INSTRUCTION

for medical use of the preparation

FLUCONAZOL

 Composition:

Active substance: fluconazol; 1 ml 2 mg fluconazol;

Auxiliary substances: sodium chloride, Trilon B, water for injections.

Medicinal form. Solution for infusions.

Pharmacotherapeutical group. Antifungal preparations for systemic use.

АТС code J02A C01.

 Clinical characteristics.

Indications.

Cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin). Treatment of AIDS carries and patients, patients after organ transplantation and other patients, receiving immunosuppressive therapy.

Maintaining therapy with the purpose of prevention of recurrent cryptococcosis in AIDS patients.

Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infection (lesion of the abdominal cavity, endocardium, eyes, respiratory and urinary tracts). Treatment of patients with malignant neoplasms, which are in the department of intense therapy and receive cytostatic and immunosuppressive therapy or feel the influence of other factors, which makes them more liable to candidiasis.

Candidiasis of mucous membranes: lesions of oropharyngeal, oesophagus, noninvasive bronchopulmonary infection, candiduria, mucocutaneous and chronic atrophic candidiasis (candidiasis, caused by dental prosthesis). As preventive measure against recurrent oropharyngeal candidiasis in AIDS patients.

Genital candidiasis, including vaginal candidiasis, acute or recurrent, and candidal balanitis. Preventive use with the purpose of decreased frequency of recurrent vaginal candidiasis (3 and more recurrences a year).

Prevention of fungal infection in patients with malignant neoplasms, who are liable to such kind of infections as a result of chemotherapy or radiation therapy.

Dermatomycosis – foot mycosis, skin mycosis, inguinal dermatomycosis, pityriasis versicolor, nail tinea (onychomycosis) and skin candidal infections.

Deep endemic mycosis in patients with intact immune system, primary coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

 Contraindications. Hypersensitivity to fluconazolу and auxiliary substances or to other azole substances, similar by theire chemical structure.

Concomitant use of terfenadine is contraindicated in patients, who receive fluconazol in the dose 400 mg a day and more.

Indication of cisapride is contraindicated in patients, who receive fluconazol.

Pregnancy and lactation.

 Way of administration and doses.

The daily dose of fluconazol depends on the nature and severity of fungal infection. Treatment of the infections, which require multiple intakes of the preparation, should continue until clinical and laboratory effect is achieved. Insufficient term of treatment may lead to recurrence of the active infectious process. Patients with AIDS and cryptococcal meningitis or with recurrent oropharyngeal candidiasis usually require maintaining therapy for recurrence prevention. The therapy may be initiated before receiving the results of culture or other laboratory investigations, and when they are received, antimicrobial preparations are also added.

Adults.

For cryptococcal meningitis and cryptococcal infections of other localizations patients are indicated 400 mg parenterally on the first day, and then continue the treatment with the doses between 200 and 400 mg once a day. The duration of therapy for cryptococcal infection depends on clinical response, but usually it lasts for at least 6 - 8 weeks for cryptococcal meningitis.

For prevention of recurrent cryptococcal meningitis in AIDS patients after the end of the whole course of primary treatment, fluconazol therapy in the dose of 200 mg/day parenterally may be continued (10 - 12 weeks).

For treatment of candidemia, disseminated candidiasis and other forms of invasive candidal infections the dose, as a rule, is 400 mg on the first day, and then – 200 mg/day parenterally. Due to the degree of clinical effect evidence, the dose may be increased up to 400 mg/day parenterally. The duration of therapy depends on clinical effect.

For treatment of oropharyngeal candidiasis the usual dose is between 50 and 100 mg once a day parenterally for 7 - 14 days.

For treatment of atrophic candidiasis of oral cavity, caused by the use of dental prosthesis, the usual dose is 50 mg once a day for 14 days, local antiseptic agents for prosthesis протеза are used concomitantly. For treatment of other candidal infections of the mucous (candidal esophagitis, noninvasive bronchopulmonary infection, candiduria, mucocutaneous candidiasis, etc.), except genital candidiasis, the usual effective dose is between 50 and 100 mg a day for 14 - 30 days.

For prevention of recurrent oropharyngeal candidiasis in AIDS patients after the whole course of the main therapy fluconazol may be indicated in the dose 150 mg once a week.

To decrease the frequency of development of recurrent vaginal candidiasis the dose of 150 mg may be used once a month. The duration of treatment is determined individually, but it should be between 4 and 12 months. Some patients may require frequent use.

For prevention of candidiasis, the recommended dose of fluconazol is 50 - 400 mg once a day due to the risk degree of fungal infection development.

If there is a high risk of generalized infection (for example, in patients with expected, evident or prolonged neutropenia), the recommended dose is 400 mg once a day. Fluconazol is indicated several days before the expected neutropenia; when the number of neutrophils increases to more than 1,000 per 1 mm³, the treatment is continued for more 7 days.

For treatment of skin infections, including foot mycosis, skin mycosis, inguinal dermatomycosis and candidal infections, the recommended dose is 150 mg parenterally once a week. Usually the treatment lasts for 2-4 weeks, but in case of foot mycosis it may last up to 6 weeks.

For treatment of pityriasis versicolor, the recommended dose is 300 mg one a week for 2 weeks; in some patients the treatment may be continued up to three weeks in the same dosage, where as in others a single dose between 300 and 400 mg may be sufficient. The alternative dosage regimen includes 50 mg parenterally once a day for 2 - 4 weeks. For treatment of nail mycosis, the recommended dose is 150 mg once a week. The treatment should be continued until the affected nail changes (a healthy nail grows). This process may vary due to individual peculiarities and patient’s age. The treatment of deep endemic mycosis may require the dose of the preparation between 200 and 400 mg a day up to 2 years. The duration of therapy is individual, but, as a rule, it is 11 - 24 months for treatment of primary coccidioidomycosis, 2 - 17 months for treatment of paracoccidioidomycosis, 1 - 16 months for treatment of sporotrichosis and 3 - 17 months for treatment of histoplasmosis.

Children.

The duration of therapy in children, similar to such kind of infections in adults, depends on clinical and antimycotic effect.

In children the preparation should not be used in daily dose, which exceeds that in adults. Fluconazol is used daily once a day.

For treatment of candidiasis of mucous membranes, the recommended dose is 3 mg/kg/day. On Day 1 a loading dose of 6 mg/kg/day may be indicated in order to achieve equilibrium constant concentrations faster.

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

For prevention of fungal infections in patients with suppressed immunity, whose risk of infection development is associated with neutropenia, developing as the result of cytotoxic chemotherapy or radiation therapy, fluconazol is indicated in the dose of 3 - 12 mg/kg/day due to the severity and duration of the induced neutropenia.

 Children under 4 weeks.

In newborns fluconazol is excreted from the organism more slowly. During first 2 weeks of life, fluconazol is indicated in the same dose (on the basis of 1 kg of body weight), as in children of older age, but with 72-hour interval. Children of 3 - 4 weeks receive the same dose with 48-hour interval.

 Elderly patients.

In patients without renal dysfunction usual dosage regimen should be recommended. In patients with disturbed renal function (creatinine clearance <50 ml/min), the dosage regimen should be as indicated below.

Use in patients with renal dysfunction.

Fluconazol is excreted mainly with urine in the unchanged state. In case of a single use, the dose should be changed. In patients (including children) with renal dysfunction in case of repeated use of the preparation, first it is necessary to introduce the loading dose, which is between 50 and 400 mg.

After loading dose introduction, the daily dose (according to indications) is determined according Table 1.

 Table 1

Creatinine clearance (ml/min)	Per cent of the recommended dose
>50	100%
≤50 (without dialysis)	50%
Patients on regular dialysis	100% after each dialysis

 Fluconazol is introduced as the infusion with the rate not exceeding 10 ml/min.

In case of transition from intravenous to oral way of administration or vice versa, there is no need to change tha daily dose.

 Side effects.

Central nervous system: headache.

Digestive system: abdominal pain, diarrhea, flatulence, nausea.

Liver/biliary tracts: toxic lesions of the liver, including single lethal cases, increased levels of alkaline phosphatase, bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Skin: rash.

In some patients, especially in those, who suffer from severe diseases (AIDS or cancer), during fluconazol therapy there were observed changed indexes of blood, renal and hepatic functions, but clinical manifestations of these changes and their connection to the use of fluconazol solution have not been established.

In addition, after introduction of the preparation in wide medical practice, there have been reports on side effects, listed below.

Hematopoietic and lymphatic system: leucopenia, including neutropenia and agranulocytosis, thrombocytopenia.

Immune system: anaphylactic reaction, including angioneurotic edema, face edema and skin itch, urticaria.

Metabolic processes/peculiarities of nutrition: hypercholesterolemia, hypertriglyceridemia, hypokaliemia.

Central and peripheral nervous system: dizziness, convulsions, taste disturbance.

Cardiovascular system: prolongation of QT interval, paroxysmal ventricular tachycardia of “pirouette” type.

Digestive system: digestion disturbance, vomiting.

Liver/biliary tracts: liver insufficiency, hepatitis, hepatocellular necrosis, jaundice.

Skin and appendages: alopecia, exfoliative skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Overdose.

It is manifested as hallucinations and paranoid behavouor.

The treatment is symptomatic. Forced diuresis may accelerate the excretion of the preparation. Hemodialysis session for 3 hours decreases plasma level of fluconazol approximately by 50%.

Use during pregnancy and lactation.

Not used. In single cases use of the preparation during pregnancy is possible only in case of severe or liver-threatening forms of fungal infections, when expected benefit for the mother overcomes potential risk for the fetus.

If use of the preparation during lactation period is necessary, breast-feeding should be discontinued.

Children.

Age-related limitations on the use of the preparation in children are not described.

Special preventive measures.

In rare cases fluconazol use was accompanied with toxic lesions of the liver, including those with fatal outcomes.

Hepatotoxic action of fluconazol, as a rule, was reversible, its signs resolved after therapy discontinuation. Patients, who demonstrate disturbed indexes of liver function during fluconazol therapy, should be monitored in order to reveal the signs of more severe lesion of the liver. In case of manifestation of liver lesion clinical signs, which may be associated with fluconazol, the preparation should be discontinued.

Very seldom there were observed exfoliative skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more liable to severe skin reactions.

If the patient with superficial fungal infection develop rash, which may be associated with fluconazol, the preparation should be discontinued.

Patients with invasive/systemic fungal infections, who develop rash, should be closely monitored and fluconazol should be discontinued in case of development of bullous lesions or erythema multiforme.

Patients receiving fluconazol in the dose less than 400 mg a day concomitantly with terfenadine should be closely monitored due to the cases of severe arrhythmic disorders.

In single cases – anaphylactic reactions as the result of fluconazol use.

Very seldom there were cases of QT-interval prolongation and ventricle flutter in patients, who take fluconazol.

Fluconazol should be indicated with caution to the patients with known potentially pro-arrhythmic conditions.

Peculiarities of the use.

The therapy may be initiated before receiving the results of culture or other laboratory investigations, and when they are received, antimicrobial preparations are also added.

Compatibility.

Fluconazol for intravenous introduction is compatible with the following solutions:

- Ringer's solution;

- Hartman's solution;

- Solution potassium chloride in dextrose;

- 4.2% solution of sodium bicarbonate;

- Aminofusin;

- 0.9% solution sodium chloride.

Fluconazol may be introduced into infusion system together with one of the solutions listed above. Also the cases of non-specific incompatibility of the preparation with other agents are not described, it is not recommended to mix it with other preparations before the infusion.

Ability to influence the reaction rate when driving or operating other mechanisms.

Experience of fluconazol use testifies to the fact that the decrease of ability to drive and operate mechanisms, associated with the use of the preparation, is unluckily. However, taking into consideration side effects (dizziness), one should be careful when driving and doing work that requires increased concentration of the attention.

 Interaction with other medicinal preparations and other forms of interaction.

Anticoagulants.

In healthy male volunteers, who took warfarin, fluconazol increased prothrombin time by 12%.

In post-registration studies there were reports on bleedings (hematoma formation, nasal hemorrhages, gastrointestinal hemorrhages, hematuria), associate with prothrombin time prolongation in patients, who received fluconazol concomitantly with warfarin. Prothrombin time should be controlled tightly in patients who take coumarin anticoagulants.

Azithromycin.

Concomitant single oral use of azithromycin in the dose of 1200 mg and fluconazol in the dose of 800 mg did not lead to any significant pharmacokinetic interactions between fluconazol and azithromycin. Interaction of fluconazol and azithromycin has no significant pharmacokinetic influence.

Benzodiazepines (short-term action).

In case of midazolam indication, fluconazol use lead to significant increase of midazolam concentrations and development of undesirable psychomotor reactions.

This effect of midazolam is more evident when fluconazol is taken in the form of capsules in comparison with fluconazol introduced intravenously.

If the patient, who receives treatment with fluconazol, need benzodiazepine indication, the dose of the latter should be decreased, and the patient should be monitored closely.

Cisapride.

In case of concomitant use of fluconazol and cisapride there are described single cases of undesirable reactions from the side of heart, including paroxysmal ventricular tachycardia of “pirouette” type. Concomitant indication of fluconazol 200 mg once a day and cisapride 20 mg four times a day lead to significant growth of cisapride concentration in plasma and QT-interval prolongation.

In patients, who receive fluconazol, cisapride is contraindicated.

Cyclosporine.

According to kinetic study results, in grafted kidneys recipient fluconazol in the dose of 200 mg/day increased cyclosporine concentration slowly. However, during another investigation at repeated fluconazol use in the dose of 100 mg/day no changes in level of cyclosporine in the recipient bone marrow were observed. During fluconazol therapy it is recommended to determine blood concentration of cyclosporine.

Hydrochlorthiazide.

During kinetic interaction study in healthy volunteers, receiving fluconazol, repeated use of hydrochlorthiazide lead to increased plasma concentration of fluconazol by 40%. The influence on this index does not require changes of fluconazol doses in patients, using diuretics, but doctors should not forget about possible interaction.

Oral contraceptives.

At administration of fluconazol 50 mg no significant incluence on hormone levels was observed, whereas at administration of 200 mg/day there was observed an increase of area under the curve concentration-time (AUC) of ethinylestradiol by 40% and that one of levonorgestrel by 24%.

In the study of fluconazol administration in the dose of 300 mg once a week, AUC of ethinylestradiol and norethindrone was greater by 24% and 13%, respectively. It is unlikely, that multiple fluconazol intake in the doses mentioned above had negative influence on the effectiveness of combined oral contraceptives.

Phenytoin.

Concomitant indication of fluconazol and phenytoin may be accompanied with increased phenytoin concentration in clinically significant degree.

If the concomitant use of the two preparations is necessary, it is necessary to monitor the level of phenytoin and make dose adjustments in order to provide therapeutic blood concentration.

Rifabutin.

It was reported on interaction of fluconazol and rifabutin with the resulting increase serum level of the latter.

In case of concomitant indication of fluconazol and rifabutin, there were described uveitis cases.

Patients, who receive rifabutin and fluconazol concomitantly, should be monitored closely. 

Rifampicin.

Concomitant indication of fluconazol and rifampicin lead to AUC decrease by 25% and prolongation of fluconazol half-life by 20%.

In patients, who receive rifampicin and fluconazol concomitantly, it is necessary to consider the appropriateness of dose increase of the latter.

Sulphonylurea preparations.

In case of concomitant use, fluconazol increased half-life of oral sulphonylurea preparations (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers.

Fluconazol and oral sulphonylurea preparations may be indicated concomitantly in diabetic patients, but in this case possible development of hypoglycemia should be taken into consideration.

Tacrolimus.

There were reports on interaction of fluconazol and tacrolimus with the resulting increase serum level of the latter. In case of concomitant indication of fluconazol and tacrolimus, there were described cases of increased renal toxicity.

Patients, who receive tacrolimus and fluconazol concomitantly, should be monitored closely.

Terfenadine.

Due to the cases of severe arrhythmic lesions in case of concomitant use of fluconazol and terfenadine there were conducted interaction studies of these preparations.

In the study on fluconazol use in the dose of 200 mg a day QT-interval prolongation was observed. At the use of 400 and 800 mg, it was demonstrated that fluconazol in the dose of 400 mg a day and more increase plasma concentrations of terfenadine significantly.

Concomitant indication of fluconazol in the doses of 400 mg a day and more with terfenadine is contraindicated.

Treatment with fluconazol in the doses less than 400 mg a day in combination with terfenadine should be carried out under tight control.

Theophylline.

Fluconazol administration in the dose of 200 mg for 14 days lead to decreases mean rate of plasma theophylline clearance by 18%.

During fluconazol therapy patients receiving theophylline in high doses, or patients with the increased risk of toxic action of theophylline, should be monitored as for development of theophylline overdose symptoms; if they appear, the therapy should be adjusted accordingly.

Zidovudine.

Kinetic studies demonstrated increased zidovudine levels, which were associated with decreased transformation of the latter into its main metabolite. Patients, receiving such a combination, should be monitored in order to reveal manifestations of zidovudine side effects.

 Astemizole.

Fluconazol use in patients, who receive concomitantly astemizole or other preparations, which metabolized by P450 cytochrome system, may demonstrate increased serum concentrations of these preparations. If reliable data are absent, caution should be exercised in case of concomitant indication of fluconazol. Patients should be monitored closely.

Interaction studies with other medicinal preparations have not been conducted, so their interaction is potentially possible.

Pharmacological properties.

Pharmacodynamics.

Fluconazol is a representative of a new class of triazol antifungal agents, a powerful selective inhibitor of sterole synthesis in fungal cells.

Fluconazol activity has been demonstrated against opportunistic mycosis, including those caused by Candida spp., including generalized candidiasis in animals with suppressed immunity; Сryptococcus neoformans; including intracranial infections; Мисrоsporum spp. and Тychophyton spp.

Fluconazol activity has also been studies on endemic mycosis models in animals, in particular in case of infections, caused by Blastomyces dermatitides, Соссиdioides иттиtis (including intracranial infections) and Ниstoplasma capsulatum in animals with normal and suppressed immunity.

There are known cases of superinfection, caused by Candida species, other than C. albicans, having natural insusceptibility to fluconazol (for example, Candida krusei). Such cases require alternative antimycotic therapy.

Fluconazol is highly specific to Р450 cytochrome-dependant fungal enzymes. Fluconazol in the dose of 50 mg a day for 28 days does not influence plasma concentration of testosterone in men and concentration of steroid hormones in women of child-bearing age.

Fluconazol in the daily dose between 200 and 400 mg does not have a significant clinical effect on the level of endogenous steroids or ACTH-stimulated response in healthy male volunteers. Cross tests with antipyrin indicate on the absence of fluconazol influence on metabolism in the dose of 50 mg in case of single or repeated intake.

Pharmacokinetics.

Plasma concentration of the preparation is proportional to the dose. 90% equilibrium concentration is achieved on Day 4 - 5 of the treatment with the preparation in case of repeated use once a day.

Introduction of the loading dose, which exceeds 2-folds the usual daily dose, in Day 1 allows achieving 90% equilibrium concentration already on Day 2. Real distribution volume of the preparation approximates total water volume in the organism.

The degree of fluconazol plasma protein binding does not exceed 11 - 12%.

Fluconazol achieves high penetrating ability in all studied fluid media of the organism. The levels of the preparation in saliva and sputum are similar, as its plasma concentrations. In patients with fungal meningitis, fluconazol level in cerebrospinal fluid achieves 80% of its plasma concentration.

High levels of fluconazol concentrations in skin, which are higher than serum ones, are achieved in corneal layer, epidermis-derma layer and in sudoriferous glands. Fluconazol is accumulated in skin corneal layer. When the preparation is used in the dose of 50 mg once a day, fluconazol concentration in 12 days was 73 µg/g and in 7 days after therapy termination, the concentration was 5.8 µg/g. In the dose of 150 mg once a week, fluconazol concentration in corneal layer on Day 7 was 23.4 µg/g and in 7 days after the second dose – 7.1 µg/g.

Fluconazol concentration in nails after 4 months of administration in the dose of 150 mg once a week was 4.05 µg/g in healthy nails and 1.8 µg/g in affected ones; fluconazol was found in nail tests in 6 months after therapy termination.

The preparation is excreted mainly by kidneys, and about 80% of the introduced dose is found in urine in the unchanged state.

Its half-life is 30 hours after single oral use in the dose of 150 mg. It allows single fluconazol introduction in case of vaginal candidiasis and using it once a day or once a week in other diseases.