Fluconazole capsules 150mg, No. 1

Fluconazole is indicated for the treatment of the following diseases in adults:
- cryptococcal meningitis;
- coccidioidomycosis;
- invasive candidiasis;
- dermatomycosis, incl. dermatophytosis of the trunk, inguinal dermatophytosis, tinea versicolor and skin candidal infections, when systemic treatment is indicated;
- dermatophytosis of the nails (onychomycosis), when treatment with other drugs is not acceptable

Inside. Adults with cryptococcal meningitis and cryptococcal infections of other localizations are usually prescribed 400 mg (8 capsules of 50 mg each) on the first day, and then continue treatment at a dose of 200 mg (4 capsules 5 mg each) - 400 mg (8 capsules 50 mg each) 1 once a day. With candidemia, disseminated candidiasis and other invasive candidiasis infections, the dosage is usually 400 mg on the first day, and then 200 mg. The duration of therapy depends on the clinical effectiveness. For vaginal candidiasis, fluconazole is taken in a single dose of 150 mg. For skin mycoses, the recommended dose is 150 mg once a week or 50 mg once a day. 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. In children, as with similar infections in adults,the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose that would exceed that in adults. The drug is used daily 1 time per day.

Fluconazole 50 or 150 mg

• Concomitant use of terfenadine or astemizole and other drugs that prolong the QT interval.

• Hypersensitivity to the drug or structurally related azole compounds.

• Children under 3 years old.

pharmachologic effect

The antifungal agent, a triazole derivative, is a potent selective inhibitor of sterol synthesis in the fungal cell.

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

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

When taken orally, fluconazole has been shown to be active in various animal models of fungal infections. Demonstrated the activity of the drug in opportunistic mycoses, incl. caused by Candida spp. (including generalized candidiasis in immunosuppressed animals); Cryptococcus neoformans (including intracranial infections); Microsporum spp. and Trichophyton spp. The activity of fluconazole was also 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 suppressed immunity.

Fluconazole is highly specific for cytochrome P450 dependent fungal enzymes. Fluconazole therapy at a dose of 50 mg / day for up to 28 days does not affect the concentration of testosterone in the blood plasma in men or the concentration of steroids in women of childbearing age. Fluconazole at a dose of 200-400 mg / day has no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

Pharmacokinetics

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

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

90% Css is reached by the 4th-5th day after the start of therapy (with repeated administration 1 time / day).

The introduction of a loading dose (on the 1st day), 2 times higher than the average daily dose, makes it possible to achieve Css 90% by the 2nd day. The apparent Vd approaches the total body water content. Plasma protein binding is low (11-12%).

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

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

Concentration of fluconazole in nails after 4 months of use at a dose of 150 mg 1 time / week. was 4.05 ?g / g in healthy and 1.8 ?g / g in affected nails; 6 months after completion of therapy, fluconazole was still detectable in the nails.

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.

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

Side effect

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

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

From the hepatobiliary system: hepatotoxicity, in some cases with a fatal outcome, an increase in the concentration of bilirubin, serum aminotransferase activity (ALT and AST), alkaline phosphatase, liver dysfunction, hepatitis, hepatocellular necrosis, jaundice, cholestasis, hepatocellular damage.

On the part of the skin: rash, alopecia, exfoliative skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, increased sweating, drug rash.

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

From the immune system: anaphylaxis (including angioedema, facial edema, urticaria, itching).

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

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

From the musculoskeletal system: myalgia.

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

Application during pregnancy and lactation

There have been no adequate and well-controlled studies of the safety of fluconazole in pregnant women. 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. Women of childbearing age should use reliable contraception during treatment. Fluconazole is determined in breast milk at concentrations close to plasma concentrations, therefore, use during lactation (breastfeeding) is not recommended.

special instructions

It is used with caution in case of 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, with the simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg / day, with potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. It is necessary to monitor the condition of patients whose liver function indicators are impaired during treatment with fluconazole in order to identify signs of more serious liver damage. If clinical signs or symptoms of liver damage appear, which may be associated with fluconazole, it should be discontinued.

AIDS patients are more likely to develop severe skin reactions with many drugs. If a patient receiving treatment for a superficial fungal infection develops a rash that can be associated with the use of fluconazole, it should be discontinued. If a rash occurs in patients with invasive / systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme appear.

Concomitant use of fluconazole at doses less than 400 mg / day and terfenadine should be closely monitored.

With the use of fluconazole, an increase in the QT interval and ventricular fibrillation / flutter have been observed 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.

Therapy can be started pending culture and other laboratory test results. However, anti-infective therapy needs to be adjusted accordingly when the results of these studies become known.

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

Drug interactions

With simultaneous use with warfarin, fluconazole increases prothrombin time (by 12%), and therefore may develop bleeding (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, it is necessary to constantly monitor the prothrombin time.

After oral administration of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole orally than when using it intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to reduce the dose of benzodiazepine accordingly.

With the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. fibrillation / flutter of the ventricles (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. Concomitant use of cisapride and fluconazole is contraindicated.

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, changes in the concentration of cyclosporine were not observed in bone marrow recipients. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.

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 dosage regimen of fluconazole in patients receiving concomitant diuretics, but this should be taken into account.

With the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, a significant effect on the level of hormones has not been established, while with a 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 ethinylestradiol and norethindrone increase 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.

The simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. With this combination, the concentration of phenytoin should be monitored and its dose adjusted accordingly in order to ensure a therapeutic concentration in the blood serum.

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 receiving rifabutin and fluconazole concomitantly should be closely monitored.

The simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T1 / 2 of fluconazole by 20%. In patients taking rifampicin at the same time, it is necessary to consider the advisability of increasing the dose of fluconazole.

Fluconazole, when taken simultaneously, leads to an increase in T1 / 2 of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus can be co-administered with fluconazole and oral sulfonylureas, but the possibility of hypoglycemia should be taken into account.

The simultaneous use of fluconazole and tacrolimus leads to an increase in plasma concentrations of the latter. Cases of nephrotoxicity have been reported. With this combination, the patient's condition should be carefully monitored.

With the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When 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 plasma concentration of terfenadine. Simultaneous administration of fluconazole at 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 closely monitored.

With simultaneous use with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline decreases by 18%. When prescribing fluconazole to patients taking high doses of theophylline, or patients with an increased risk of developing the toxic effect of theophylline, the symptoms of theophylline overdose should be monitored and, if necessary, the therapy should be adjusted accordingly.

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) found a significant increase in the AUC of zidovudine (20%).

When used in HIV-infected patients, 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 the AUC of zidovudine was found (74%) with simultaneous use with fluconazole. Patients receiving this combination should be monitored for side effects of 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 serum concentrations of these drugs. With such combinations, the patient's condition should be carefully monitored.