Vero-Fluconazole (Capsules) Instructions for Use

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

Antifungal agent, a triazole derivative, is a potent selective inhibitor of sterol synthesis in the fungal cell.

Fluconazole is active in vitro and in clinical infections against most of the following microorganisms: Candida albicans, Candida glabrata (many strains are moderately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

Activity of fluconazole in vitro against the following microorganisms has been demonstrated, however its clinical significance is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

When administered orally, Fluconazole exhibited activity in various models of fungal infections in animals. The drug’s activity has been demonstrated in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in immunocompromised animals); Cryptococcus neoformans (including intracranial infections); Microsporum spp. and Trichophyton spp. Activity of fluconazole 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 high specificity for fungal cytochrome P450-dependent enzymes. Therapy with fluconazole at a dose of 50 mg/day for up to 28 days does not affect plasma testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole at a dose of 200-400 mg/day does not have a clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

Pharmacokinetics

The pharmacokinetics of fluconazole are similar following intravenous administration and oral administration.

After oral administration, Fluconazole is well absorbed, its plasma levels (and overall bioavailability) exceed 90% of the plasma levels of fluconazole after intravenous administration. Concurrent food intake does not affect absorption after oral administration. C_max is achieved 0.5-1.5 hours after taking fluconazole on an empty stomach. Plasma concentration is proportional to the dose.

90% of C_ss is reached by the 4th-5th day after the start of therapy (with multiple administrations once/day).

Administration of a loading dose (on day 1), twice the average daily dose, allows achieving 90% C_ss by the 2nd day. The apparent V_d approaches the total body water content. Binding to plasma proteins is low (11-12%).

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

High concentrations are achieved in the stratum corneum, epidermis-dermis and sweat fluid, which exceed serum concentrations. Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg once/day, the concentration of fluconazole after 12 days was 73 mcg/g, and 7 days after stopping treatment – only 5.8 mcg/g. When used at a dose of 150 mg once/week, the concentration of fluconazole in the stratum corneum on the 7th day was 23.4 mcg/g, and 7 days after the second dose – 7.1 mcg/g.

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

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. The clearance of fluconazole is proportional to the CC. No circulating metabolites were detected.

The long T_1/2 from plasma allows Fluconazole to be taken as a single dose for vaginal candidiasis and once/day or once/week for other indications.

Indications

Cryptococcosis, including cryptococcal meningitis and infections of other locations (e.g., lungs, skin), including in patients with a normal immune response and in patients with AIDS, transplant recipients and patients with other forms of immunodeficiency; maintenance therapy to prevent relapse of cryptococcosis in AIDS patients.

Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tracts, including in patients with malignant tumors, in the ICU and receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis.

Candidiasis of mucous membranes, including mucous membranes of the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic oral candidiasis (associated with wearing dentures), including in patients with normal and suppressed immune function; prevention of relapse of oropharyngeal candidiasis in AIDS patients.

Genital candidiasis; acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrence of vaginal candidiasis (3 or more episodes per year); candidal balanitis.

Skin mycoses, including mycoses of the feet, body, groin area, pityriasis versicolor, onychomycosis and cutaneous candidal infections.

Deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

Prevention of fungal infections in patients with malignant tumors predisposed to developing such infections as a result of cytotoxic chemotherapy or radiation therapy.

ICD codes

Dosage Regimen

Capsules

For oral administration.

The dosage regimen is set individually, depending on the indications, clinical situation, treatment regimen, and patient’s age.

For adults, the daily dose is 50-800 mg, the frequency of administration is once/day.

For children, the dose is 3-12 mg/kg/day, the frequency of administration is once/day.

In patients with impaired renal function, the dose of fluconazole is reduced depending on CC.

The duration of treatment depends on the clinical and mycological effect.

Adverse Reactions

Nervous system disorders headache, dizziness, seizures, taste perversion, paresthesia, insomnia, somnolence, tremor.

Digestive system disorders abdominal pain, diarrhea, flatulence, nausea, dyspepsia, vomiting, dry oral mucosa, constipation.

Liver and biliary tract disorders hepatotoxicity, in some cases with fatal outcome, increased bilirubin concentration, serum aminotransferase activity (ALT and AST), ALP, impaired liver function, hepatitis, hepatocellular necrosis, jaundice, cholestasis, hepatocellular damage.

Skin and subcutaneous tissue disorders rash, alopecia, exfoliative skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, increased sweating, drug eruption.

Hematopoietic system disorders leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Immune system disorders anaphylaxis (including angioedema, facial edema, urticaria, pruritus).

Cardiovascular system disorders increased QT interval on ECG, ventricular tachyarrhythmia of the “torsades de pointes” type, arrhythmia.

Metabolism and nutrition disorders increased plasma cholesterol and triglyceride concentrations, hypokalemia.

Musculoskeletal and connective tissue disorders: myalgia.

Other weakness, asthenia, increased fatigue, fever, vertigo.

Contraindications

Hypersensitivity to fluconazole or azole substances with a structure similar to fluconazole; concurrent use of terfenadine during multiple administration of fluconazole at a dose of 400 mg/day and higher; concurrent use with drugs that increase the QT interval and are metabolized by the CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine.

With caution

Hepatic insufficiency; renal insufficiency; appearance of rash during fluconazole use in patients with superficial fungal infection and invasive/systemic fungal infections; concurrent 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 that may contribute to the development of such disorders).

Use in Pregnancy and Lactation

Adequate and controlled studies on the safety of fluconazole use in pregnant women have not been conducted. The use of fluconazole during pregnancy should be avoided, except in cases of severe and potentially life-threatening fungal infections, where the expected benefit of treatment outweighs the possible risk to the fetus. Women of childbearing age should use reliable contraception during treatment. Fluconazole is detected in breast milk at concentrations close to plasma concentrations, therefore its use during lactation (breastfeeding) is not recommended.

Use in Hepatic Impairment

Fluconazole should be used with caution in patients with severe liver function impairment.

Use in Renal Impairment

Fluconazole should be used with caution in patients with renal insufficiency. If CC <50 ml/min, adjustment of the dosage regimen is required.

Pediatric Use

Used in children in appropriate dosage forms.

Geriatric Use

In elderly patients without signs of renal insufficiency, Fluconazole is used at the usual dose. If a single dose is required, a doctor’s consultation is necessary.

Special Precautions

Use with caution in cases of impaired liver function parameters during fluconazole use, in case of rash appearance during fluconazole use in patients with superficial fungal infection and invasive/systemic fungal infections, in case of concurrent use of terfenadine and fluconazole at a dose of less than 400 mg/day, in potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that may contribute to the development of such disorders).

The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. It is necessary to monitor the condition of patients whose liver function parameters become impaired during treatment with fluconazole in order to detect signs of more serious liver damage. If clinical signs or symptoms of liver damage that may be associated with fluconazole appear, it should be discontinued.

AIDS patients 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 can be associated with the use of fluconazole, it should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be carefully monitored and Fluconazole should be discontinued if bullous lesions or erythema multiforme appear.

Concurrent use of fluconazole at doses less than 400 mg/day and terfenadine should be carried out under careful supervision.

When using fluconazole, an increase in the QT interval and ventricular fibrillation/flutter have been reported very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalance and concomitant therapy that may contribute to the development of such disorders.

Therapy can be started before the results of cultures and other laboratory tests are obtained. However, anti-infective therapy must be adjusted appropriately when the results of these studies become known.

There have been reports of cases of superinfection caused by Candida strains other than Candida albicans, which often do not show sensitivity to fluconazole (e.g., Candida krusei). In such cases, alternative antifungal therapy may be required.

Drug Interactions

When used concomitantly with warfarin, Fluconazole increases prothrombin time (by 12%), which may lead to bleeding (hematomas, nosebleeds and gastrointestinal bleeding, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time should be constantly monitored.

After oral administration of midazolam, Fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after oral administration of fluconazole than after its intravenous administration. If concomitant therapy with benzodiazepines is necessary in patients taking Fluconazole, they should be monitored for appropriate reduction of the benzodiazepine dose.

When fluconazole and cisapride are used concomitantly, adverse cardiac reactions are possible, including ventricular fibrillation/flutter (torsades de pointes arrhythmia). The use of fluconazole at a dose of 200 mg once/day and cisapride at a dose of 20 mg 4 times/day leads to a significant increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concurrent administration of cisapride and fluconazole is contraindicated.

In patients after kidney transplantation, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in the concentration of cyclosporine. However, with multiple administrations of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentration were observed in bone marrow recipients. When fluconazole and cyclosporine are used concomitantly, it is recommended to monitor the blood concentration of cyclosporine.

Multiple administration of hydrochlorothiazide concomitantly with fluconazole leads to a 40% increase in the plasma concentration of fluconazole. An effect of this magnitude does not require a change in the dosage regimen of fluconazole in patients receiving diuretics concomitantly, but this should be taken into account.

When a combined oral contraceptive is used concomitantly with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, whereas with daily administration of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole once a week, the AUC of ethinyl estradiol and norethindrone increases by 24% and 13%, respectively. Thus, multiple administration of fluconazole at the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentration. With this combination, the concentration of phenytoin should be monitored and its dose adjusted accordingly to ensure therapeutic serum concentration.

Concomitant use of fluconazole and rifabutin may lead to an increase in serum concentrations of the latter. Cases of uveitis have been described with concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and Fluconazole concomitantly should be carefully monitored.

Concomitant use of fluconazole and rifampicin leads to a 25% decrease in AUC and a 20% decrease in the half-life (T_1/2) of fluconazole. In patients concurrently taking rifampicin, the advisability of increasing the dose of fluconazole should be considered.

Concomitant use of fluconazole leads to an increase in the half-life (T_1/2) of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide, and tolbutamide). Fluconazole and oral sulfonylurea drugs can be co-administered to patients with diabetes mellitus, but the possibility of hypoglycemia should be taken into account.

Concomitant use of fluconazole and tacrolimus leads to an increase in the plasma concentrations of the latter. Cases of nephrotoxicity have been reported. With this combination, patients’ condition should be carefully monitored.

Concomitant use of azole antifungal agents and terfenadine may lead to serious arrhythmias as a result of QT interval prolongation. When fluconazole is taken at a dose of 200 mg/day, QT interval prolongation has not been established; however, the use of fluconazole at doses of 400 mg/day and higher causes a significant increase in terfenadine plasma concentration. Concomitant use of fluconazole at doses of 400 mg/day and higher with terfenadine is contraindicated. Treatment with fluconazole at doses less than 400 mg/day in combination with terfenadine should be carried out under careful monitoring.

Concomitant use with fluconazole at a dose of 200 mg for 14 days leads to an 18% decrease in the mean plasma clearance rate of theophylline. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of theophylline toxicity, symptoms of theophylline overdose should be monitored, and therapy should be adjusted accordingly if necessary.

Concomitant use with fluconazole results in increased concentrations of zidovudine, which is likely due to a reduction in its metabolism to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was established.

When used in HIV-infected patients receiving zidovudine at a dose of 200 mg every 8 hours for 7 days in combination with fluconazole at a dose of 400 mg/day or without it, with a 21-day interval between the two regimens, a significant increase in the AUC of zidovudine (74%) was established with concomitant use of fluconazole. Patients receiving such a combination should be monitored for the occurrence of zidovudine adverse effects.

Concomitant use of fluconazole with astemizole or other drugs metabolized by cytochrome P450 system isoenzymes may be accompanied by an increase in the serum concentrations of these agents. With such combinations, patients’ condition should be carefully monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.