Diflucan 50 mg
Diflucan
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Active Ingredient: Fluconazole

Diflucan is used for treating and preventing certain yeast and fungal infections. Diflucan is an azole antifungal. It kills sensitive fungi by interfering with the formation of the fungal cell membrane.

Pharmacodynamics

Fluconazole, a triazole antifungal agent, is a potent selective inhibitor of sterol synthesis in the cell of fungi.

Fluconazole has demonstrated activity in vitro and in clinical studies in relation to most of the following microorganisms: Candida albicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

In vitro fluconazole activity was shown against the following microorganisms, however, its clinical significance is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

When ingested, fluconazole is active on various models of fungal infections in animals. The activity of the drug was demonstrated in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychophyton spp. Fluconazole activity has also been 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 has a high specificity for fungal enzymes dependent on cytochrome P450. Fluconazole therapy at a dose of 50 mg/day for up to 28 days does not affect the plasma testosterone concentration in men or the steroid concentration in women of childbearing age. Fluconazole at a dose of 200-400 mg/day does not have a clinically significant effect on the levels of endogenous steroids and their response to the stimulation of adrenocorticotropic hormone (ACTH) in healthy male volunteers.

Mechanisms of development of resistance to fluconazole

Fluconazole resistance may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target of fluconazole (lanosteril 14-α-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene, which encodes a target enzyme, lead to a modification of the target and a decrease in the affinity to the azoles. Increasing the expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates the need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.

The second significant mechanism of resistance lies in the active elimination of fluconazole from the intracellular space by activating two types of transporters involved in the active elimination (efflux) of drugs from the fungal cell. Such transporters include the main mediator encoded by the MDR genes (multidrug resistance) and the ATP-binding transporter cassette superfamily encoded by the CDR genes (the genes for the resistance of Candida fungi to azole antimycotics).

Overexpression of the MDR gene leads to resistance to fluconazole, while overexpression of CDR genes can lead to resistance to various azoles.

Resistance to Candida glabrata is usually mediated by overexpression of the CDR gene, which leads to resistance to many azoles. For those strains in which the minimum inhibitory concentration (MIC) is defined as an intermediate (16-32 µg/ml) it is recommended to use the maximum dose of fluconazole.

Candida krusei should be regarded as resistant to fluconazole. The mechanism of resistance is associated with a reduced sensitivity of the target enzyme to the inhibitory effects of fluconazole.

Pharmacokinetics

The pharmacokinetics of fluconazole is similar with intravenous administration and ingestion. After oral administration, fluconazole is well absorbed, its plasma concentration (and total bioavailability) exceed 90% of those when administered intravenously. A simultaneous meal does not affect the absorption of fluconazole. Plasma concentration is proportional to the dose and reaches a maximum (Cmax) 0.5–1.5 hours after fasting fluconazole, and the half-life is about 30 hours. 90% of the equilibrium concentration is reached by the 4-5th day after the start of therapy ( with repeated use of the drug once a day). The maximum concentration of fluconazole in saliva when taking a capsule is reached after 4 hours.

The administration of a loading dose (on the 1st day), twice the normal daily dose, makes it possible to achieve 90% equilibrium concentration by the 2nd day. The volume of distribution is close to the total water content in the body. Plasma protein binding is low (11-12%).

Fluconazole penetrates well into all body fluids. The concentrations of fluconazole in saliva and sputum are similar to its concentrations in plasma. In patients with fungal meningitis, the concentration of fluconazole in the cerebrospinal fluid is about 80% of its concentration in the blood plasma.

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are reached that exceed the serum levels. Fluconazole builds up in the stratum corneum. When taken in a dose of 50 mg once a day, the concentration of fluconazole after 12 days is 73 µg/g, and 7 days after stopping treatment - only 5.8 µg/g. When used at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on the 7th day is 23.4 µg/g, and 7 days after taking the second dose - 7.1 µg/g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 mcg/g in healthy and 1.8 mcg/g in the affected nails; 6 months after completion of therapy, fluconazole is still detected in the nails.

The drug is excreted mainly by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. Circulating metabolites not found.

The long half-life from plasma allows you to take fluconazole once for vaginal candidiasis and once a day or once a week for other indications.

Pharmacokinetics in Elderly Patients

It was found that with a single use of fluconazole at a dose of 50 mg orally in elderly patients aged 65 and older, some of whom took diuretics at the same time, Cmax was reached 1.3 h after administration and was 1.54 µg/ml, average values AUC - 76.4 ± 20.3 µg • h/ml, and the average half-life is 46.2 hours. The values of these pharmacokinetic parameters are higher than in younger patients, which is probably due to the reduced renal function characteristic of the elderly. The simultaneous intake of diuretics did not cause a pronounced change in AUC and Cmax.

Creatinine clearance (74 ml/min), the percentage of fluconazole excreted by the kidneys unchanged (0–24 h, 22%) and the renal clearance of fluconazole (0.124 ml/min/kg) is lower in elderly patients compared with young.

Indications for use

Fluconazole is indicated for the treatment of the following diseases in adults:

  • cryptococcal meningitis;
  • coccidioidomycosis;
  • invasive candidiasis;
  • mucous candidiasis, including oropharyngeal candidiasis, esophageal candidiasis, candiduria, and chronic mucocutaneous candidiasis;
  • chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures), when adherence to oral hygiene or local treatment is not enough;
  • Vaginal candidiasis, acute or recurrent, when local therapy is not applicable;
  • Candida balanitis, when local therapy is not applicable;
  • dermatomycosis, including foot dermatophytosis, trunk dermatophytosis, inguinal dermatophytosis, multi-colored lichen and cutaneous candidiasis when systemic treatment is indicated;
  • dermatophytosis of the nails (onychomycosis), when treatment with other drugs is not acceptable.

Fluconazole is indicated for the prevention of the following diseases in adults

:
  • recurrence of cryptococcal meningitis in patients with a high risk of recurrence;
  • relapses of oropharyngeal candidiasis and esophageal candidiasis in HIV-infected patients with a high risk of relapse;
  • to reduce the frequency of recurrences of vaginal candidiasis (4 or more episodes per year);
  • for the prevention of candidal infections in patients with prolonged neutropenia (such as patients with hemoblastosis undergoing chemotherapy, or patients undergoing hematopoietic stem cell transplantation).

Fluconazole is indicated for the treatment of children

Fluconazole is used to treat mucous candidiasis (oropharyngeal candidiasis and esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and the prevention of candidal infections in patients with a weakened immune system. Fluconazole can be used as a maintenance therapy to prevent the recurrence of cryptococcal meningitis in children with a high risk of relapse.

Contraindications

  • hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole;
  • simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg / day or more;
  • simultaneous use with drugs that increase the QT interval and are metabolized using CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide, quinidine and amiodarone;
  • intolerance to galactose, lactase deficiency and impaired glucose / galactose absorption;
  • children's age up to 3 years (for this dosage form).

Carefully

  • liver failure;
  • renal failure;
  • the appearance of a rash on the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections;
  • simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day;
  • potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, and concomitant therapy promoting the development of such disorders).

Use during pregnancy and during breastfeeding

Adequate and controlled studies of the use of fluconazole in pregnant women have not been conducted.

During pregnancy, fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment for the mother outweighs the possible risk to the fetus.

It is necessary to consider effective methods of contraception in women of childbearing age during the entire period of treatment and approximately within a week (5-6 elimination half-life) after taking the last dose of the drug.

Cases of spontaneous abortion and the development of congenital anomalies in infants whose mothers received fluconazole 150 mg once or repeatedly in the first trimester of pregnancy have been reported. Cases of multiple congenital malformations in newborns whose mothers for most or all of the first trimester received high-dose fluconazole therapy (400-800 mg/day) have been described. The following developmental disorders were noted: brachycephaly, impaired development of the facial part of the skull, impaired formation of the cranial vault, cleft palate, curvature of the femur bones, thinning and elongation of the ribs, arthrogryposis and congenital heart defects.

Fluconazole is found in breast milk at concentrations close to plasma, so its use in women during breastfeeding is not recommended.

Special instructions

Cases of superinfection have been reported, caused by Candida strains other than Candida albicans, which are often naturally resistant to fluconazole (for example, Candida krusei). In such cases, alternative antifungal therapy may be required.

During pregnancy, fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment for the mother outweighs the possible risk to the fetus.

It is necessary to consider effective methods of contraception in women of childbearing age during the entire period of treatment and approximately within a week (5-6 elimination half-lives) after taking the last dose of the drug. In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including death, Thus, in patients with serious comorbidities. In the case of hepatotoxic effects associated with the use of fluconazole, they are not marked by their apparent dependence on the total daily dose of the drug, the duration of therapy, sex and age of the patient. The hepatotoxic effect of the drug was usually reversible; his symptoms disappeared after cessation of therapy. Patients in whom liver function indices are violated during drug treatment should be monitored in order to identify signs of more serious liver damage. If clinical signs or symptoms of liver damage appear that may be associated with the use of fluconazole, the drug should be discontinued.

As with other azoles, fluconazole can rarely cause anaphylactic reactions.

During treatment with fluconazole, patients rarely developed exfoliative skin lesions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more likely to develop severe skin reactions with the use of many drugs. When a patient has a surface rash that can be associated with fluconazole during treatment, the drug should be discontinued. When a rash appears in patients with invasive or systemic fungal infections, they should be carefully monitored and the drug withdrawn when a bullous lesion or multiforme exudative erythema occurs.

The simultaneous use of fluconazole in doses of less than 400 mg/day and terfenadine should be carried out under close supervision.

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. With the use of fluconazole, an increase in the QT interval and ventricular fibrillation or flutter were very rarely observed in patients with severe diseases with multiple risk factors such as organic heart disease, electrolyte imbalance, and concomitant development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole should be used with caution.

Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using the drug. When using fluconazole 150 mg for vaginal candidiasis, patients should be warned that symptom improvement is usually observed after 24 hours, but sometimes it takes several days to completely disappear. If symptoms persist for several days, you should consult a doctor.

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