After oral administration fluconazole is well absorbed. The bioavailability of fluconazole is 90% (the maximum plasma concentration of fluconazole (C max ) after oral administration on an empty stomach at a dose of 150 mg is 90% of its concentration in plasma when administered intravenously at the same dose). Simultaneous food intake has no effect on the absorption of the drug taken orally. Upon receiving the inwardly fluconazole (C max ) reached after 0.5-1.5 hours, its half-life testosterone sustanon is about 30 hours. Plasma concentrations are directly proportional to the dose. The 90% level is reached the equilibrium concentration of the 4-5 day daily administration of 1 fluconazole once daily.
The introduction of the first day loading dose of 2 times the normal daily dose, achieves a 90% level of equilibrium concentration by the second day.
The volume of distribution close to the total water content in the body. Plasma protein binding -11-12%.
Fluconazole penetrates well into all body fluids. Drug concentrations in saliva and sputum are similar to its concentration in plasma. Patients fluconazole fungal meningitis in the cerebrospinal fluid content reaches 80% of its concentration in plasma.
The stratum corneum, epidermis, dermis and achieve high liquid sweat fluconazole concentration which exceeds its serum concentration. When receiving fluconazole 150 mg once weekly fluconazole concentration in the stratum corneum was 23.4 g / g, and 7 days after the second dose – 7.1 g / g. Concentration of fluconazole in nails after 4 months of his receiving a dose of 150 mg 1 time per week was 4.05 g / g in healthy nails, and 1.8 ug / g – in the affected nails. 6 months after discontinuation of treatment in the nails there is still amenable to determine the concentration of fluconazole.
Fluconazole is derived mainly kidneys; approximately 80% of the administered dose is excreted in the urine in unchanged form. Fluconazole clearance is proportional to creatinine clearance.
Metabolites of fluconazole were found in the peripheral blood.
- Cryptococcosis, including cryptococcal meningitis and other localization of the infection (including lung, skin), in patients with a normal immune response, and patients with various forms of immunodepression (in t. H. In patients with acquired immunodeficiency syndrome (AIDS ), organ transplantation); preparation can be used for preventing relapse cryptococcal infection in AIDS patients.
- Generalized candidiasis including candidemia, disseminated candidiasis and other forms of invasive Candida infections (infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, liver, spleen and other organs). The treatment can be carried out in patients with cancer, patients in intensive care units, patients undergoing a course of cytostatic or immunosuppressive therapy, as well as the presence of other factors predisposing to the development of candidiasis.
- Candidiasis of the mucous membranes, including oral cavity and pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, skin candidiasis in patients with normal function of the immune system and in patients with reduced immune system function; Prevention of relapse of oropharyngeal candidiasis in patients with AIDS.
- Genital candidiasis: vaginal candidiasis (acute and chronic recurrent), prophylactic use to reduce the frequency of relapses of vaginal candidiasis (3 or more episodes per year); Candida balanitis.
- Prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of chemotherapy, cytostatics or radiation therapy.
- Fungal infections of the skin , including tinea pedis, body, groin; pityriasis versicolor, onychomycosis; candidiasis skin.
- Deep endemic mycoses , including coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.
- Simultaneous administration of terfenadine, if necessary, receive fluconazole 400 mg per day or more, as well as the concomitant use of astemizole, and cisapride (risk of QT prolongation and ventricular tachycardia interval of development, including ventricular tachycardia type “pirouette”).
- Increased sensitivity to fluconazole or close in structure to azole compounds and excipients and drug substances included in the composition of the capsule shell.
- Children weighing less than 40 kg (data dosages – 100 mg and 150 mg).
- Congenital galactose intolerance, lactase deficiency, glucose-galactose malabsorption (because of the content of lactose in the composition of the drug).
- The period of lactation.
- Liver failure.
- Renal failure (requires correction dose fluconazole).
- Potentially proaritmogennoe status in patients with multiple risk factors (organic heart disease, disorders of water and electrolyte balance, concomitant use of drugs that cause arrhythmias).
- Simultaneous administration of terfenadine when receiving fluconazole at a dose of less than 400 mg per day.
- Simultaneous administration of hypoglycemic agents for oral use, sulfonylureas (increased risk of hypoglycaemia requires careful control of the concentration of glucose in the blood, if necessary, correction of hypoglycemic therapy).
Pregnancy and lactation
The drug should not be used in pregnant women, with the exception of serious or life-threatening forms of fungal infections, if the expected benefit to the mother outweighs the potential risk to the fetus.
Fluconazole is in the breast milk in the same concentration as in plasma, so his appointment women are not recommended to nursing.
Dosing and Administration
The drug is taken orally.
Adults In cryptococcal meningitis and cryptococcal infections at other sites on the first day is usually prescribed 400 mg, and then continue treatment at a dose of 200-400 mg 1 time / day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; cryptococcal meningitis treatment 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 administered at a dose of 200 mg / day for a long period of time. Whencandidemia, disseminated and other invasive candidiasis candidiasis infections dose is usually 400 mg in the first day, and then – 200 mg per day. When insufficient clinical efficacy of the dose can be increased to 400 mg / day. In life-threatening infections, candidiasis dose may be increased to 800 mg once a day. The duration of therapy depends on clinical efficacy. If candidiasis of the oral cavity and pharynx is usually administered fluconazole 100 mg 1 times / day; Duration of treatment – 7-14 days. If necessary, in patients with a severely reduced immune treatment may be longer. In other locales candidiasis (except genital candidiasis), such as oesophagitis, noninvasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, and so on. E., The effective dose is usually is 100 mg / day for the duration of treatment 14-30 days. For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the completion of a full course of primary therapy may be administered at 150 mg 1 time per week. When vaginal candidiasis fluconazole taking a single oral dose of 150 mg. To reduce the frequency of relapses vaginal candidiasis preparation may be applied at 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 the drug. In Candida balanitis , fluconazole administered a single dose of 150 mg orally. For the prevention of candidiasis recommended dose of fluconazole 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 testosterone sustanon persistent neutropenia, the recommended dose is 400 mg 1 time / day. Fluconazole is administered 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 skin mycoses, mycoses including feet, groin skin, and skin candidosis recommended dose is 150 mg 1 time per week. Duration of therapy in ordinary cases is 2-4 weeks, but at the athlete’s foot may require a more prolonged treatment (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 a week, while in some cases it is sufficient single dose of 300-400 mg;Alternative treatment scheme is the use of 50 mg 1 time a day for 2-4 weeks. When onychomycosis the recommended dose is 150 mg 1 time per week. Treatment should be continued until the full replacement of the affected nail healthy. This process usually lasts for 3-6 months, and with the defeat of the big toe nail – a period of 6-12 months. Nail growth rate is very individual and depends on the age of the patient. After curing chronic nail infections is possible to maintain the deformation of the nail plate. 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 with paracoccidioidomycosis; Sporotrichosis 1-16 months at 3-17 months and at histoplasmosis. Children In children, as well as in 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 of adults. The drug is used every day 1 time / day. In children with candidiasis mucous membranes of the recommended dose of fluconazole is 3 mg / kg / day. The first day can be assigned to a loading dose of 6 mg / kg in order to more quickly achieve constant equilibrium concentrations. 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 children immunocompromised, in whom the risk of infection associated with neutropenia, developing as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed for 3-12 mg / kg / day, depending on the severity and duration of preservation-induced neutropenia. inchildren with impaired renal function the daily dose should be reduced (in the same proportion as in adults, according to the severity of renal failure. see below.) in elderly patients without renal dysfunction should follow the usual dose regimen of the drug. The doses for elderly patients with renal insufficiency (creatinine clearance less than 50 mL / min), see below. In patients with impaired renal function. Fluconazole is derived mainly kidneys unchanged. When receiving a single dose of its changes are not required. In exchange taking the drug to patients with impaired renal function should first enter a loading dose of 50 mg to 400 mg. If creatinine clearance (BCH) is more than 50 ml / min, applied the usual dose (100% of the recommended dose). When CC from 11 to 50 ml / min is applied dose equal to 50% of the recommended dose. Patients on dialysis regularly after each hemodialysis session used the usual dose of the drug.
The incidence of adverse drug reactions (NDP), the following was determined according to the classification of frequency of occurrence of the NDP to the World Health Organization: very often – more than 1/10; often – from more than 1/100 to less than 1/10; more rarely-from 1/1000 to less than 1/100; rarely – from more to less than 1/10000 1/1000; very rare -less 1/10000, including isolated reports; unknown frequency – the available data to determine adverse reaction frequency of occurrence is not possible.
Typically fluconazole is well tolerated. Adverse reactions that have been observed in clinical trials (with a 7-day and more taking the drug) General disorders Uncommon: weakness, restlessness, muscle weakness, fever. Disorders of the nervous system Common: headache. Uncommon: dizziness, convulsions, paraesthesia, tremor, vertigo. Violations of the skin and subcutaneous tissue disorders Common:skin rash. Uncommon: itching, increased sweating. rare: exfoliative skin lesions (Stevens-Johnson syndrome). Violations of the gastrointestinal tract Common: nausea and vomiting, abdominal pain, diarrhea.Uncommon: anorexia, constipation, dyspepsia, flatulence, dryness of the oral mucosa, changes in taste sensations. Violations by the skeletally -Muscular and connective tissue disorders Uncommon:myalgia. Psychiatric disorders Uncommon: insomnia, somnolence. Violations of the liver and biliary tract is often: a clinically significant increase in alanine aminotransferase activity, aspartate aminotransferase, increased activity of alkaline phosphatase. Uncommon: cholestasis, hepatic tissue injury, hyperbilirubinemia, jaundice . rare: hepatic necrosis. Violations of the blood and lymphatic systemUncommon: anemia. Violations by the immune system rare: anaphylaxis Adverse reactions were more common in infected with human immunodeficiency virus (HIV) patients than in HIV-uninfected patients.The following adverse reactions noted in posmarketingovyh studies of the nervous system rare: seizures. Violations of the skin and subcutaneous tissue disorders testosterone sustanon rare: alopecia Very rare: exfoliative skin lesions (Stevens-Johnson syndrome and toxic epidermal necrolysis), exudative erythema multiforme. Violations of the liver and biliary tract rare: hepatic failure, hepatitis, liver necrosis, including fatal.Violations by the immune system Very rare: anaphylaxis, angioedema, face edema, pruritus. Unknown frequency: anaphylactoid reactions. Violations of the blood and lymphatic system rare: leucopenia, including neutropenia and agranulocytosis; thrombocytopenia. Violations of the metabolism and nutrition Rare: hypercholesterolemia, hypertriglyceridemia, hypokalemia. Violations of the kidney and urinary tract Unknown frequency: renal failure.
Overdose symptoms: hallucinations, paranoid behavior. Treatment: symptomatic: gastric lavage, forced diuresis. Haemodialysis for 3 hours reduces the plasma concentration of fluconazole by approximately 50%.
Interactions with other drugs Indirect anticoagulants . At simultaneous reception of fluconazole during treatment with coumarin derivatives (warfarin), an increase in prothrombin time. Patients simultaneously receiving indirect anticoagulants, coumarin derivatives, requires careful monitoring of the prothrombin time. Azithromycin: . There were no significant pharmacokinetic interaction between fluconazole and azithromycin . Terfenadine Some azoles in combination with terfenadine have been associated with the occurrence of severe arrhythmias including paroxysmal ventricular tachycardia ( torsades de points), due to the increase in the duration of the QT interval on the ECG. Studies with fluconazole, have shown that with a daily dose of 200 mg fluconazole was observed interval lengthening QT. When applying fluconazole 400 or 800 mg there was a significant increase in plasma concentrations of terfenadine. Receiving fluconazole 400 mg or more in combination with terfenadine contraindicated.Patients should be carefully observed while taking terfenadine and fluconazole at a dose of less than 400 mg per day. Astemizole. Simultaneous treatment with fluconazole and astemizole and other drugs metabolized via the cytochrome P450 isoenzymes may lead to increased plasma concentrations of these drugs. Patients receiving these drugs simultaneously with fluconazole should be under close medical supervision. Hydrochlorothiazide. Patients receiving hydrochlorothiazide, while receiving fluconazole may increase the plasma concentrations of fluconazole by 40%. The effect of this expression should not affect the dose of fluconazole. Gipogpikemicheskie for oral use, sulfonylurea derivatives. It has been demonstrated that the plasma concentration of fluconazole increases and increases the half-life of concomitant glibenclamide, tolbutamide and glipizide. Concomitant use of fluconazole and hypoglycemic agents for oral use, sulfonylurea derivatives, is possible, but should take into account the possibility of hypoglycemia, and to control the level of glucose in blood; In rare cases it may be necessary to adjust hypoglycemic agents for oral use of the sulfonylurea derivative. short-acting benzodiazepines. After oral administration of midazolam, fluconazole increased midazolam concentrations in blood plasma, which can lead to psychotic affect. This effect of fluconazole on the concentration of midazolam is more pronounced when receiving midazolam orally than when administered intravenously. You may need to decrease doses of midazolam, when using this combination should be monitored closely for the condition of the patient. Phenytoin. Concomitant use of fluconazole and phenytoin clinically significant increases in blood concentration of phenytoin. It is necessary to monitor the concentration of phenytoin in blood and, if necessary to adjust the dose of phenytoin to maintain its concentration in the blood within the therapeutic range. Rifampicin. Reduction fluconazole half-life of approximately 20% and a decrease in its plasma concentration is 25% when combined with fluconazole rifampicin. Therefore, patients receiving concomitant rifampicin, the dose of fluconazole is expedient to increase. Rifabutin. Concomitant use of fluconazole and rifabutin may result in increased plasma concentrations of rifabutin. In patients who are concurrently taking fluconazole and rifabutin may develop uveitis. We must carefully monitor patients while receiving rifabutin and fluconazole. Cisapride. There were reports of adverse events from the heart, including ventricular tachycardia type “pirouette” (torsades de pointes) in patients concomitantly receiving fluconazole and cisapride. In controlled studies, it was found that co-administration of fluconazole 200 mg once daily and cisapride 20 mg four times daily resulted in a significant increase in plasma concentrations of cisapride and prolongation of the QT interval. Simultaneous administration of cisapride in patients receiving fluconazole contraindicated (see. The section “Contra”). Cyclosporine. In patients with renal transplantation when used fluconazole 200 mg per day there was a slight increase in the blood concentration of cyclosporine. However, in patients with bone marrow transplantation, fluconazole taking 100 mg per day, the concentration of cyclosporine in the blood did not change. It is recommended to monitor the plasma concentration of cyclosporine in patients receiving fluconazole. Theophylline.Fluconazole increases plasma concentrations of theophylline. Fluconazole 200 mg for 14 days resulted in a 18% decrease in the mean values of the plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who have a chance of developing theophylline toxicity should be kept under observation for early detection of the symptoms of theophylline overdose. Zidovudine.Higher doses of fluconazole (400 mg and above), clinically significant increase plasma concentrations of zidovudine, which is associated with reduction in the conversion of the last of its major metabolite.Therefore, we should expect an increase in the side effects of zidovudine. Patients receiving this combination should moniterirovatsya for the development of zidovudine-related adverse reactions.Tacrolimus. Fluconazole increases plasma concentrations of tacrolimus with possible clinical manifestations of toxicity (nephrotoxicity, hyperglycemia, hyperkalemia). Should be monitored plasma concentration of tacrolimus and decrease the dose may be required if necessary. Leroralnye contraceptives. By simultaneous application of fluconazole at 50 mg and oral contraceptives, there were no significant changes in plasma concentrations of ethinyl estradiol and levonorgestrel, but when using 200 mg of fluconazole was observed increase AUC (area under pharmacokinetic curve “concentration-time”) of ethinyl estradiol by 40% and levonorgestrel – 24%. It is therefore not expected to influence fluconazole on the effectiveness of combined oral contraceptives. Treating physicians should keep in mind that research on drug interactions with other drugs have not been conducted, but the development of such interactions possible. On Interaction Studies have shown that while food intake, cimetidine or irradiation whole body for bone marrow transplantation, there were no clinically significant impairment of fluconazole absorption.
For all indications drug treatment must be continued until the clinical and laboratory remission. Premature discontinuation of treatment leads to relapse. During treatment it is necessary to monitor hematology, kidney and liver function.
In rare cases, the use of fluconazole was accompanied by toxic liver changes in Vol. H. Fatal primarily in patients with serious underlying medical conditions. In the case of hepatotoxic effects associated with fluconazole, no obvious dependence of the total daily dose, duration of therapy, the patient’s age and sex. Hepatotoxic effects of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. If you have liver dysfunction should stop taking the medication.
If you have renal dysfunction also requires removal of the drug.
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 fluconazole, 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 testosterone sustanon erythema multiforme or changes. Care must be taken while taking fluconazole with rifabutin or other drugs metabolized via isoenzyme system P-450.
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the ECG. During post-marketing use of the drug reported rare cases of QT prolongation and development of ventricular tachycardia type “pirouette” during treatment with fluconazole. This effect was observed more frequently in patients with severe heart disease and multiple risk factors, such as myopathy, disturbances of water and electrolyte balance and the simultaneous use of drugs that may contribute to arrhythmias.