Diflazon, 150 mg capsules

Pharmgroup:

antifungal agent.

Pharmic action:

Diflazon is an antifungal drug. Fluconazole, representative of the class of triazole antifungal agents, is a potent selective inhibitor of the fungal enzyme 14-α-demethylase. The drug prevents conversion of lanosterol into ergosterol – the main component of cell membranes of fungi.

It is active against pathogens of opportunistic mycoses, including those caused by Candida spp. (Candida albicans, Candida tropicalis), Cryptococcus neoformans, Microsporum spp, Trichophyton spp. Fluconazole activity has also been shown in models of endemic mycoses, including infections caused by Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.

Pharmacokinetics:

Intake
Fluconazole is well absorbed after oral administration. Bioavailability is 90%. After oral administration on an empty stomach in a dose of 150 mg, Cmax is 90% of the plasma level in a dose of 2.5-3.5 mg/l. Simultaneous intake of food has no effect on absorption when administered orally. Cmax is reached 0.5-1.5 hours after fluconazole administration. Plasma concentration is directly proportional to the dose taken.

Distribution
90% of Css is reached by 4-5 days of treatment with the drug (if administered once daily).
Administration of a shock dose (on day 1), 2 times the average daily dose, allows reaching 90% of Css by day 2. The apparent Vd is close to the total body water content. Protein binding is 11-12%.
Fluconazole penetrates well into all body fluids, including cerebrospinal fluid. Fluconazole concentrations in saliva and sputum are similar to its level in plasma. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid are about 80% of those in plasma.

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are achieved that exceed serum levels.

Metabolism
Less than 5% of fluconazole is metabolized by “first passage” through the liver. No fluconazole metabolites have been detected in the blood.

Elimination
The long T1/2 allows a single dose of the drug for the treatment of vaginal candidiasis and provides once-daily administration for other indications. Fluconazole is mainly excreted by the kidneys; about 80% of the administered dose is excreted unchanged by the kidneys. Fluconazole clearance is proportional to creatinine clearance.

Indications

Active ingredient

Composition

1 capsule contains:

The active ingredient:

fluconazole 150 mg;

Associates:

Lactose monohydrate;

Corn starch;

Colloidal anhydrous silica;

sodium lauryl sulfate;

magnesium stearate.

How to take, the dosage

In adults with cryptococcal meningitis and cryptococcal infections of other localizations, 400 mg is prescribed on the first day and then treatment is continued at a dose of 200-400 mg once daily. The duration of treatment of cryptococcal infections depends on clinical efficacy confirmed by mycological examination; in cryptococcal meningitis, therapy usually continues for at least 6-8 weeks.

In order to prevent relapse of cryptococcal meningitis in AIDS patients, after completion of the full course of initial treatment, fluconazole therapy at a dose of 200 mg/day may be continued for a very long period of time.

In candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose averages 400 mg the first day and then 200 mg/day. In case of insufficient clinical efficacy, the dose may be increased to 400 mg/day. Duration of therapy depends on clinical effectiveness.

In oropharyngeal candidiasis the drug is prescribed on average 50-100 mg once daily; therapy duration is 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment may be longer.

In atrophic oral candidiasis associated with wearing dentures, the drug is prescribed in an average dose of 50 mg once daily for 14 days in combination with local antiseptic agents for denture treatment.

In other candida infections (except genital candidiasis), such as esophagitis, non-invasive bronchopulmonary lesions, candiduria, candidiasis of skin and mucous membranes, the effective dose is on average 50-100 mg/day with a treatment duration of 14-30 days.

For prevention of relapses of oropharyngeal candidiasis in AIDS patients after completion of the complete course of primary therapy, fluconazole may be prescribed 150 mg once weekly.

For vaginal candidiasis, fluconazole is taken once orally in a dose of 150 mg. To reduce the recurrence rate of vaginal candidiasis, the drug may be used in a dose of 150 mg once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use.

Fluconazole is given as a single oral dose of 150 mg for balanitis caused by Candida.

For prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg once daily, depending on the risk of fungal infection. If there is a high risk of generalized infection, such as in patients with anticipated severe or prolonged neutropenia, the recommended dose is 400 mg once daily. Fluconazole is administered several days before the expected appearance of neutropenia; after an increase in neutrophil count above 1000/μL, treatment is continued for another 7 days.

In mycoses of the skin, including mycoses of the feet, smooth skin, inguinal area, and candidiasis of the skin, the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of therapy in normal cases is 2-4 weeks, but longer therapy (up to 6 weeks) may be required for mycoses of the feet.

In pityriasis the recommended dose is 300 mg once a week for 2 weeks; some patients need a third dose of 300 mg a week, while in some cases a single dose of 300-400 mg is sufficient. An alternative treatment regimen is to use 50 mg once daily for 2-4 weeks.

In onychomycosis the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (the uninfected nail grows back). It normally takes 3-6 months and 6-12 months, respectively, for nails on fingers and feet to re-grow.

In deep endemic mycoses, it may be necessary to use the drug at a dose of 200-400 mg/day for up to 2 years. The duration of therapy is determined individually; it is 11-24 months for coccidioidomycosis, 2-17 months for paracoccidioidomycosis, 1-16 months for sporotrichosis, and 3-17 months for histoplasmosis.

In children, as in similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children the drug should not be used in a daily dose higher than that in adults. Diflazon is used daily once a day.

In mucosal candidiasis, the recommended dose of fluconazole is 3 mg/kg/day. A shock dose of 6 mg/kg may be administered on the first day in order to achieve steady-state equilibrium concentrations more quickly.

For the treatment of generalized candidiasis and cryptococcal infection, the recommended dose is 6-12 mg/kg/day depending on the severity of the disease.

For the prevention of fungal infections in immunocompromised children whose risk of infection is associated with neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is indicated at 3-12 mg/kg/day, depending on the severity and duration of the induced neutropenia.

In children with impaired renal function the daily dose of the drug should be reduced (in the same proportional relationship as in adults) according to the severity of renal failure.

In elderly patients in the absence of signs of renal failure, the usual dosing regimen of the drug should be followed.

In patients with renal impairment (CKD)

Fluconazole is mainly excreted unchanged in the urine. There is no need to change the dose if administered once. When repeatedly administered to patients with impaired renal function, a shock dose of 50 mg to 400 mg should be administered.

In CK>50 ml/min, the average recommended dose of the drug is used; in CK>11 to 50 ml/min, a dose that is 50% of the recommended dose is used. For patients who are regularly on hemodialysis, one dose of the drug is administered after each session of hemodialysis.

Interaction

When using fluconazole with warfarin an increase in prothrombin time by 12% was noted. In this regard, it is recommended to monitor prothrombin time in patients receiving Diflazone in combination with coumarin anticoagulants.

When used concomitantly fluconazole increases T 1/2 of oral hypoglycemic drugs – sulphonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Concomitant administration of fluconazole and oral hypoglycemic agents is allowed, but the possibility of hypoglycemia should be taken into account.

The concomitant use of fluconazole and phenytoin may be accompanied by clinically significant increases in phenytoin concentrations. If concomitant use of the two drugs is required, phenytoin levels should be monitored and the dose should be adjusted to ensure therapeutic serum concentrations.

The concomitant use of fluconazole and rifampicin decreases AUC by 25% and shortens T 1/2 of fluconazole by 20%. In patients receiving rifampicin concomitantly it is necessary to consider the advisability of increasing fluconazole dose.

It is recommended to monitor cyclosporine blood concentrations in patients receiving fluconazole, because fluconazole and cyclosporine slowly increased cyclosporine concentrations in patients with kidney transplantation.

Patients who receive theophylline in high doses or who are likely to develop theophylline intoxication should be monitored for early detection of symptoms of theophylline overdose, because concomitant administration of fluconazole decreases the average plasma clearance rate of theophylline.

In concomitant use of fluconazole and cisapride there have been described cases of adverse cardiac reactions, including paroxysmal ventricular tachycardia (“pirouette-type” arrhythmia).

There have been reports of interaction between fluconazole and rifabutin, with increased serum levels of the latter. If fluconazole and rifabutin are used concomitantly, there have been cases of uveitis. Patients receiving rifabutin and fluconazole concomitantly should be closely monitored.

In concomitant use of zidovudine and fluconazole an increase in plasma concentration of zidovudine is observed, which is caused by a decrease in conversion of the latter to the main metabolite, therefore an increase in side effects of zidovudine should be expected.

Special Instructions

Treatment can be initiated in the absence of results of culture or other laboratory tests, but if available, appropriate correction of fungicidal therapy is recommended.

Contraindications

Side effects

Digestive system disorders: nausea, diarrhea, flatulence, vomiting, abdominal pain, change in taste, rarely – increased liver enzymes activity and liver function disorders (jaundice, hyperbilirubinemia, increased ALT, ACT and ALF activity, hepatitis, hepatocellular necrosis, including fatal).

Nervous system disorders: headache, dizziness; rarely – seizures.

Hematopoietic system: rarely – agranulocytosis, neutropenia. In patients with severe fungal infections hematologic changes (leukopenia and thrombocytopenia) may be observed.

Cardiovascular system: prolongation of the QT interval in electrocardiogram (ECG), ventricular fibrillation/tripping.

Allergic reactions: skin rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), bronchial asthma (more often with intolerance to acetylsalicylic acid), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: gastric lavage and symptomatic therapy are recommended. Since fluconazole is excreted with urine, forced diuresis increases its excretion. Hemodialysis during 3 hours reduces fluconazole concentration in plasma by 50%.

Pregnancy use

The use of Diflazon during pregnancy is not advisable, except for severe or life-threatening forms of fungal infections, if the expected benefits to the mother exceed the possible risk to the fetus.

Fluconazole is detected in breast milk at the same concentration as in plasma, so prescribing the drug during lactation is not recommended.

Similarities