Pharmacological properties
Antifungal agent of the class of triazole compounds. Fluconazole has a pronounced antifungal effect, specifically blocks the synthesis of fungal sterols. It has a specific effect on fungal enzymes dependent on cytochrome P450. Active against various strains of Candida spp. (including visceral candidiasis), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trichophyton spp. Fluconazole is also active against pathogens of endemic mycoses: Blastomyces dermatitidis, Coccidioides immitis (including intracranial infections), Hystoplasma capsulatum.
After oral administration, it is well absorbed in the digestive tract. Food intake does not affect the absorption of fluconazole. The maximum concentration in the blood plasma is reached 0.5-1.5 hours after oral administration. The half-life of the drug is 30 hours, which allows the drug to be used once a day during a course of treatment with fluconazole and provides a therapeutic effect in vaginal candidiasis after a single dose of the drug. The concentration of the active substance in the blood plasma is directly proportional to the dose taken. 11-12% of fluconazole binds to blood proteins. With daily single administration of fluconazole for 4-5 days, a stable concentration in the blood plasma is achieved in 90% of patients. When a loading (twice daily) dose is administered on the 1st day of treatment, the above effect is achieved by the 2nd day of treatment.
Fluconazole penetrates well into all body fluids. In the cerebrospinal fluid, the concentration of fluconazole reaches 80% of its concentration in blood plasma. Fluconazole is excreted from the body in the urine, 80% of which is unchanged. Fluconazole clearance is directly proportional to creatinine clearance.
Indication
Infections caused by fungi of the genus Candida, including generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection (infections: internal, endocardium, eye, respiratory and urinary tract); candidiasis of the mucous membranes, including the oral cavity and pharynx, esophagus; non-invasive bronchopulmonary infections, candiduria; mucocutaneous and chronic atrophic candidiasis of the oral mucosa (caused by wearing dentures); genital candidiasis - vaginal candidiasis (acute or recurrent), prevention of recurrence of vaginal candidiasis (with a frequency of occurrence of 3 or more times a year), as well as candidal balanitis. Fluconazole is used for cryptococcal infections, dermatomycoses, including mycoses of the skin of the feet, body, groin area, lichen; onychomycosis; deep endemic mycoses, including coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis, as well as for the prevention of fungal infections in patients receiving cytostatic or radiation therapy.
Application
Inside, daily 1 time per day. Depending on the nature and course of the fungal infection, the daily dose can be from 50 mg to 400 mg. The duration of treatment depends on the clinical and mycological effect. The daily dose for children should not exceed the dose for adults.
In candidemia, disseminated candidiasis and other invasive candidal infections, the dose is usually 400 mg on the 1st day, and then up to 200 mg/day. Depending on the severity of the clinical effect, therapy can be continued and the dose increased to 400 mg/day. For the treatment of generalized candidiasis, the dose of fluconazole for children is 6-12 mg/kg per day.
In case of oropharyngeal candidiasis, adults are usually prescribed 50-100 mg of fluconazole once a day for 7-14 days. In patients with severe immunosuppression, treatment is continued for a longer period if necessary. In case of atrophic candidiasis of the oral mucosa caused by wearing dentures, the drug is usually prescribed at a dose of 50 mg once a day for 14 days in combination with local antiseptic agents for treating the prosthesis. In other candidal infections of the mucous membranes (except genital candidiasis, for example, esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, etc.), the effective dose is usually 50-100 mg/day with a treatment duration of 14-30 days. For the prevention of relapses of oropharyngeal candidiasis in AIDS patients after completion of the primary therapy, fluconazole is prescribed at a dose of 150 mg once a week. For candidiasis of the mucous membranes, the recommended dose of fluconazole for children is 3 mg/kg per day. On the first day, a loading dose of 6 mg/kg can be prescribed for faster achievement of stable equilibrium concentration.
For the prevention of candidiasis, the recommended dose is 50-400 mg once a 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 suspected severe or prolonged neutropenia, the recommended dose is 400 mg once a day. Fluconazole is prescribed a few days before the expected onset of neutropenia; after an increase in the number of neutrophils to more than 1000 in 1 mm 3, treatment is continued for another 7 days. Children are prescribed fluconazole at 3-12 mg / kg per day, depending on the severity of the induced neutropenia. For cryptococcal infections, 400 mg is usually prescribed on the 1st day, and then treatment is continued at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on the achievement of a clinical and mycological effect. For the treatment of cryptococcal infection, the dose of fluconazole for children is 6-12 mg/kg per day. For skin infections, including mycoses of the feet, smooth skin, inguinal region and candidal infections, the recommended dose is 150 mg 1 time per week or 50 mg 1 time per day. The duration of therapy is usually 2-4 weeks, however, for mycoses of the skin of the feet, longer treatment may be required (up to 6 weeks). For lichen, the recommended dose is 300 mg 1 time per week for 2 weeks; some patients require a third dose of fluconazole - 300 mg, while in some cases a single dose of 300-400 mg of the drug is sufficient. An alternative treatment regimen is the use of the drug at 50 mg 1 time per day for 2-4 weeks. For onychomycosis, the recommended dose is 150 mg 1 time per week. Treatment should be continued until the affected nail is completely replaced by a healthy one. Fingernails and toenails typically take 3-6 and 6-12 months to regrow, respectively, but the rate of nail growth can vary widely between individuals and with age.
In deep endemic mycosis, prolonged (up to 2 years) use of the drug at a dose of 200-400 mg/day may be required. The duration of therapy is determined individually; usually it is 11-24 months for coccidioidomycosis, 2-17 months for paracoccidioidomycosis, 1-16 months for sporotrichosis and 3-17 months for histoplasmosis.
For the treatment of elderly people in the absence of signs of renal failure, the drug is used in the usual dose. For patients with renal failure (creatinine clearance 11-50 ml/min), the initial loading dose is 50-400 mg, the daily dose of fluconazole for subsequent administrations is reduced by 2 times. Patients who are constantly on dialysis, fluconazole is prescribed after each dialysis session.
Contraindication
Hypersensitivity to fluconazole or azole compounds close to it in chemical structure, simultaneous use of terfenadine in patients receiving fluconazole therapy at a dose of 400 mg/day or higher, pregnancy and breastfeeding, age up to 1 year.
Side effects
It is usually well tolerated, but nausea, abdominal pain, diarrhea, flatulence, skin rash, headache, anaphylactic reactions, and hepatotoxic effects may occur.
Special instructions
Patients who develop abnormal liver function tests during treatment with fluconazole should be monitored closely. Fluconazole should be discontinued if clinical signs of liver damage appear.
Patients with AIDS are more prone to developing severe skin reactions when using many drugs. If a patient receiving treatment for a superficial fungal infection develops a rash that may be due to the use of fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, their condition should be monitored, and fluconazole should be discontinued if a polymorphic rash appears.
Fluconazole should be avoided during pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit to the woman outweighs the potential risk to the fetus. Fluconazole is excreted in breast milk in the same concentration as in the blood, so it should not be used during breastfeeding.
Interactions
Simultaneous administration of warfarin and fluconazole increases prothrombin time; fluconazole and oral sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide) increases their half-life (the possibility of hypoglycemia should be taken into account); fluconazole and phenytoin - clinically significantly increases the concentration of phenytoin in the blood serum (concentration monitoring and dose selection are necessary).
Repeated use of hydrochlorothiazide increases the concentration of fluconazole in the blood plasma, but a change in the dosage regimen of fluconazole is usually not required.
Fluconazole at a dose of 50-200 mg has no significant effect on the effectiveness of combined oral contraceptives.
Concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. In patients receiving this combination, consideration should be given to increasing the dose of fluconazole.
Due to the occurrence of severe arrhythmias due to prolongation of the Q-T interval in patients receiving azole antifungals in combination with terfenadine, simultaneous administration of fluconazole at a dose of 400 mg/day and above with terfenadine is contraindicated. Treatment with fluconazole at a dose below 400 mg/day in combination with terfenadine should be carried out under strict medical supervision.
With the simultaneous use of fluconazole and cisapride, side effects from the cardiovascular system are possible, including paroxysms of ventricular tachycardia.
The condition of patients who are prescribed a combination of fluconazole and zidovudine should be monitored for early detection of adverse symptoms of zidovudine, the AUC of which in this case increases significantly.
The use of fluconazole in patients who are simultaneously receiving cisapride, astemizole, rifabutin, tacrolimus or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in the concentration of these drugs in the blood serum.
Concomitant administration of cimetidine or antacids has no clinically significant effect on the absorption of fluconazole.
Overdose
It manifests itself as hallucinations and paranoid behavior.
Treatment - gastric lavage, symptomatic and supportive therapy. Fluconazole is excreted mainly in the urine, so forced diuresis can accelerate the elimination of the drug. A 3-hour hemodialysis session reduces the level of fluconazole in the blood plasma by approximately 50%.
Storage conditions
In a place protected from light at a temperature not exceeding 30 °C.
Translation of the instructions can be
