliminate fungal infections.

Indications

Is Diflucan an antibiotic or not? The agent belongs to infectious antibiotics with antifungal effects.

What helps Diflucan?

Among the indications for use are:

cryptococcosis;
generalized candidiasis - infection of the eyes, abdominal part or pathology of the respiratory tract, as well as the oral cavity, esophagus, pharynx;
vaginal candidiasis in any form, including acute, chronic or relapse;
mycoses of the body and feet;
onychomycosis - nail fungus;
other types of fungal infections.

pharmachologic effect

The main pharmacological action is antifungal. The composition of all forms of the drug includes fluconazole, which has a pronounced antimycotic effect. The medicine does not affect the state of the hormonal background of a woman, even with repeated use.

Diflucan - 12 capsules

The drug has been previously tested. It is effective against many types of fungus, including Candida spp, Blastomyces dermatitides, Coccidioides immitis. Especially effective in onychomycosis.

Instructions for use Diflucan

Remember that the dosage is often calculated individually, at the discretion of the doctor. In this case, the personal characteristics of the patient are taken into account, including the diagnosis and state of health, as well as age. There are no differences in use for men and women.

Many are interested in how to take the drug, how to give it to a child? Capsules are taken orally, swallowed whole. The suspension must first be prepared from the powder. It is thoroughly mixed with 24 ml of purified water and gently shaken. Do this before each use of the medicine.

It does not matter how you drink the medicine - before or after a meal.

The daily dose often depends on the degree of infection and the nature of the disease. For example, in the treatment of thrush, it is enough to use Diflucan once, then simply observing prophylaxis, and for other mycoses, it is necessary to continue therapy until the affected area is completely restored.

With cryptococcosis

The duration of treatment is 6-8 weeks, but a positive result may be noticeable earlier. Initially, the patient is prescribed 400 mg of Diflucan, then 200-400 mg / day, based on the degree of the disease, side effects.

Manifestations of cryptococcosis

Prevention can take a long time. The recommended dosage is 200 mg/day.

For genital candidiasis

Usually a single dose of 150 mg is sufficient. To reduce the number of re-infections, Diflucan is used once a month in the same amount, and the duration of therapy is determined individually by the doctor. Usually the duration of treatment is up to 12 months. Sometimes the patient needs more frequent use of the drug.

For prevention, it is necessary to first determine the risk of infection of the patient with a fungal infection. Depending on this, the dose is determined - from 50 to 400 mg / day.

Diflucan is often prescribed during menstruation: a relapse of thrush is especially likely.

With mycoses of the body and feet

The recommended amount of the drug is 150 mg if Diflucan is used once a week, or 50 mg / day. For fungal diseases of the feet, the duration of antimycotic treatment is up to 6-7 weeks, based on the degree of infection and the area affected, as well as the preventive measures followed.

With generalized candidiasis

Initially, the patient consumes 400 mg of the drug, the rest of the time - 200 mg / day. In acute or chronic form, the dose may be increased to 400 mg.

The duration of therapy is determined individually in the presence of a specialist. How long Diflucan takes to work depends on the degree of infection.

With pityriasis versicolor

There are several Diflucan therapy regimens for pityriasis versicolor:

300 mg / week, the recommended duration of treatment is up to 2-3 weeks;
50 mg/day for 3-4 weeks.

This is what pityriasis looks like

For some patients with milder infection, a single dose of 300-400 mg of the drug is sufficient. This should be discussed with your doctor.

For nail fungus

The dosage is 150-200 mg/week. Treatment lasts until complete recovery and regrowth of the infected nail: onychomycosis of the hands usually goes away in 6 months, and it will take 9 to 12 months for the fungus to disappear on the plates of the legs.

Dosage for children and the elderly

For the treatment of mucosal candidiasis: 6 mg / kg on the first day of use with a further decrease in the amount of the drug to 3 mg / kg.

With generalized candidiasis and cryptococcosis - from 6 to 12 mg / kg per day, the exact dosage and duration of treatment depends on the severity of the disease, the degree of infection.

For the prevention of mycoses - 3-12 mg / kg, depending on the severity of neutropenia.

Fluconazole, the main substance of Diflucan, is excreted much more slowly in newborns than in older children. Therefore, for infants in the first few weeks of life, the drug is prescribed in the usual, "children's" dosage. But the interval between applications is 72 hours.

From 3-4 weeks, the interval is reduced to 48 hours.

For the elderly, the drug is prescribed in an "adult" dosage, if the patient does not suffer from liver and / or kidney failure.

Contraindications and side effects

The main contraindication is hypersensitivity to the main active ingredient of the drug (fluconazole) or excipients that make up the drug. The simultaneous use of Diflucan with cisapride, terfenadine and astemizole is also prohibited.

During pregnancy, it is recommended to abandon the use of the drug if the expected harm outweighs the likely benefits. During lactation, the drug is also not advised: the components enter in equal amounts both into the blood and into the milk of a nursing woman, and this can adversely affect the health of a child with HB.

In case of renal and / or hepatic insufficiency, rashes on the skin and burning, as well as in the manifestation of bullous lesions, it is recommended to refrain from using Diflucan.

According to the annotation to the drug, among the main side effects are:

dizziness, stomach and headaches;
nausea followed by vomiting;
flatulence, diarrhea - Diflucan acts as a laxative;
severe swelling;
in rare cases - convulsions, a change in taste sensations.

The most severe consequences occur in patients with AIDS and malignant tumors. In such people, interruptions in the work of the kidneys and / or liver are most likely.

Headache is one of the possible side effects of the drug.

Analogues and prices

Cost in the Diflucan pharmacy:

solution: 50 ml - 215 rubles, 100 ml - 330 rubles, 200 ml - 650-690 rubles;
suspension (powder) - 515-540 rubles;
Diflucan capsules (150 mg): 400 rubles (1 pc.), 880 rubles (4 pcs.), 2100 rubles (12 pcs.);
capsules (50 mg): 850 rubles (7 pcs.).

There are cheap analogues with a similar principle of action and active ingredients. For example, Flucostat (1 capsule - 200 rubles, 2 capsules - 360 rubles), Mikosist (300 rubles), (37 rubles).

Diflucan or Flucostat: which is better?

Often people tend to buy a more expensive tool, explaining that it is more effective by default. But this is not always the case, and an example of this is Flucostat, an equally effective analogue with similar contraindications, side effects and a description of the composition.

You should understand the main differences between these two drugs.

Diflucan is an imported drug (Pfizer PGM, France, USA), Flucostat is domestic (Pharmstandard-Leksredstva, Russia).
Flucostat has cheaper auxiliary components, so the composition can cause an additional side effect in the form of an allergy.

Flucostat is a cheaper analogue of Diflucan

Separately, it is worth noting the cost of funds with their same impact:

Flucostat costs only 200 rubles (1 capsule), but is no less effective in relation to fungal infections.

Many patients choose the domestic drug, looking at how much Diflucan costs.

PHARMACHOLOGIC EFFECT

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

When administered orally and intravenously, fluconazole was active in various models of fungal infections in animals. The activity of the drug in opportunistic mycoses, 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 a high specificity for cytochrome P450 dependent fungal enzymes. Therapy with fluconazole 50 mg/day for up to 28 days did not affect plasma testosterone levels in men or steroid levels in women of childbearing age. Fluconazole at a dose of 200-400 mg/day had no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

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

PHARMACOKINETICS

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

Suction

Distribution

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

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

Metabolism and excretion

Long T 1/2 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 have been identified:

* - indicator marked on the last day.

V d 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 (within 1040-1680 ml/kg) on the 13th day.

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

INDICATIONS

- cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), incl. in patients with a normal immune response and in AIDS patients, recipients of transplanted organs and patients with other forms of immunodeficiency; maintenance therapy to prevent recurrence of cryptococcosis in AIDS patients;

- generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, incl. in patients with malignant tumors in the ICU and receiving cytotoxic or immunosuppressive agents, 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 recurrence of oropharyngeal candidiasis in AIDS patients;

- genital candidiasis; acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrence 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, inguinal region, pityriasis versicolor, onychomycosis and skin candidal infections;

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

DOSING MODE

Treatment can be started before culture and other laboratory results are available. However, therapy should be changed accordingly when the results of these studies become known.

For prevention of recurrence of oropharyngeal candidiasis in patients with AIDS after completion of the full course of primary therapy, fluconazole can be prescribed 150 mg 1 time / week.

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

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

At skin infections, including fungal infections of the feet, smooth skin, inguinal region 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 (up to 6 weeks) may be required.

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 for 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 at the same dose (in mg / kg) as for older children, but with an interval of 72 hours. Children aged 3 and 4 weeks of life the same dose is administered 48 hours apart.

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

Patients with renal insufficiency (KK<50 мл/мин) dosage adjustment is required.

Capsules should be swallowed whole.

When preparing a suspension for oral administration, 24 ml of water should be added to the contents of one vial and shaken thoroughly. Shake the suspension before each use.

SIDE EFFECT

The most frequently reported side effects were reported in clinical and post-marketing (*) studies of Diflucan ® .

From the side of 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 levels of aminotransferases (ALT and AST), impaired liver function*, hepatitis*, hepatocellular necrosis*, jaundice*.

From the side of the cardiovascular system*: an increase in the QT interval on the ECG, ventricular fibrillation / flutter.

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

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

From the side of metabolism*: increased plasma cholesterol and triglyceride levels, hypokalemia.

Allergic reactions*: anaphylactic reactions (including angioedema, swelling of the face, 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 violations of liver function indicators against the background of the use of fluconazole, with the appearance of a rash against the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, while using 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

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 at concentrations close to plasma, so 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, sex and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after cessation of therapy. Patients who experience abnormal liver function tests during treatment with fluconazole should be monitored for signs of more severe liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole, the drug should be discontinued.

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

The simultaneous use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored.

Influence on the ability to drive vehicles and control mechanisms

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

OVERDOSE

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

Fluconazole is excreted primarily in the urine, so forced diuresis could probably hasten its elimination. A 3-hour hemodialysis session reduces plasma levels of fluconazole by approximately 50%.

DRUG INTERACTIONS

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, it is necessary to constantly monitor the prothrombin time.

Azithromycin: with simultaneous use of oral 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 it is administered intravenously. If concomitant benzodiazepine therapy is required, patients taking fluconazole should be monitored for an appropriate dose reduction of the benzodiazepine.

Cisapride: with the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. flickering / flutter of the ventricles (pirouette-type 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 pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Co-administration 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 the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporine in bone marrow recipients was observed. With the simultaneous use of fluconazole and cyclosporine, 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 concentration of fluconazole by 40%. The effect of this degree of severity does not require a change in the dosing regimen of fluconazole in patients receiving diuretics at the same time, but this should be taken into account.

Oral contraceptives: with the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, a significant effect on hormone levels has not been established, while with daily intake of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increase by 40% and 24%, respectively, and when taking 300 mg of fluconazole 1 time per 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.

Rifabutin: the simultaneous use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described. Patients simultaneously receiving rifabutin and fluconazole should be carefully monitored.

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

Sulfonylureas: fluconazole, when taken simultaneously, leads to an increase in T 1/2 of oral sulfonylurea preparations (chlorpropamide, glibenclamide, glipizide and tolbutamide). Fluconazole and oral sulfonylurea preparations can be co-administered to patients with diabetes mellitus, but the possibility of hypoglycemia should be considered.

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

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 was not 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. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole at doses less than 400 mg/day in combination with terfenadine should be carefully monitored.

Zidovudine: with simultaneous use with fluconazole, an increase in zidovudine concentrations is noted, which 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, patients with AIDS and ARC (AIDS-related complex) showed a significant increase in AUC of zidovudine (20%).

The listed interaction was established with repeated use of fluconazole; interaction with drugs as a result of a single dose of fluconazole is unknown.

It should be borne in mind that the interaction with other drugs has not been specifically studied, but it is possible.

Pharmaceutical interaction

STORAGE CONDITIONS AND EXPIRY DATES

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

Powder for 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.