Blocks the conversion of lanosterol to ergosterol cells of fungi; increases the permeability of cell membranes, violates its growth and replication.
Fluconazole, being highly selective for fungal cytochrome P450, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole less inhibits cytochrome P450 dependent oxidative processes in human liver microsomes). There has antiadrogennoy activity.
Active opportunistic fungal infections, including those caused by Candida spp.
After oral fluconazole is well absorbed, its plasma levels (and total bioavailability) over 90% of fluconazole plasma levels when administered intravenously. Simultaneous food intake does not affect absorption (suction) of the drug when taken orally. The time to maximum concentration (T Cmax ) after oral administration of 150 mg fluconazole fasting – 0.5-1.5 hours and 90% of the concentration in plasma when administered intravenously at a dose of 2.5-3.5 mg / l.
concentration in plasma is in direct proportion to the dose. About 90% of the equilibrium concentration of drug in plasma (Css) achieved a 4-5 day admission (when taking 1 per day). Introduction “shock” dose (the first day), 2 times the normal sustanon 250 daily dose, achieves a concentration corresponding to 90% Css, 2 to day. It penetrates into all body fluids. The concentration of active substance in breast milk, synovial fluid, saliva, sputum, peritoneal fluid and are similar to those in plasma. Fixed values attained in vaginal secretions after 8 hours after oral administration and are maintained at this level for at least 24 hours. It penetrates into cerebrospinal fluid (CSF) in fungal meningitis concentration in CSF is about 85% of that in plasma. In the sweat fluid, the dermis and the stratum corneum (the selective accumulation) achieved high concentrations exceeding serum. When you receive a dose of 50 mg 1 time per day the concentration of fluconazole after 12 days was 73 mg / g and 7 days after cessation of treatment it was 5.8 mg / l. After oral administration of 150 mg 1 time per week. – 7 day rrgovom fluconazole concentration in the skin layer was 23.4 g / g, and 7 days after the second dose – 7.1 g / g.
The concentration in nails after 4 months of use in a dose of 150 mg 1 time per week: healthy nails – 4.05 ug / g in the affected – 1.8 g / g. After 6 months. after completion of therapy, fluconazole was still determined in the nails.
The apparent volume of distribution (Vd) approaches to total body water. Relationship to plasma proteins is low – 11-12%.
Metabolism and elimination
half-life (T1 / 2) -. 30 hours is an inhibitor of CYP2C9 isoenzymes in the liver. Displayed mostly kidneys (80% – unchanged, 11% – in the form of metabolites). Fluconazole clearance is proportional to creatinine clearance.
The pharmacokinetics of fluconazole depends essentially on renal function, in this case! there is an inverse relationship between the T1 / 2 and creatinine clearance (CC). After dialysis for 3 h, the plasma concentration of fluconazole is reduced by 50%.
The pharmacokinetics of fluconazole are similar after intravenous injection and ingestion, making it easy to switch from one mode to another reception.
– System lesions caused by fungi Cryptococcus, including meningitis, sepsis, infections of the skin and lungs, as in patients with a normal immune response, and patients with various forms of immunodepression (including AIDS patients, organ transplant recipients jail.); maintenance therapy for the prevention of cryptococcal infection in AIDS patients.
– Generalized candidiasis: candidemia, disseminated candidiasis (with eye disease, endocarditis, abdominal organs, respiratory and urinary organs), treatment may be performed for patients with cancer and receiving a course of cytostatic or immunosuppressive therapy and the presence of other factors predisposing to their development – treatment and prevention.
– candidiasis of the mucous membranes: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic oral atrophic candidiasis (associated with the wearing of dental prostheses); prevention of relapse of oro-pharyngeal candidiasis in patients with AIDS,
– Genital | candidiasis: vaginal (acute and recurrent). Prophylactic use to reduce the frequency of relapses of vaginal candidiasis (three or more episodes per year). . Candida balanitis
– Prevention of fungal infections in patients with malignant tumors in the background hrshyo- or radiation therapy; . Prevention of relapse of oropharyngeal candidiasis in AIDS brlnyh
– Fungal infections of the skin: the feet, body, groin, onychomycosis, pityriasis versicolor, skin candida infection.
– Deep endemic mycoses (coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis) in patients with normal immunity.
: Hypersensitivity to the drug’s components (including to other azole antifungal medicines); concomitant use of terfenadine (on the background of continuous use of fluconazole 400 mg / day or more) or astemizole; lactation.
for children under 3 years of age is recommended the use of fluconazole as a solution for infusion, syrup or powder for suspension for oral administration, and not of solid dosage forms. Liver failure, rash during treatment with fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, concomitant use of terfenadine and fluconazole at a dose of less than 400 mg / day, potentially proaritmogennoe status in patients with multiple risk factors (organic heart disease, disorders electrolyte imbalance, concomitant use of drugs that cause arrhythmias), pregnancy.
Application of pregnancy and lactation
should be avoided fluconazole during pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of the use of fluconazole for the mother is much higher than the potential risk to the fetus. Since fluconazole concentration in breast milk and in the plasma of the same, use the drug during lactation – contraindicated.
Dosage and administration
The daily dose of fluconazole depends on the nature and severity of the fungal infection.
Adults and children over 15 years (weighing more than 50 kg):
– In cryptococcal meningitis and cryptococcal infections at other sites on the first day is usually prescribed 400 mg of fluconazole, and then continue treatment at a dose of 200-400 mg 1 time per day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; cryptococcal meningitis it is usually continued for at least 6-8 weeks.
For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the completion of a full course of primary therapy, fluconazole therapy continued at a dose of 200 mg / day for a long period of time.
– When candidemia, disseminated candidiasis and other invasive Candida infections usually dose is 400 mg on the first day, and then – 200 mg per day. With the lack of clinical efficacy of fluconazole dose may be increased to 400 mg / day. The duration of therapy depends on clinical efficacy.
– When fluconazole oropharyngeal candidiasis usually prescribed at 150 mg 1 time per day for 7-14 days. If necessary, in patients with a severely reduced immunity, the treatment may be longer.
For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the completion of a full course of primary therapy, fluconazole may be assigned to 150 mg 1 time per week.
In atrophic oral candidiasis associated with wearing dentures, fluconazole, typically administered at 50 mg 1 time / day for 14 days in combination with local antiseptic agents for treatment of prosthesis.
In other locales candidiasis (except sustanon 250 genital candidiasis), such as oesophagitis, noninvasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose of fluconazole is 150 mg / day, with treatment duration of 14-30 days.
– Vaginal candidiasis fluconazole receive a single oral dose of 150 mg. To reduce the frequency of relapses vaginal candidiasis irpolzovan preparation may be in a dose of 150 mg 1 time per month. The duration of therapy is determined individually; it varies between 4 and 12 months. Some patients may require more frequent use of fluconazole.
– When balanitis; caused by Candida, fluconazole administered a single dose of 150 mg orally.
– For the prevention of candidiasis recommended dose is 50-400 mg 1 time / day, depending on the degree of risk of fungal infection. If you have a high risk of generalized infection, eg in patients with severe or long-anticipated persistent neutropenia, the recommended dose is 400 mg 1 time / day. The drug is prescribed for a few days before the expected occurrence of neutropenia; after increasing the number of neutrophils more than 1000 mm 3, treatment was continued for 7 days.
– When mycosis of the skin, including tinea pedis, smooth skin and skin groin recommended dose is 150 mg 1 time per week or 50 mg 1 time / day. Duration of therapy in ordinary cases is 2-4 weeks, however, with athlete’s foot may require longer therapy (up to 6 weeks).
– In pityriasis versicolor the recommended dose is 300 mg 1 time per week for 2 weeks. Some patients required a third dose of 300 mg per week, while in some cases it is sufficient single dose of 300-400 mg.
An alternative regimen is the use of the drug at 50 mg 1 times / day for 2-4 weeks.
– In onychomycosis the recommended dose of fluconazole is 150 mg 1 time per week. Treatment should be continued until the replacement of the infected nail (uninfected nail sprouting). For the re-growth of nails on the fingers and feet normally requires 3-6 months. and 6-12 months. respectively. However, the growth rate can vary widely from person to person and also depends on the age.
– In deep endemic mycoses may require 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 can be 11 -24 months. with coccidioidomycosis;2-17 months. when paracoccidioidomycosis; 1 -16 months. with sporotrichosis and 3-17 months. with histoplasmosis.
In children, as well as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be applied in a daily dose that would be higher than that in adults, that is no more than 400 mg per day. The drug is used every day 1 time / day.
When children esophageal candidiasis, fluconazole is assigned once in a daily dose of 3 mg / kg doses of the following medium: aged 3-6 years (body weight 15-20 kg) – 50 mg; aged 7-9 years (body weight 21-29 kg) – 50-100 mg; aged 10-12 years (weight 30-40 kg) – 100-150 mg; aged 12-15 years (weight 40-50 kg) – 100-150 mg. Duration trrapii – at least 3 weeks, and more in 2 weeks after symptoms regression.
When candidiasis | mucosal children assigned fluconazole once daily at a dose of 3: mg / kg doses of the following medium: aged 3-6 years (body weight 15-20 kg) – 1 day to 100-150 mg, more – 50 mg; aged 7-9 years (body weight 21-29 kg) – 1 Day 100-200 mg, more – 100 mg; aged 10-12 years (weight 30-40 kg) – in the 1 st day of 100-150 mg, then – 50-100 mg; aged 12-15 years (body weight 30-40 kg) – 1 day to 250-300 mg, more – 100-150 mg. Duration of treatment – at least 3 weeks.
When generalized candidiasis and cryptococcal infections (including meningitis) in drtey fluconazole once assigned to a daily dose of 6-12 mg / kg, the following average doses: at the age of 3-6 years (15-20 kg body weight) – 100-250 mg; aged 7-9 years (21-29 kg body macca) -100-300 mg; aged 10-12 years (weight 30-40 kg) – 200-350 mg; aged 12-15 years (weight 40-50 kg) – 250-400 mg. Duration of treatment – within 10-12 weeks (before laboratory confirmation of the absence of pathogens in the CSF).
For the prevention of fungal infections in immunocompromised children in whom the risk of infection associated with neutropenia that develops as a result of cytotoxic chemotherapy or radiotherapy, fluconazole assigned once in a daily dose of 3-12 mg / kg doses of the following medium: aged 3- 6 years. (15-20 kg body macca) – 50-250 mg; aged 7-9 years (body weight 21-29 kg) – 50-300 mg; aged 10-12 years (weight 30-40 kg) – 100-350 mg; aged 12-15 years (weight 40-50 kg) – 100-400 mg. Duration of therapy – until the elimination of induced neutropenia.
Children with impaired renal function the daily dose should be reduced (in the same proportion as in adults), in line with the severity of renal failure.
The use in the elderly. In the absence of renal dysfunction should follow the usual dose regimen of the drug. Patients with renal failure (creatinine clearance (CC) of less than 50 ml / min), the dosing regimen should be adjusted as described below.
Use of the drug in patients with sustanon 250 impaired renal function.
Fluconazole is excreted mainly with urine in unchanged form. When receiving a single dose of its change is not required. With the reappointment of the drug to patients with impaired renal function should first enter a loading dose of 50 to 400 mg; with CK> 40 ml / min; Fluconazole is used once a day in a normal dose. When CC = 21-40 ml / min – every 48 hours (time 1 to 2 days), or once a day in a daily dose of a conventional half; with CC = 10-20 ml / min – with an interval of 72 hours (one every 3 days), or once a day at a daily dose equal to one third of the calculated value.
Patients who are on dialysis regularly, one dose is applied after each hemodialysis.
Mikoflyukan usually well tolerated.
Allergic reactions: skin rash, rarely – exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactoid reactions (including angioedema, face edema, urticaria, itching of the skin).
Co the central nervous system: headache, dizziness, rarely -sudorogi.
Go the digestive system: nausea, diarrhea, flatulence, abdominal pain, change in taste, vomiting, rarely – liver dysfunction (jaundice, hyperbilirubinemia, increased ALT, ACT and AP, hepatitis, hepatocellular necrosis), including fatal .
Co side of hematopoiesis: rarely – leukopenia, thrombocytopenia, neutropenia, agranulocytosis.
Since the cardiovascular system: an increase in the length of Q-T interval, flicker / ventricular flutter.
Other: rarely – renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
symptoms: hallucinations, paranoid behavior.
Treatment: symptomatic. Gastric lavage, forced diuresis. Haemodialysis for 3 hours reduces the plasma concentration of fluconazole by approximately 50%.
Interaction with other drugs
Fluconazole increases in prothrombin time coumarin anticoagulants (eg, warfarin) by an average of 12%, so careful monitoring of prothrombin time in patients receiving fluconazole and coumarin anticoagulants.
At the same time taking Fluconazole and oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) half-life last longer, which may lead to hypoglycemia. It should periodically monitor blood glucose concentration and, if necessary, correct the dose of hypoglycemic drugs.
Hydrochlorothiazide increases the concentration of fluconazole in plasma by 40%, but it does not require changes in the fluconazole dose regimen in patients receiving concomitant diuretics.
Concurrent administration of fluconazole and phenytoin is accompanied by an increase in the concentration of the latter in a clinically significant degree. It is therefore necessary level of monitoring and selection phenytoin its dose for therapeutic serum concentrations.
Repeated fluconazole (doses 50-200 mg) did not affect the efficiency of the combined contraceptive.
Simultaneous administration of fluconazole and rifampicin resulted AUG decrease by 25% and the duration of the half-life of fluconazole by 20%. It is necessary to increase the dose of fluconazole during their simultaneous appointment.
In the treatment of fluconazole is recommended to monitor the concentration of cyclosporine in the blood.
Fluconazole prolongs the half-life of theophylline, and increases the risk of intoxication (a correction of the dose).
Simultaneous administration of fluconazole at doses of 400 mg / day or more is contraindicated with terfenadine. Treatment of fluconazole at doses less than 400 mg / day in combination with terfenadine should be carried out under the close supervision of a physician.
Simultaneous administration of fluconazole and cisapride – adverse reaction from the heart, including paroxysms of ventricular tachycardia (torsades de pointes).
There are cases of uveitis.
Increasing the concentration of tacrolimus, and therefore, increases the risk of nephrotoxicity.
In patients receiving the combination of zidovudine and fluconazole observed increased concentrations of zidovudine, which is caused by a decrease in the conversion of the latter into its main metabolite, so you should expect an increase in the side effects of zidovudine.
Increases concentration midozalama, and therefore increases the risk of psychomotor effects (most pronounced when using fluconazole inside than intravenously).
Treatment should continue until clinical remission. Premature discontinuation of treatment leads to relapse.
Treatment can be started in the absence of culture results or other laboratory tests, but if any corresponding correction is recommended antifungal therapy.
During treatment it is necessary to monitor blood counts, kidney and liver function. Requires monitoring prothrombin index while the use of coumarin anticoagulants. In the event of renal and hepatic function should stop taking the drug.
In rare cases, the use of fluconazole was accompanied by toxic liver changes. In the case of hepatotoxic effects associated with fluconazole, no obvious dependence of the total daily dose, duration of treatment, gender, and age of the patient. Gepatrtoksicheskoe effect of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. At the onset of clinical signs of liver damage, which may be associated with fluconazole, the drug should be discontinued.
AIDS patients are more prone to the development of severe skin reactions in the application of many drugs. In cases where patients with superficial fungal infection develops a rash, and she is regarded as definitely related to flukonazo≤lom, the drug should be discontinued. When a rash in patients with invasive / systemic fungal infections, they should be monitored closely and fluconazole cancel the appearance of bullous erythema multiforme or changes.
It is sustanon 250 recommended to monitor the concentration of cyclosporine in the blood of patients treated with fluconazole, since patients receiving a transplanted kidney Fluconazole, 200 mg / day results in a slow increase in the concentration of cyclosporine | plasma.
Care must be taken while taking fluconazole with cisapride, rifabutin or other drugs metabolized by the cytochrome P450 system.