Pharmacological properties
Pharmacodynamics. Mechanism of action. Fluconazole, a triazole antifungal agent, is a potent and selective inhibitor of fungal enzymes required for ergosterol synthesis. Its primary mechanism of action is inhibition of fungal cytochrome P450-mediated 14α-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. Accumulation of 14α-methylsterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.
Fluconazole 50 mg/day for 28 days had no effect on plasma testosterone levels in men or on endogenous steroid levels in women of reproductive age. Fluconazole 200-400 mg/day had no clinically significant effect on endogenous steroid levels or the response to ACTH stimulation in healthy male volunteers.
An interaction study with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole did not affect the metabolism of antipyrine.
In vitro susceptibility: Fluconazole has demonstrated antifungal activity in vitro against the most commonly observed Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, while C. krusei is resistant to it.
Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mold fungi Blastomices dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.
Pharmacodynamics - pharmacokinetics. According to the results of animal studies, there is a correlation between MIC and efficacy against experimental models of mycoses caused by Candida species. According to clinical studies, there is a linear relationship between AUC and dose of fluconazole (approximately 1: 1). There is also a direct, but insufficient relationship between AUC or dose and a positive clinical response to the treatment of oral candidiasis and to a lesser extent - candidemia. Similarly, the treatment of infections caused by strains for which fluconazole shows a high minimum inhibitory concentration is less satisfactory.
Mechanism of resistance. Candida species exhibit multiple mechanisms of resistance to azole antifungals. Fluconazole exhibits high minimum inhibitory concentrations against fungal strains with ≥1 mechanism of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection with Candida spp., caused by species other than C. albicans, often insensitive to fluconazole (e.g. Candida krusei), has been reported. Alternative antifungal agents should be used in the treatment of such patients.
Pharmacokinetics. The pharmacokinetic properties of fluconazole are similar after intravenous and oral administration.
Absorption. Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of the plasma levels achieved after oral administration. Concomitant food intake does not affect the absorption of the drug after oral administration. Cmax in plasma is achieved 0.5-1.5 hours after administration. The concentration of the drug in plasma is proportional to the dose. Steady-state concentrations of 90% are achieved on the 2nd day of treatment when the drug is administered on the 1st day in a loading dose that is 2 times the usual daily dose.
Distribution: The volume of distribution is approximately equal to the total body water content. Plasma protein binding is low (11-12%).
Fluconazole penetrates well into all studied body fluids. The drug level in saliva and sputum is similar to the drug concentration in blood plasma. In patients with fungal meningitis, the level of fluconazole in the cerebrospinal fluid reaches 80% of the concentration in blood plasma.
High concentrations of fluconazole in the skin, exceeding those in blood plasma, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum.
Biotransformation. Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted unchanged in the urine. Fluconazole is a selective inhibitor of CYP 2C9 and CYP 3A4 isoenzymes, as well as an inhibitor of the 2C19 isoenzyme.
Excretion. T½ of fluconazole from blood plasma is about 30 hours. Most of the drug is excreted by the kidneys, with 80% of the dose found in the urine unchanged. Fluconazole clearance is proportional to creatinine clearance. Circulating metabolites have not been identified.
The long T½ from blood plasma allows for a single use of the drug for vaginal candidiasis, as well as the use of the drug once a week for other indications.
Renal failure. In patients with severe renal failure (glomerular filtration rate 20 ml/min) T ½ increases from 30 to 98 hours. Therefore, this category of patients requires a reduced dose of fluconazole. Fluconazole is removed by hemodialysis, to a lesser extent by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the level of fluconazole in the blood plasma by approximately 50%.
Elderly patients: Changes in pharmacokinetics in elderly patients depend on renal function parameters.
Treatment in adults of diseases such as:
cryptococcal meningitis; coccidioidomycosis; invasive candidiasis; candidiasis of the mucous membranes, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic candidiasis of the skin and mucous membranes; chronic atrophic candidiasis (candidiasis caused by the use of dentures) when local dental hygiene products are ineffective; vaginal candidiasis, acute or recurrent, when local therapy is inappropriate; candidal balanitis, when local therapy is inappropriate; dermatomycosis, including mycoses of the feet, mycoses of smooth skin, inguinal dermatomycosis; lichen multicolor and candidal skin infections, when systemic therapy is inappropriate; Dermatophyte onychomycosis, when the use of other drugs is inappropriate.
Prevention in adults of diseases such as:
Recurrence of cryptococcal meningitis in patients at high risk of developing it; Recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it; Reduction of the frequency of recurrences of vaginal candidiasis (≥4 cases per year); Prevention of candidal infections in patients with prolonged neutropenia (e.g., patients with blood malignancies receiving chemotherapy or during hematopoietic stem cell transplantation).
Children. The drug in tablet form can be used in this category of patients when children are able to safely swallow a tablet, usually from the age of 5.
The drug is used in children for the treatment of candidiasis of the mucous membrane (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and for the prevention of candidal infections in patients with reduced immunity. The drug can be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children with a high risk of its development.
Therapy may be initiated prior to the results of culture and other laboratory tests; once results are available, antibacterial therapy should be adjusted accordingly.
Application
The drug is to be administered orally. The drug is not dependent on food intake.
The daily dose of fluconazole depends on the type and severity of the fungal infection. If repeated use of the drug is necessary, treatment for infection should be continued until the disappearance of clinical and laboratory manifestations of the activity of the fungal infection. Insufficient duration of therapy may lead to the resumption of the active infectious process.
Dispersible tablets of 50 mg are used in children and adults. Dissolve the tablet in 1 teaspoon of water according to the dose (50 mg / 5 ml).
Adults. Cryptococcosis. Treatment of cryptococcal meningitis: loading dose is 400 mg on day 1. Maintenance dose is 200-400 mg/day. Duration of treatment is usually at least 6-8 weeks. In life-threatening infections, the daily dose can be increased to 800 mg.
Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of developing it: the recommended dose is 200 mg/day for an unlimited period.
Coccidioidomycosis. The recommended dose is 200-400 mg/day. The duration of treatment is 11-24 months or longer depending on the patient's condition. For the treatment of some forms of infection, especially meningitis, it may be appropriate to use the drug at a dose of 800 mg/day.
Invasive candidiasis. Loading dose is 800 mg on day 1. Maintenance dose is 400 mg/day. The usual recommended duration of treatment for candidemia is 2 weeks after the first negative blood culture results and resolution of signs and symptoms of candidemia.
Mucosal candidiasis
Oropharyngeal candidiasis: loading dose is 200-400 mg on day 1, maintenance dose is 100-200 mg/day. Duration of treatment is 7-21 days (until remission is achieved), but may be increased for patients with severe immunodeficiency; Esophageal candidiasis: loading dose is 200-400 mg on day 1, maintenance dose is 100-200 mg/day. Duration of treatment is 14-30 days (until remission is achieved), but may be increased for patients with severe immunodeficiency; Candiduria: recommended dose is 200-400 mg/day for 7-21 days. For patients with severe immunodeficiency, the duration of treatment may be increased; Chronic atrophic candidiasis: recommended dose is 50 mg/day for 14 days; Chronic candidiasis of the skin and mucous membranes: the recommended dose is 50-100 mg/day. The duration of treatment is up to 28 days, but may be increased depending on the severity and type of infection or with reduced immunity.
Prevention of recurrence of mucosal candidiasis in HIV patients at high risk of developing it. Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100-200 mg/day or 200 mg 3 times a week. The duration of treatment is unlimited in immunocompromised patients.
genital candidiasis
Acute vaginal candidiasis, candidal balanitis: the recommended dose is 150 mg once; treatment and prevention of recurrent vaginal candidiasis (≥4 relapses of the disease per year): the recommended dose is 150 mg 1 time in 3 days. A total of 3 doses should be used (1; 4 and 7th day). After that, the drug should be taken in a maintenance dose of 150 mg 1 time per week for 6 months.
ringworm
Athlete's foot, smooth skin mycosis, inguinal ringworm, candidal skin infections: the recommended dose is 150 mg once a week or 50 mg once a day. The duration of treatment is 2-4 weeks. Treatment for athlete's foot can last up to 6 weeks; lichen planus: the recommended dose is 300-400 mg once a week for 1-3 weeks; Dermatophyte onychomycosis: the recommended dose is 150 mg once a week. Treatment should be continued until a healthy nail grows in place of the infected nail. It usually takes 3-6 and 6-12 months, respectively, to grow healthy nails on the fingers and big toes. However, the rate of nail growth in patients may vary and depend on age. After successful treatment for long-term chronic infections, the shape of the nail sometimes remains changed.
Children. The drug in tablet form can be used in this category of patients when children are able to safely swallow a tablet, which is usually possible from the age of 5 years.
The maximum daily dose of 400 mg should not be exceeded.
As with similar infections in adults, the duration of treatment depends on the clinical and mycological response. The drug is administered once a day.
Dosage in children with renal impairment is given below. The pharmacokinetics of fluconazole have not been studied in children with renal impairment.
Children over 12 years of age. Depending on body weight and pubertal development, the physician should assess which dose (adult or pediatric) is optimal for the patient. Clinical data indicate that children have a higher clearance of fluconazole than adults. Doses of 100, 200, and 400 mg in adults and 3, 6, and 12 mg/kg body weight in children result in comparable systemic exposure.
The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. If there is an urgent need for the drug in adolescents (aged 12-17 years), the drug should be taken in the usual adult doses.
Children aged 5 to 11 years. Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose can be administered on day 1 to achieve steady-state more quickly.
Invasive candidiasis, cryptococcal meningitis: the dose is 6-12 mg/kg/day depending on the severity of the disease.
Maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of its development: the dose of the drug is 6 mg/kg/day, depending on the severity of the disease.
Prevention of candidiasis in immunocompromised patients: the dose of the drug is 3-12 mg/kg/day depending on the severity and duration of induced neutropenia (see Dosage for adults).
Elderly patients: The dose should be adjusted according to renal function (see below).
Patients with renal insufficiency. With a single use, it is not necessary to adjust the dose of fluconazole. Patients (including children) with impaired renal function, if multiple use of the drug is necessary, should take an initial dose of 50-400 mg on the 1st day of treatment, depending on the therapeutic indications. After that, the daily dose (depending on the indications) should be calculated according to the table below.
Creatinine clearance, ml/min Amount of recommended dose,%
| 50 | 100 |
| ≤50 (without dialysis) | 50 |
| Patients on regular dialysis | 100 (after each dialysis session) |
|
Patients on regular dialysis should receive 100% of the recommended dose after each dialysis. On non-dialysis days, the patient should receive a dose adjusted based on creatinine clearance.
Patients with hepatic impairment: Fluconazole should be used with caution in patients with hepatic impairment, as there is insufficient information on the use of fluconazole in this patient population.
Contraindication
Hypersensitivity to fluconazole, other azole compounds or to any of the excipients
