FLUNOL instructions for use, description of the drug FLUNOL: contraindications, side effects, dosages, composition

Description of the drug FLUNOL

When used simultaneously with warfarin, fluconazole increases prothrombin time (by 12%), and therefore bleeding may develop (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time must be constantly monitored.

After oral administration of midazolam, fluconazole significantly increases midazolam concentrations and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally than when administered intravenously. If concomitant benzodiazepine therapy is necessary, patients taking fluconazole should be monitored for an appropriate benzodiazepine dose reduction.

With the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. ventricular fibrillation/flutter (ari). The use of fluconazole at a dose of 200 mg 1 time / day and cisapride at a dose of 20 mg 4 times / day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concomitant use 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 cyclosporine concentrations. However, with repeated doses of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. When using fluconazole and cyclosporine concomitantly, it is recommended to monitor the concentration of cyclosporine in the blood.

Repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in plasma concentrations of fluconazole by 40%. An effect of this magnitude does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but this should be taken into account.

With the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily intake 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 1 time per day week - AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole in 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 concentrations. With this combination, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.

Concomitant use of fluconazole and rifabutin may lead to increased serum concentrations of the latter. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

The simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T1/2 of fluconazole by 20%. In patients concomitantly taking rifampicin, the advisability of increasing the dose of fluconazole must be considered.

Fluconazole, when taken simultaneously, leads to an increase in T1/2 of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide). In patients with diabetes mellitus, fluconazole and oral sulfonylureas can be prescribed together, but the possibility of hypoglycemia should be taken into account.

The simultaneous use of fluconazole and tacrolimus leads to an increase in plasma concentrations of the latter. Cases of nephrotoxicity have been described. Patients with this combination should be carefully monitored.

With the simultaneous use of azole antifungals and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

When used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of developing theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.

When used simultaneously with fluconazole, an increase in zidovudine concentrations is observed, which is likely due to a decrease in the metabolism of the latter 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 found.

When zidovudine 200 mg every 8 hours for 7 days was used in HIV-infected patients with or without fluconazole 400 mg/day with an interval of 21 days between the two regimens, a significant increase in zidovudine AUC was found (74%) when used simultaneously with fluconazole. Patients receiving this combination should be monitored for side effects of zidovudine.

The simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by isoenzymes of the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Patients with such combinations should be carefully monitored.

Flunol capsules 150 mg No. 2x1

Name

Flunol caps. 150 mg per bl. in pack №2x1

Main active ingredient

Fluconazole

Release form

capsules

Compound

1 capsule contains: fluconazole 50 mg, excipients: lactose monohydrate, anhydrous colloidal silicon dioxide (Aerosil 200), corn starch, magnesium stearate (E572), sodium lauryl sulfate (texapon K 12 P) (E478); capsule body: titanium dioxide (E171), gelatin (E441); capsule cover: indigo carmine FD&C blue 2 (E132), titanium dioxide (E171), gelatin (E441).

Description

Dark blue matte/white matte hard gelatin capsules No. 3

Dosage

150mg

Indications for use

Flunol 50 mg is indicated for the treatment of the following diseases in adults: • cryptococcal meningitis (see section "Precautions"); • coccidioidomycosis (see section “Precautions”); • invasive candidiasis; • candidiasis of the mucous membranes, including oropharyngeal candidiasis, esophageal candidiasis, candiduria and chronic candidiasis of the skin and mucous membranes; • chronic atrophic candidiasis of the oral cavity (associated with wearing dentures) with insufficient effectiveness of oral hygiene or local treatment; • acute or recurrent vaginal candidiasis, when local therapy is not appropriate; • candidal balanitis, when local therapy is not appropriate; • dermatomycosis, including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and candidal skin infections if systemic therapy is necessary; • tinea ungium (onychomycosis) in cases where the prescription of other medications is not acceptable. Flunol 50 mg is indicated for the prevention of the following diseases in adults: • relapses of cryptococcal meningitis in patients at high risk of developing relapses; • relapses of oropharyngeal candidiasis or esophageal candidiasis in HIV-infected patients with a high risk of developing relapses; • to reduce the frequency of relapses of vaginal candidiasis (4 or more episodes per year); • for the prevention of candidal infections in patients with prolonged neutropenia (for example, in patients with hematological malignancies undergoing chemotherapy, or patients who have undergone hematopoietic stem cell transplantation. Use of Flunol 50 mg for the treatment of full-term newborns, infants, toddlers and primary school children, as well as adolescents aged 0 to 17 years: The drug can be used in the form of capsules for this category of patients when children are able to swallow the capsule. Flunol 50 mg is not intended for use in children under 6 years of age due to the characteristics of the dosage form. Flunol 50 mg is used for treatment mucosal candidiasis (oropharyngeal candidiasis and esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and the prevention of candidal infections in immunocompromised patients. Flunol 50 mg can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children at high risk of developing relapses (see. section "Precautions"). Therapy can be started before the results of culture and other laboratory research methods become known. However, once these results become known, appropriate adjustments to anti-infective therapy should be made. Official guidelines for the appropriate use of antifungals should be taken into account.

Contraindications

• patients taking fluconazole are contraindicated in the simultaneous administration of drugs that prolong the QT interval and are metabolized by the CYP3A4 isoenzyme of cytochrome P450, such as cisapride, astemizole, pimozide, quinidine and erythromycin; • simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg/day or more; • hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole. The drug is prescribed with caution in case of abnormal liver function tests during the use of fluconazole, when a rash appears during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, with simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day, with potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders.

Use during pregnancy and lactation

Pregnancy The results of an observational study showed an increased risk of spontaneous abortion in women taking fluconazole during the first trimester of pregnancy. Cases of multiple malformations in newborns (including brachycephaly, auricular dysplasia, excessive enlargement of the anterior fontanel, hip curvature, humeroulnar synostosis) whose mothers took high doses of fluconazole (400-800 mg per day) for three or more months for treatment have been described. coccidioidomycosis. The cause-and-effect relationship of these cases to fluconazole is unclear. Animal studies have shown reproductive toxicity of the drug. Fluconazole in standard doses and for short-term treatment should not be used during pregnancy unless the expected benefit significantly outweighs the risk. Fluconazole in high doses and/or long-term use should not be used during pregnancy except in cases of potentially life-threatening infections. Breastfeeding Fluconazole passes into breast milk, and its concentration in breast milk is lower than in blood plasma. Breastfeeding can be continued after a single dose of fluconazole at a standard dose of 200 mg or less. Breastfeeding is not recommended during repeated use of fluconazole or when used in high doses.

Directions for use and doses

Dosage The dose of fluconazole depends on the nature and severity of the fungal infection. For infections that require repeated administration of an antifungal drug, treatment should be continued until clinical or laboratory signs of active fungal infection disappear. Insufficient duration of treatment may lead to recurrence of the fungal infection. Adult patients Indications Dosage regimen Duration of treatment Cryptococcosis - Treatment of cryptococcal meningitis Loading dose: 400 mg on the 1st day. Maintenance dose: 200-400 mg per day Typically for at least 6-8 weeks. In cases of treatment of life-threatening infections, the daily dose can be increased to 800 mg. -Maintenance therapy for the prevention of relapses of cryptococcal meningitis in patients at high risk of developing relapses 200 mg per day For an unlimited period of time at a dose of 200 mg per day. Coccidioidomycosis 200-400 mg for 11-24 months or more, depending on patient response. For the treatment of some forms of injections, especially with damage to the meninges, it may be advisable to use the drug at a dose of 800 mg per day. Invasive candidiasis Loading dose: 800 mg on the 1st day. Maintenance dose: 400 mg per day In general, the recommended duration of therapy for candidemia is 2 weeks after the first negative blood culture result and resolution of signs and symptoms of candidemia. Treatment of candidiasis of the mucous membranes - Oropharyngeal candidiasis Loading dose: 200-400 mg on the 1st day. Maintenance dose: 100-200 mg per day for 7-21 days (until remission of oropharyngeal candidiasis is achieved). In patients with severely impaired immune system function, longer treatment can be carried out - Candidiasis of the esophagus Loading dose: 200-400 mg on the 1st day. Maintenance dose: 100-200 mg per day for 14-30 days (until remission of esophageal candidiasis is achieved). In patients with severely impaired immune system function, longer treatment can be carried out - Candiduria 200-400 mg per day for 7-21 days. In patients with severely impaired immune system function, longer treatment can be carried out - Chronic atrophic candidiasis 50 mg per day for 14 days - Chronic candidiasis of the skin and mucous membranes 50-100 mg per day Up to 28 days, but the duration of treatment can be increased depending on the severity and type of infection or if the immune system is dysfunctional. Prevention of relapses of mucosal candidiasis in HIV-infected patients with a high risk of developing relapses - Oropharyngeal candidiasis 100-200 mg per day or 200 mg 3 times a week for an unlimited period of time in patients with chronically decreased immunity. -Esophageal candidiasis 100-200 mg per day or 200 mg 3 times a week for an unlimited period of time in patients with chronically decreased immunity. Genital candidiasis - Acute vaginal candidiasis - Candidal balanitis 150 mg Once - Treatment and prevention of relapses of vaginal candidiasis (4 or more episodes per year) 150 mg once every three days - a total of 3 doses (on the 1st, 4th and 7th 1st day), followed by taking the drug at a maintenance dose of 150 mg once a week. Maintenance dose: 6 months. Ringworm -tinea pedis, -tinea corporis, -tinea cruris, -candida infection 150 mg once weekly or 50 mg once daily for 2-4 weeks, but treatment for tinea pedis may require up to 6 weeks of therapy. -tinea versicolor 300-400 mg once a week for 1-3 weeks 50 mg once a day for 2-4 weeks -tinea ungium (onychomycosis) 150 mg once a week The course of treatment should be continued until the infected nail is completely replaced (until it grows back) healthy nail). Restoration of fingernails and toenails usually takes 3 to 6 months and 6 to 12 months, respectively. However, growth rates can vary significantly between individuals and depend on age. In some cases, after successful treatment of a long-term chronic infection, the nail plates remain deformed. Prevention of candidal infections in patients with prolonged neutropenia 200-400 mg Treatment should begin several days before the expected development of neutropenia and continue for 7 days after the neutrophil count exceeds 1000 cells per mm3. Special categories of patients Elderly patients The dose of the drug should be adjusted based on the state of renal function (see subsection “Impaired renal function”). Impaired renal function When taking the drug once, no dose adjustment is required. In patients (including children) with impaired renal function, if repeated use of fluconazole is necessary, the initial dose should be from 50 mg to 400 mg, depending on the recommended daily dose for this indication. After which the daily dose of the drug is determined (depending on the indications) in accordance with the following table: Creatinine clearance (ml/min) Percentage of the recommended dose >50 100% ?50 (without dialysis) 50% Regular dialysis 100% after each dialysis procedure For patients Those on regular dialysis must take the drug at 100% of the recommended dose after each session. On days free from dialysis, patients should take a lower dose of the drug, depending on the value of creatinine clearance. Impaired liver function Since there is insufficient information on the use of fluconazole in patients with impaired liver function, fluconazole should be used with caution in this category of patients (see sections "Precautions" and "Side Effects"). Children: In pediatric patients, the maximum dose of 400 mg/day should not be exceeded. As in the case of treatment of corresponding infections in adults, the duration of treatment depends on the clinical effect and the results of microbiological studies. Flunol 50 mg is used daily once a day. Information on children with impaired renal function is given in the subsection “Impaired kidney function”. The pharmacokinetics of fluconazole have not been studied in children with renal failure (for information on “term newborns”, who often have renal immaturity, see below). Children from 6 to 11 years of age Indication Dosage regimen Recommendations - Candidiasis of the mucous membranes Loading dose: 6 mg/kg Maintenance dose: 3 mg/kg per day To more quickly achieve the equilibrium concentration of the drug on the first day, you can receive a loading dose. — Invasive candidiasis — Cryptococcal meningitis Dose: 6-12 mg/kg per day Depending on the severity of the disease. — Maintenance therapy to prevent relapses of cryptococcal meningitis in children at high risk of developing relapses Dose: 6 mg/kg per day Depending on the severity of the disease. — Prevention of candidal infections in immunocompromised patients Dose: 3-12 mg/kg per day Depending on the severity and duration of induced neutropenia (see dosing recommendations in the “Adults” section) Adolescents (aged 12 to 17 years) Depending on body weight and pubertal development, the doctor should evaluate which dose of the drug (for adults or for children) is most optimal for the patient. Clinical data indicate that the clearance of fluconazole is higher in children compared to adults. Doses of 100, 200 and 400 mg in adults and doses of 3, 6 and 12 mg/kg in children result in comparable systemic exposure. The effectiveness and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Currently available data on the safety of the drug for other indications in children are presented in the “Side Effects” section. If it is necessary to use the drug for the treatment of genital candidiasis in adolescents (aged 12 to 17 years), the dosage should be the same as for adults. Method of administration Fluconazole can be administered orally or intravenously, the method of administration depends on the clinical condition of the patient. When switching from intravenous administration to oral administration or vice versa, it is not necessary to change the daily dose of the drug. Capsules are taken orally without opening or chewing, regardless of food intake.

Side effect

The most frequently reported adverse reactions (>1/10) were headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, increased blood alkaline phosphatase levels and rash. When taking fluconazole, the development of the following adverse reactions was observed with the following frequency: very often (?1/10), often (from?1/100 to

Overdose

Symptoms: hallucinations, paranoid state. Treatment: symptomatic, gastric lavage, forced diuresis. Hemodialysis within 3 hours reduces fluconazole plasma concentrations by approximately 50%.

Interaction with other drugs

The combined use of fluconazole and the following drugs is contraindicated: Cisapride: In patients taking fluconazole and cisapride at the same time, the development of cardiac reactions was observed, incl. paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes). In a controlled study, coadministration of fluconazole 200 mg once daily and cisapride 20 mg four times daily resulted in a significant increase in plasma cisapride concentrations and prolongation of the QTc interval. The simultaneous use of fluconazole and cisapride is contraindicated (see section "Contraindications"). Terfenadine: Due to the development of severe cardiac arrhythmias associated with prolongation of the QTc interval, drug interaction studies have been conducted in patients taking azole antifungals concomitantly with terfenadine. In one study, fluconazole 200 mg/day did not prolong the QTc interval. Another study using fluconazole 400 mg/day and 800 mg/day demonstrated that fluconazole at doses of 400 mg/day or higher significantly increased plasma terfenadine levels when these drugs were coadministered. Concomitant use of fluconazole in doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When using fluconazole at a dose of less than 400 mg/day simultaneously with terfenadine, the patient's condition should be carefully monitored. Astemizole: Concomitant use of fluconazole and astemizole may result in decreased clearance of astemizole. The resulting increase in the concentration of astemizole in the blood plasma can, in turn, lead to a prolongation of the QT interval and, in rare cases, to the development of paroxysmal ventricular tachycardia of the torsade de pointes type. The simultaneous use of fluconazole and astemizole is contraindicated (see section “Contraindications”). Pimozide: Although appropriate in vitro or in vivo studies have not been performed, it is believed that concomitant use of fluconazole and pimozide may result in inhibition of the metabolism of pimozide. In turn, an increase in the concentration of pimozide in the blood plasma can lead to a prolongation of the QT interval and, in rare cases, to the development of paroxysmal ventricular tachycardia of the torsades de pointes type. The simultaneous use of fluconazole and pimozide is contraindicated (see section “Contraindications”). Quinidine: Although appropriate in vitro or in vivo studies have not been conducted, it is believed that the combined use of fluconazole and quinidine may lead to inhibition of the metabolism of the latter. The use of quinidine was accompanied by prolongation of the QT interval and, in rare cases, the development of paroxysmal ventricular tachycardia of the torsades de pointes type. The simultaneous use of fluconazole and quinidine is contraindicated (see section "Contraindications"). Erythromycin: Concomitant use of erythromycin and fluconazole increases the risk of cardiotoxicity (QT prolongation, torsade de pointes) and, consequently, sudden coronary death. The simultaneous use of fluconazole and erythromycin is contraindicated (see section "Contraindications"). Amiodarone: Concomitant use of fluconazole in combination with amiodarone may result in inhibition of amiodarone metabolism. Prolongation of the QT interval has been identified with the use of amiodarone. The simultaneous use of fluconazole with amiodarone is contraindicated (see section "Contraindications"). The simultaneous use of fluconazole and the following drugs is not recommended: Halofantrine: Fluconazole may increase the plasma concentration of halofantrine due to its inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine may increase the risk of cardiotoxicity (QT prolongation, torsade de pointes) and, consequently, sudden coronary death. The use of a combination of these drugs should be avoided (see section "Precautions"). Concomitant use with the following medicinal products requires caution and dosage adjustment: Effect of other medicinal products on fluconazole Rifampicin: Concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the half-life of fluconazole. In patients taking rifampicin, consideration should be given to increasing the dose of fluconazole. Drug interaction studies have shown that oral administration of fluconazole with food, with cimetidine, antacids, or after total body irradiation (in preparation for bone marrow transplantation) does not have a clinically significant effect on the absorption of fluconazole. Hydrochlorothiazide: In a pharmacokinetic drug interaction study, repeated administration of hydrochlorothiazide to healthy volunteers receiving fluconazole resulted in a 40% increase in fluconazole plasma concentrations. Given this severity of exposure, there is no need to change the dosage of fluconazole in patients concomitantly taking diuretics. Effect of Fluconazole on other drugs Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9 and a moderate inhibitor of CYP3A4. In addition, fluconazole is an inhibitor of CYP2C19. In addition to the identified/established interactions (listed below), there is a risk of increased plasma concentrations of other drugs that are metabolized by CYP2C9, CYP2C19 and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations of drugs should be used with caution; In this case, it is necessary to carefully monitor the patient's condition. Due to the long half-life of fluconazole, its inhibitory effect on enzymes persists for 4-5 days after the end of treatment (see section “Contraindications”). Alfetanil: In healthy volunteers, coadministration of fluconazole (400 mg) and alfentanil (20 mcg/kg IV) resulted in a twofold increase in AUC10 (probably due to inhibition of CYP3A4). Alfentanil dosage adjustment may be required. Amitriptyline, nortriptyline: Fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and/or S-amitriptyline are recommended to be determined at the beginning of combination therapy and after the first week of treatment. If necessary, the dose of amitriptyline/nortriptyline should be adjusted. Amphotericin B: When fluconazole and amphotericin B were administered concomitantly in infected mice with normal and suppressed immunity, the following results were obtained: a small additive antifungal effect against systemic infection caused by C. albicans; lack of interaction with intracranial infection caused by Cryptococcus neoformans; and antagonism of two drugs in systemic infection due to Aspergillus fumigatus. The clinical significance of the results obtained in these studies is unknown. Anticoagulants: During post-marketing surveillance, there have been reports of bleeding (hematoma formation, epistaxis, gastrointestinal bleeding, hematuria and melena) caused by prolongation of prothrombin time with the simultaneous use of fluconazole and warfarin. Similar phenomena were observed when using other antifungal agents from the azole group. With the simultaneous use of fluconazole and warfarin, a twofold increase in prothrombin time was observed, probably due to inhibition of the metabolism of warfarin mediated by the CYP2C9 isoenzyme. In patients taking coumarin anticoagulants or indancion together with fluconazole, it is recommended to carefully monitor prothrombin time. If necessary, the dose of the anticoagulant should be adjusted. Short-acting benzodiazepines, eg midazolam, triazolam: After oral administration of midazolam and fluconazole, a significant increase in midazolam serum concentrations and increased psychomotor effects were observed. Co-administration of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally led to an increase in AUC and an extension of the half-life of midazolam by 3.7 and 2.2 times, respectively. Concomitant use of fluconazole at a dose of 200 mg/day and triazolam at a dose of 0.25 mg orally led to an increase in AUC and an extension of the half-life of triazolam by 4.4 and 2.3 times, respectively. With the simultaneous use of fluconazole and triazolam, potentiation and prolongation of the effects of trialozam were observed. If concomitant therapy with benzodiazepines is necessary in patients receiving fluconazole, a dosage reduction of the latter should be considered and appropriate monitoring of the patient's condition should be established. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the concentration of carbamazepine in the blood plasma by 30%, which in turn may be accompanied by the development of toxic effects of carbamazepine. It may be necessary to adjust the dose of carbamazepine depending on the level of its concentration in the blood and the severity of the therapeutic effect. Calcium channel blockers: Some calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole may increase the systemic exposure of calcium channel blockers. Close monitoring for adverse reactions is recommended. Celecoxib: With simultaneous use of fluconazole (at a dose of 200 mg/day) and celecoxib (at a dose of 200 mg), an increase in the maximum concentration and AUC of celecoxib was observed by 68% and 134%, respectively. When using celecoxib and fluconazole simultaneously, it may be necessary to reduce the dose of celecoxib by half. Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole leads to an increase in serum bilirubin and creatinine levels. These drugs can be used simultaneously, taking into account the possible risk of increasing the concentration of bilirubin and creatinine in the blood serum. Fentanyl: A case of fatal fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. Additionally, in a study in healthy volunteers, it was demonstrated that fluconazole significantly delayed the elimination of fentanyl. Increased concentrations of fentanyl may lead to respiratory depression. Patients should be carefully monitored for potential risk of respiratory depression. Fentanyl dosage adjustment may be required. HMG-CoA reductase inhibitors: Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP2C9 (such as fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, carefully monitor the patient for symptoms of myopathy and rhabdomyolysis and monitor creatine kinase levels. If there is a marked increase in creatine kinase levels, as well as if myopathy/rhabdomyolysis is suspected or detected, HMG-CoA reductase inhibitors should be stopped. Immunosuppressants (eg, cyclosporine, everolimus, sirolimus and tacrolimus): Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine. With simultaneous use of fluconazole at a dose of 200 mg/day and cyclosporine (at a dose of 2.7 mg/kg/day), an increase in the AUC of cyclosporine by 1.8 times was observed. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration. Everolimus: Although appropriate in vitro and in vivo studies have not been performed, fluconazole is believed to be able to increase serum concentrations of everolimus through inhibition of CYP3A4. Sirolimus: Fluconazole increases plasma concentrations of sirolimus, probably by inhibiting the metabolism of sirolimus by CYP3A4 and P-glycoprotein. This combination can be used subject to dose adjustment of sirolimus depending on the concentration level and severity of the therapeutic effect. Tacrolimus: Fluconazole can increase serum concentrations of tacrolimus up to 5-fold when administered orally by inhibiting the intestinal metabolism of tacrolimus by CYP3A4. When tacrolimus was administered intravenously, no significant changes in pharmacokinetics were observed. Increased serum tacrolimus concentrations have been associated with the development of nephrotoxicity. The dose of tacrolimus for oral administration should be reduced depending on its concentration in the blood. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotesin II receptor antagonism when taking losartan. It is recommended to continuously monitor blood pressure in patients throughout the entire treatment period. Methadone: Fluconazole may increase serum concentrations of methadone. Methadone dose adjustment may be required. Non-steroidal anti-inflammatory drugs (NSAIDs): When co-administered with fluconazole, the Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared with similar values when using flurbiprofen alone. Similarly, when fluconazole and racemic ibuprofen (400 mg dose) were coadministered, the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen were increased by 15% and 82%, respectively, compared with racemic ibuprofen alone. Although targeted studies are lacking, fluconazole is known to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). If these drugs are used together, frequent monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. NSAID dose adjustment may be required. Phenytoin: Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous repeated use of fluconazole 200 mg and phenytoin 250 mg intravenously resulted in an increase in phenytoin AUC24 and Cmin by 75% and 128%, respectively. When using these drugs simultaneously, the concentration of phenytoin in the blood plasma should be monitored to exclude the development of toxic effects of phenytoin. Prednisone: There is a report of the development of acute adrenal insufficiency in a patient after liver transplantation while fluconazole was discontinued after a 3-month course of therapy. Presumably, cessation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased metabolism of prednisone. Patients receiving long-term combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to identify adrenal insufficiency. Rifabutin: Fluconazole increases serum concentrations of rifabutin, resulting in an increase in the AUC of rifabutin by up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described. When using this combination of drugs, it is necessary to take into account the symptoms of toxic effects of rifabutin. Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of the hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Interaction studies between fluconazole and saquinavir/ritonavir have not been conducted, so the interaction may be even more pronounced. Dose adjustment of saquinavir may be required. Sulfonylureas: Studies in healthy volunteers showed that concomitant use of fluconazole with oral sulfonylureas (eg, chlorpropamide, glibenclamide, glipizide, tolbutamide) resulted in a prolongation of their half-life. When used simultaneously with fluconazole, regular monitoring of blood glucose levels and, if necessary, timely reduction of the dose of sulfonylurea drugs is necessary. Theophylline: In a placebo-controlled drug interaction study, fluconazole 200 mg for 14 days reduced the mean plasma clearance rate of theophylline by 18%. When prescribing fluconazole to patients using high doses of theophylline or who are at increased risk of developing theophylline toxicity, it is necessary to monitor the appearance of symptoms of theophylline toxicity. If signs of toxicity occur, appropriate therapy adjustments should be made. Barvinka alkaloids: Despite the lack of targeted studies, it is believed that fluconazole is able to increase the concentrations of Barvinka alkaloids in blood plasma (for example, vincristine and vinblastine) and, thus, lead to the development of neurotoxicity, which may be associated with the inhibiting of the CYP3A4 isoenzyme. Vitamin A: There is a message about one case of the development of undesirable reactions on the part of the central nervous system in the form of a pseudo -poucupo of the brain while using completely transretinoic acid (acidic form of vitamin A) and fluconazole, which were resolved after the cancellation of fluconazole. The use of this combination is possible, but it should be remembered about the possibility of developing undesirable reactions by the central nervous system. Voriconazole (inhibitor of inserfront CYP2C9, CYP2C19 and CYP3A4): simultaneous oral use of a thorikonazole (400 mg every 12 hours, the first day, then 200 mg every 12 hours for 2.5 days) and flkonazole (400 mg on the first day, then according to the first day 200 mg every 24 hours for 4 days) in 8 healthy male volunteers led to an increase in the CMAX and AUC of the Toriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether a decrease in the dose and/or frequencies of the use of funazol or fluconazole leads to the elimination of this effect. When using a toriconazole, together with fluconazole, it is recommended to control the condition of patients for the development of unwanted phenomena associated with the use of a toriconazole. Zidovudine: With oral use, fluconazole reduces Zidovudin clearance by approximately 45% and increases CMAX and AUC Zidovudin by 84% and 74%, respectively. In addition, with simultaneous use with fluconazole, an extension of the half -life of Zidovudin was noted by about 128%. Patients receiving such a combination of drugs should be under supervision in order to identify unwanted reactions associated with the use of zidovudine. If necessary, it is possible to reduce the dose of zidovudin. Azitromycin: to establish the effect of a single -to -rate azithromycin at a dose of 1200 mg on the pharmacokinetics of fluconazole when it is used in a dose of 800 mg, as well as the effect of fluconazole on the pharmacokinetics of azithromycin, open, randomized, trilateral

Instructions for medical use of the drug

FLUNOL® 50 FLUNOL® 150

International nonproprietary name

Fluconazole

Dosage form

Capsules 50 mg, 150 mg

Compound

One capsule contains the active substance - fluconazole 50 mg and 150 mg, excipients: lactose monohydrate, colloidal silicon dioxide (Aerosil 200), corn starch, magnesium stearate, sodium lauryl sulfate, capsule shell composition: body: titanium dioxide (E 171), gelatin , cap for dosage 50 mg: titanium dioxide E 171, sparkling black (E151), gelatin cap for dosage 150 mg: titanium dioxide E 171, iron oxide (III) red (E 172), gelatin Description Hard gelatin capsules size No. 3 c matte white body and matte dark blue cap (for a dosage of 50 mg). Hard gelatin capsules size No. 1 with a matte white body and a matte pink cap (for a dosage of 150 mg).

Pharmacotherapeutic group

Antifungal drugs for systemic use. Triazole derivatives. Fluconazole. Pharmacological properties

Pharmacokinetics

Fluconazole is well absorbed after oral administration, bioavailability is more than 90%. Eating does not affect the absorption of the drug. The maximum concentration is reached after 0.5 - 1.5 hours. Fluconazole penetrates well into body fluids. Levels of fluconazole in saliva and sputum approach its concentration in plasma. In patients with fungal meningitis, the level of fluconazole in the cerebrospinal fluid is about 80% of its plasma level. In the stratum corneum of the epidermis, dermis and sweat glands, high concentrations of fluconazole are achieved, which exceed serum concentrations. Fluconazole binds poorly to plasma proteins (12%). The half-life is 30 hours. Not metabolized. No fluconazole metabolites were detected in peripheral blood. Fluconazole is excreted primarily by the kidneys; approximately 80% of the dose taken is found unchanged in the urine. Pharmacokinetics in special clinical cases In children, the following pharmacokinetic parameters of fluconazole were identified: Age of children Dose (mg/kg) Half-life (hour) AUC (mcg h/ml) 11 days - 11 months Single dose - 3 mg/kg 23 110.1 9 months - 13 years Single dose - orally 2 mg/kg 25.0 94.7 9 months - 13 years Single dose - orally 8 mg/kg 19.5 362.5 5 years - 15 years Repeated dose - 2 mg/kg 17.4 67.4 5 years - 15 years Repeated dose - 4 mg/kg 15.2 139.1 5 years-15 years Repeated dose - 8 mg/kg 17.6 196.7 Average age 7 years Repeated dose - orally 3 mg/kg 15.5 41.6 For premature children (about 28 weeks of development), fluconazole was administered intravenously at a dose 6 mg/kg every 3rd day until a maximum of 5 doses are administered while children remain in the intensive care unit (ICU). The average T1/2 was 74 hours on day 1, decreasing on the 7th day to an average of 53 hours and on the 13th day to an average of 47 hours (range 27-68 hours). AUC values were 271 mcg x h/mL on day 1, increased to 490 mcg x h/mL on day 7, and decreased to an average of 360 mcg x h/mL by day 13. Vd was 1183 ml/kg on day 1, then increased to an average of 1184 ml/kg on day 7 and to 1328 ml/kg on day 13.

Pharmacodynamics Fluconazole

– a representative of the class of triazole antifungal agents, is a selective inhibitor of ergosterol synthesis in the fungal membrane. Increases the permeability of the cell membrane, disrupts its growth and replication. Pharmacological effect - fungicidal. It has a specific effect on fungal enzymes dependent on cytochrome P450. Does not have antiandrogenic activity. Treatment with fluconazole 50 mg/day for 28 days did not affect blood testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole is effective against superficial and systemic fungal infections caused by Candida spp., Cryptococcus neoformans, Coccidiodes immitis, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Histoplasma capsulatum.

Indications for use

- genital candidiasis, acute or recurrent vaginal candidiasis, prophylaxis to reduce the frequency of relapses of vaginal candidiasis, candidal balanitis - candidiasis of the mucous membranes, including the mucous membranes of the mouth, pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic candidiasis oral cavity - dermatomycosis, including mycoses of the feet, smooth skin of the trunk, limbs, pityriasis versicolor, skin candidal infections - generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infections, such as infections of the peritoneum, endocardium, respiratory and urinary tract, in including in patients with malignant tumors who are in intensive care units and receiving cytotoxic or immunosuppressive therapy, as well as in patients with other factors predisposing to the development of candidiasis - cryptococcosis, including cryptococcal meningitis and infections of other localizations (for example, lungs, skin), incl. in patients with a normal immune response and patients with AIDS, organ transplant recipients and patients with other forms of immunodeficiency; maintenance therapy to prevent relapses of cryptococcosis in patients with AIDS - prevention of fungal infections in patients with malignant neoplasms predisposed to the development of such infections as a result of cytotoxic chemotherapy or radiation therapy

Directions for use and doses

Adults: - for oropharyngeal candidiasis, on the first day the drug is usually prescribed at 200 mg, then continued at 100 mg once a day. Treatment is continued for 2 weeks to reduce the likelihood of relapse. — For vaginal candidiasis, take a single dose orally at a dose of 150 mg. To reduce the frequency of relapses of vaginal candidiasis, the drug can be used at a dose of 150 mg once a month. The duration of therapy is determined individually - it varies from 4 to 12 months. — For chronic recurrent vulvo-vaginal candidiasis (relapse rate 4 or more times a year), pulse therapy is recommended: 150 mg once a week for 1-3 months. — For candidal balanitis – 150 mg once. — For mycosis of the skin, the recommended dose is 150 mg once a week. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy (up to 6 weeks) may be required. — For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until an uninfected nail grows out. Fingernails and toenails normally take 3-6 and 6-12 months to re-grow, respectively. — For pityriasis versicolor, 300 mg once a week for 2 weeks. The maximum daily dose for adults should not be exceeded in children. Fluconazole is taken every day in a single dose. 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 patients with immunodeficiency, considered at risk due to neutropenia, receiving cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day, depending on the severity and duration of persistence of induced neutropenia. Use in the elderly In the absence of signs of renal failure, the drug is prescribed at the usual dose. Use in patients with renal failure With a single dose, no dose change is required. In patients with impaired renal function, with repeated use of the drug, a loading dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indication) is set according to the following table: Creatinine clearance (ml/min) Percentage of recommended dose > 50 ≤50 (without dialysis) Regular dialysis 100% 50% 100% after each dialysis Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on days when there is no dialysis, patients should receive a reduced dose according to their creatinine clearance.

Side effects

Common (from ≥1/100 to <1/10) - headache - abdominal pain, diarrhea, nausea, vomiting - increased levels of alkaline phosphatase, serum aminotransferase levels (ALT and AST) - rash Uncommon (from ≥1/1,000 to ≤1/100) - insomnia, drowsiness - convulsions, dizziness, paresthesia, change in taste - vertigo - dyspepsia, flatulence, dry mouth - cholestasis, jaundice, increased bilirubin - itching, urticaria, increased sweating, dermatitis - myalgia - fatigue, malaise , weakness, increased body temperature Rarely (from ≥1/10,000 to ≤1/1,000) - agranulocytosis, leukopenia, neutropenia, thrombocytopenia - anaphylaxis, angioedema - hypertriglyceridemia, hypercholesterolemia, hypokalemia - tremor - tachycardia, ventricular fibrillation/flutter, increased interval QT - hepatotoxicity, including rare cases with fatal outcome, liver failure, hepatocellular necrosis, hepatitis, hepatocellular damage - toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, facial edema, alopecia In patients with AIDS or cancer, with During treatment with fluconazole and similar drugs, changes in blood counts, renal and liver function were observed, but the clinical significance of these changes and their relationship with treatment have not been established.

Contraindications

hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole - simultaneous use of terfenadine during repeated doses of fluconazole at a dose of 400 mg / day or more - simultaneous use of drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine  hereditary lactose intolerance, Lapp-lactase enzyme deficiency, glucose-galactose malabsorption  pregnancy and lactation period  children under 18 years of age With caution Impaired liver function tests during the use of fluconazole; the appearance of a rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections; potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

Drug interactions

With simultaneous use of FLUNOL® 50, FLUNOL® 150: - with coumarin anticoagulants - fluconazole increases prothrombin time. Patients receiving coumarin anticoagulants should be under strict medical supervision - with cisapride - cases of adverse cardiac events have been described, including paroxysms of ventricular tachycardia (AR) - with cyclosporine - monitoring of the concentration of cyclosporine in the blood is recommended, as it may increase; - with hydrochlorothiazide - leads to an increase in the concentration of fluconazole in the blood by 40%. However, this does not require a change in dosage regimen - with ethinyl estradiol and levonorgestrel - fluconazole increases their areas under the concentration-time curve (AUC). However, this does not affect the effectiveness of the combined oral contraceptive drug - with phenytoin - a significant increase in phenytoin concentrations may be observed. If it is necessary to use combined treatment with phenytoin, monitoring the level of the latter is necessary, and adequate dose selection to ensure therapeutic concentrations in serum - with rifampicin - leads to a decrease in AUC of fluconazole by 25% and T1/2 by 20%. It is necessary to take into account the advisability of increasing the dose of fluconazole - with oral hypoglycemic agents (sulfonylurea derivatives) - fluconazole prolongs their half-life. Frequent monitoring of blood glucose and a corresponding reduction in the dose of sulfonylurea are recommended - with antifungals from the group of azole derivatives, with terfenadine and astemizole - the likelihood of developing serious arrhythmias with prolongation of the QT interval increases (if necessary, the use of such a combination requires careful medical monitoring) - with theophylline - possible prolongation the half-life of theophylline from plasma and the development of symptoms of its overdose; - with zidovudine - leads to an increase in the concentration of zidovudine in plasma. Patients receiving this combination should be monitored for side effects of zidovudine - with antipyrine - fluconazole at a dose of 50 mg does not affect the metabolism of antipyrine - with midazolam - fluconazole significantly increases the concentration of midazolam and psychomotor effects; - with triazolam - increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32% and t½ by 25-50%, due to inhibition of triazolam metabolism. Triazolam dose adjustment may be required - with benzodiazepines - close monitoring is necessary to ensure appropriate benzodiazepine dose reduction - with calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) - fluconazole may significantly increase the systemic exposure of calcium channel antagonists. Frequent monitoring for side effects of drugs is recommended - with non-steroidal anti-inflammatory drugs (celecoxib, flurbiprofen, ibuprofen, naproxen, lornoxicam, meloxicam, diclofenac) - increases the Cmax and AUC of NSAIDs. Frequent monitoring for NSAID-related adverse effects and toxicities is recommended. Dose adjustment may be required. NSAIDs - with cyclophosphamide - increases serum bilirubin and creatinine levels. The combination can be used before there is a risk of increased serum bilirubin and creatinine levels - with fentanyl - fluconazole significantly delays the elimination of fentanyl. Elevated concentrations of fentanyl can lead to respiratory failure - alfentanil: with simultaneous therapy with fluconazole, a decrease in clearance and volume of distribution, as well as a prolongation of the elimination period of alfentanil, is observed. A possible mechanism of action is inhibition of the CYP3A4 enzyme by fluconazole. A dose adjustment of alfentanil may be required - with halofantrine - fluconazole may increase plasma concentrations of halofantrine due to an inhibitory effect on CYP3A4; - with hydroxymethylglutaryl-A reductase (HMG-CoA reductase) inhibitors - the risk of myopathy and acute skeletal muscle necrosis (rhabdomyolysis) increases when fluconazole is prescribed concomitantly with HMG-CoA reductase inhibitors that are metabolized through CYP3A4, such as atorvastatin and simvastatin, or via CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. HMG-CoA reductase inhibitors should be discontinued if a significant increase in creatine kinase levels is observed, or if myopathy/rhabdomyolysis is diagnosed or suspected - with losartan - fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most antagonism of angiotensin II receptors, which occurs during treatment with losartan. Patients should monitor blood pressure closely - with methadone - serum concentrations of methadone increase, methadone dosage adjustment may be required - with vinca alkaloid - may increase plasma levels of vinca alkaloid (eg, vincristine and vinblastine) and lead to neurotoxicity due to inhibitory effects on CYP3A4 - with vitamin A - careful monitoring of patients is required in order to identify side effects associated with the central nervous system - with voriconazole - simultaneous administration of voriconazole and fluconazole at any dose is not recommended. Concomitant use of oral voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) led to an increase in the concentration and AUC of voriconazole by an average of 57% (9% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively - with cimetidine, antacids - no clinically significant effect was observed on the absorption of fluconazole - with prednisolone - patients on long-term treatment with fluconazole and prednisolone should be monitored for the development of adrenal insufficiency after discontinuation of fluconazole - with rifabutin - increases serum rifabutin levels up to 80%. Cases of uveitis have been reported in patients who were simultaneously prescribed fluconazole and rifabutin. Careful monitoring of the condition of patients receiving rifabutin and fluconazole simultaneously with saquinavir is necessary - the AUC of saquinavir increases by approximately 50%, Cmax by approximately 55% and reduces the clearance of saquinavir by approximately 50% due to inhibition of the hepatic metabolism of saquinavir via CYP3A4 and inhibition of P-glycoprotein. Dose adjustments of saquinavir may be necessary; - with sirolimus - the plasma concentration of sirolimus increases, presumably by inhibiting the metabolism of sirolimus through CYP3A4 and P-glycoprotein. This combination may be used to adjust the dose of sirolimus based on effect/concentration measurements; - with tacrolimus - serum concentrations of tacrolimus when taken orally may increase up to 5-fold due to inhibition of the metabolism of tacrolimus in the intestine via CYP3A4. No significant pharmacokinetic changes were observed with intravenous tacrolimus. Increased tacrolimus levels have been associated with nephrotoxicity. The dosage of oral tacrolimus should be reduced depending on the concentration of the drug - amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and/or S-amitriptyline may be measured at the start of combination therapy and after one week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted - carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the concentration of the latter in the blood serum by 30%. There is a risk of carbamazepine toxicity. Carbamazepine dosage adjustments may be necessary based on concentration/effect measurements.

special instructions

Treatment must be continued until clinical and mycological remission of the disease occurs. Premature cessation of treatment leads to relapses. Treatment can begin before receiving the results of culture or other laboratory tests, with subsequent correction of fungicidal therapy based on the results of the studies. During treatment, it is necessary to monitor blood counts, kidney and liver function. If renal or liver dysfunction occurs, you should stop taking the drug. In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including death, mainly in patients with concomitant diseases. Patients whose liver function tests are impaired during treatment with fluconazole should be monitored for signs of 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. The hepatotoxic effect of fluconazole is usually reversible, and symptoms disappear after discontinuation of therapy. If skin rashes occur in patients with immunosuppression, careful observation is necessary, and if the skin reaction progresses, treatment should be discontinued (risk of developing Stevens-Johnson syndrome, Lyell's syndrome). People with AIDS are more likely to develop severe skin reactions. If a patient receiving treatment for a superficial fungal infection develops a rash that can be associated with fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme appear. In rare cases, anaphylactic reactions have been observed. Fluconazole may cause prolongation of the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation/flutter were observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalances and concomitant therapy that contributes to the development of such disorders. Therefore, fluconazole should be used with caution in such patients with potentially proarrhythmic conditions. Patients with liver, heart and kidney diseases are advised to consult a doctor before use. When using Flunol® 50 mg or Flunol® 150 for vaginal candidiasis, patients should be warned that improvement in symptoms is usually observed after 24 hours, but sometimes takes several days for them to completely disappear. Fluconazole is a strong CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Patients receiving treatment with fluconazole who are taking concomitant therapy with drugs with a narrow therapeutic window that are metabolized through CYP2C9 and CYP3A4 should be monitored. Flunol® 50 or Flunol® 150 should be taken with caution by patients with renal dysfunction. Pediatric Population The examples and incidence of adverse events and laboratory abnormalities observed in children are comparable to those observed in adults. Pregnancy and lactation During pregnancy, the use of the drug should be avoided, except in patients with severe or potentially life-threatening fungal infection for whom fluconazole can be used if the expected benefit is higher than the possible risk to the fetus. Use during breastfeeding Fluconazole has been found in breast milk at concentrations similar to those found in plasma and is therefore not recommended for use in nursing mothers. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous machinery Patients should be informed about the dangers associated with driving vehicles, servicing mechanical equipment and other potentially hazardous activities. Overdose Symptoms: hallucinations, paranoid behavior. Treatment: supportive and symptomatic therapy is used, if necessary, gastric lavage. Since fluconazole is excreted primarily in the urine, forced diuresis is likely to increase the rate of elimination. A 3-hour hemodialysis session reduces the plasma concentration of fluconazole by approximately 50%.

Release form

and packaging 7 capsules (for a dosage of 50 mg) or 1 or 2 capsules (for a dosage of 150 mg) are placed in a blister pack made of transparent polyvinyl chloride film and printed aluminum foil. 1 or 2 (for a dosage of 50 mg) or 1 (for a dosage of 150 mg) blister packs together with instructions for medical use in the state and Russian languages are placed in a cardboard pack with a hologram of the manufacturer .

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 0C. Keep out of the reach of children!

Shelf life

4 years Do not use after expiration date
Attention! The description of the drug on this page is simplified. Before purchasing and using the drug, consult your doctor or pharmacist, and also read the instructions approved by the manufacturer. Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. ATTENTION! This section is provided for informational purposes only and is not a catalog or price list of our company. To obtain information about the availability of drugs, call + 99871 202 0999 Pharmacy Network Helpline 999.

Flunol syrup 25mg/5ml 70.0 ml (fluconazole)

Full description

[RU]

Tradename

FLUNOL® 50

FLUNOL® 150

International nonproprietary name

Fluconazole

Dosage form

Capsules 50 mg, 150 mg

Compound

One capsule contains

active substance – fluconazole 50 mg and 150 mg,

excipients: lactose monohydrate, colloidal silicon dioxide (Aerosil 200), corn starch, magnesium stearate, sodium lauryl sulfate,

capsule shell composition:

body: titanium dioxide (E 171), gelatin,

cap for 50 mg dosage: titanium dioxide E 171, sparkling black (E151), gelatin

cap for dosage 150 mg: titanium dioxide E 171, iron oxide (III) red (E 172), gelatin

Description

Hard gelatin capsules size No. 3 with a matte white body and a matte dark blue cap (for a dosage of 50 mg).

Hard gelatin capsules size No. 1 with a matte white body and a matte pink cap (for a dosage of 150 mg).

Pharmacotherapeutic group

Antifungal drugs for systemic use. Triazole derivatives. Fluconazole.

ATX code J02AC01

Pharmacological properties

Pharmacokinetics

In the stratum corneum of the epidermis, dermis and sweat glands, high concentrations of fluconazole are achieved, which exceed serum concentrations. Fluconazole binds poorly to plasma proteins (12%). The half-life is 30 hours. Not metabolized. No fluconazole metabolites were detected in peripheral blood. Fluconazole is excreted primarily by the kidneys; approximately 80% of the dose taken is found unchanged in the urine.

Pharmacokinetics in special clinical situations

The following pharmacokinetic parameters of fluconazole were identified in children:

Children's age	Dose (mg/kg)	Half-life (hour)	AUC (mcg h/ml)
11 days - 11 months	Single dose - 3 mg/kg	23	110.1
9 months - 13 years	Single dose - orally 2 mg/kg	25.0	94.7
9 months - 13 years	Single dose - orally 8 mg/kg	19.5	362.5
5 years - 15 years	Repeated dose - 2 mg/kg	17.4	67.4
5 years - 15 years	Repeated dose - 4 mg/kg	15.2	139.1
5 years - 15 years	Repeated dose - 8 mg/kg	17.6	196.7
Average age 7 years	Multiple dose - orally 3 mg/kg	15.5	41.6

In preterm infants (approximately 28 weeks of development), fluconazole was administered IV at a dose of 6 mg/kg every 3rd day for a maximum of 5 doses while the infants remained in the intensive care unit (ICU). The average T1/2 was 74 hours on day 1, decreasing on the 7th day to an average of 53 hours and on the 13th day to an average of 47 hours (range 27-68 hours).

AUC values were 271 mcg x h/mL on day 1, increased to 490 mcg x h/mL on day 7, and decreased to an average of 360 mcg x h/mL by day 13.

Vd was 1183 ml/kg on day 1, then increased to an average of 1184 ml/kg on day 7 and to 1328 ml/kg on day 13.

Pharmacodynamics

Fluconazole, a member of the class of triazole antifungal agents, is a selective inhibitor of ergosterol synthesis in the fungal membrane. Increases the permeability of the cell membrane, disrupts its growth and replication. Pharmacological effect - fungicidal. It has a specific effect on fungal enzymes dependent on cytochrome P450. Does not have antiandrogenic activity. Treatment with fluconazole 50 mg/day for 28 days did not affect blood testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole is effective against superficial and systemic fungal infections caused by Candida spp., Cryptococcus neoformans, Coccidiodes immitis, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Histoplasma capsulatum.

Indications for use

- genital candidiasis, acute or recurrent vaginal candidiasis, prophylaxis to reduce the frequency of relapses of vaginal candidiasis, candidal balanitis

— candidiasis of the mucous membranes, including the mucous membranes of the mouth, pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic candidiasis of the oral cavity

— dermatomycosis, including mycoses of the feet, smooth skin of the trunk, limbs, pityriasis versicolor, skin candidiasis infections

- generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, respiratory and urinary tract, including in patients with malignant tumors in intensive care units and receiving cytotoxic or immunosuppressive therapy, and also in patients with other factors predisposing to the development of candidiasis

— cryptococcosis, including cryptococcal meningitis and infections of other localizations (for example, lungs, skin), incl. in patients with normal

immune response and AIDS patients, organ transplant recipients and patients with other forms of immunodeficiency; maintenance therapy to prevent relapses of cryptococcosis in patients with AIDS

- prevention of fungal infections in patients with malignant neoplasms predisposed to the development of such infections as a result of cytotoxic chemotherapy or radiation therapy

Directions for use and doses

For adults:

for oropharyngeal candidiasis, on the first day the drug is usually prescribed at 200 mg, then continued at 100 mg once a day. Treatment is continued for 2 weeks to reduce the likelihood of relapse.
For vaginal candidiasis, take a single dose of 150 mg orally. To reduce the frequency of relapses of vaginal candidiasis, the drug can be used at a dose of 150 mg once a month. The duration of therapy is determined individually - it varies from 4 to 12 months.
For chronic recurrent vulvo-vaginal candidiasis (relapse rate 4 or more times a year), pulse therapy is recommended: 150 mg once a week for 1-3 months.
For candidal balanitis - 150 mg once.
For mycosis of the skin, the recommended dose is 150 mg once a week. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy (up to 6 weeks) may be required.
For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until an uninfected nail grows out. Fingernails and toenails normally take 3-6 and 6-12 months to re-grow, respectively.
For pityriasis versicolor, 300 mg once a week for 2 weeks.

The maximum daily dose for adults should not be exceeded in children. Fluconazole is taken every day in a single dose.

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 patients with immunodeficiency, considered at risk due to neutropenia, receiving cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day, depending on the severity and duration of persistence of induced neutropenia.

Use in the elderly

In the absence of signs of renal failure, the drug is prescribed at the usual dose.

Use in patients with renal failure

With a single dose, no dose change is required. In patients with impaired renal function, with repeated use of the drug, a loading dose of 50 mg to 400 mg should initially be administered, after which the daily dose (depending on the indication) is set according to the following table:

Creatinine clearance (ml/min)

Percentage of recommended dose

> 50

≤50 (without dialysis)

Regular dialysis

100 %

50 %

100% after every dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on days when there is no dialysis, patients should receive a reduced dose according to their creatinine clearance.

Side effects

Common (≥1/100 to <1/10)

headache
abdominal pain, diarrhea, nausea, vomiting
increased levels of alkaline phosphatase, serum levels of aminotransferases (ALT and AST)
rash

Uncommon (≥1/1,000 to ≤1/100)

insomnia, drowsiness
convulsions, dizziness, paresthesia, change in taste
vertigo
dyspepsia, flatulence, dry mouth
cholestasis, jaundice, increased bilirubin
itching, urticaria, increased sweating, dermatitis
myalgia
fatigue, malaise, weakness, increased body temperature

Rare (≥1/10,000 to ≤1/1,000)

agranulocytosis, leukopenia, neutropenia, thrombocytopenia
anaphylaxis, angioedema
hypertriglyceridemia, hypercholesterolemia, hypokalemia
tremor

tachycardia, ventricular fibrillation/flutter, increased QT interval
hepatotoxicity, including rare cases of death, liver failure, hepatocellular necrosis, hepatitis, hepatocellular injury
toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, facial edema, alopecia

In patients with AIDS or cancer, changes in blood counts, renal and liver function have been observed during treatment with fluconazole and similar drugs, but the clinical significance of these changes and their relationship to treatment have not been established.

Contraindications

hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole
simultaneous use of terfenadine during repeated doses of fluconazole at a dose of 400 mg/day or more
concomitant use of drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine
hereditary lactose intolerance, Lapp-lactase enzyme deficiency, glucose-galactose malabsorption
pregnancy and lactation
children under 18 years of age

Carefully

Impaired liver function parameters due to the use of fluconazole; the appearance of a rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections; potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

Drug interactions

With simultaneous use of FLUNOL® 50, FLUNOL® 150:

with coumarin anticoagulants - fluconazole increases prothrombin time. Patients receiving coumarin anticoagulants should be under strict medical supervision
with cisapride - cases of adverse cardiac events have been described, including paroxysms of ventricular tachycardia (AR)
with cyclosporine - it is recommended to control the concentration of cyclosporine in the blood, as it may increase;
with hydrochlorothiazide - leads to an increase in the concentration of fluconazole in the blood by 40%. However, this does not require a change in dosage regimen
with ethinyl estradiol and levonorgestrel - fluconazole increases their areas under the concentration-time curve (AUC). However, this does not affect the effectiveness of the combined oral contraceptive drug
with phenytoin - a significant increase in phenytoin concentrations may be observed. If it is necessary to use combined treatment with phenytoin, it is necessary to control the level of the latter and adequate dose selection to ensure therapeutic concentrations in the serum
with rifampicin - leads to a decrease in fluconazole AUC by 25% and T1/2 by 20%. It is necessary to consider the advisability of increasing the dose of fluconazole
with oral hypoglycemic agents (sulfonylurea derivatives) - fluconazole prolongs their half-life. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended
with antifungal drugs from the group of azole derivatives, with terfenadine and astemizole - the likelihood of developing serious arrhythmias with prolongation of the QT interval increases (if necessary, the use of such a combination requires careful medical supervision)
with theophylline - it is possible to lengthen the half-life of theophylline from plasma and develop symptoms of its overdose;
with zidovudine - leads to an increase in the concentration of zidovudine in plasma. Patients receiving this combination should be monitored for side effects of zidovudine.
with antipyrine - fluconazole at a dose of 50 mg does not affect the metabolism of antipyrine
with midazolam - fluconazole significantly increases the concentration of midazolam and psychomotor effects;
with triazolam - increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32% and t½ by 25-50%, due to inhibition of triazolam metabolism. Triazolam dose adjustment may be required
with benzodiazepines - careful monitoring is necessary in order to reduce the benzodiazepine dose accordingly
with slow calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) - fluconazole can significantly increase the systemic exposure of calcium channel antagonists. Frequent monitoring for drug side effects is recommended
with non-steroidal anti-inflammatory drugs (celecoxib, flurbiprofen, ibuprofen, naproxen, lornoxicam, meloxicam, diclofenac) - increases the Cmax and AUC of NSAIDs. Frequent monitoring for NSAID-related adverse effects and toxicities is recommended. NSAID dose adjustment may be required
with cyclophosphamide - increases the levels of bilirubin and creatinine in the blood serum. The combination may be used before there is a risk of increased serum bilirubin and creatinine levels
with fentanyl - fluconazole significantly delays the elimination of fentanyl. Elevated concentrations of fentanyl may lead to respiratory failure
alfentanil: with simultaneous therapy with fluconazole, a decrease in clearance and volume of distribution, as well as an extension of the elimination period of alfentanil, is observed. A possible mechanism of action is inhibition of the CYP3A4 enzyme by fluconazole. Alfentanil dose adjustment may be required
with halofantrine - fluconazole may increase plasma concentrations of halofantrine due to an inhibitory effect on CYP3A4;
with hydroxymethylglutaryl-A reductase (HMG-CoA reductase) inhibitors - the risk of myopathy and acute skeletal muscle necrosis (rhabdomyolysis) increases when fluconazole is prescribed concomitantly with HMG-CoA reductase inhibitors that are metabolized through CYP3A4, such as atorvastatin and simvastatin , or via CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. HMG-CoA reductase inhibitors should be discontinued if a significant increase in creatine kinase levels is observed or if myopathy/rhabdomyolysis is diagnosed or suspected.
with losartan - fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the angiotensin II receptor antagonism that occurs during treatment with losartan. Patients should constantly monitor blood pressure
with methadone – the concentration of methadone in the blood serum increases, methadone dosage adjustment may be required
with vinca alkaloid—may increase plasma levels of vinca alkaloid (eg, vincristine and vinblastine) and lead to neurotoxicity due to inhibitory effects on CYP3A4
with vitamin A – close monitoring of patients is required to identify CNS-related side effects
with voriconazole - simultaneous administration of voriconazole and fluconazole at any dose is not recommended. Concomitant use of oral voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in voriconazole concentration and AUC of 57% (9% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively.
with cimetidine, antacids - no clinically significant effect on the absorption of fluconazole is observed
with prednisolone - patients on long-term treatment with fluconazole and prednisolone should be monitored for the development of adrenal insufficiency after discontinuation of fluconazole
with rifabutin – increases serum rifabutin levels by up to 80%. Cases of uveitis have been reported in patients who were simultaneously prescribed fluconazole and rifabutin. Careful monitoring of the condition of patients receiving rifabutin and fluconazole simultaneously is necessary.
with saquinavir - increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55% and reduces the clearance of saquinavir by approximately 50% due to inhibition of the hepatic metabolism of saquinavir via CYP3A4 and inhibition of P-glycoprotein. Dose adjustments of saquinavir may be necessary;
with sirolimus - the plasma concentration of sirolimus increases, presumably by inhibiting the metabolism of sirolimus through CYP3A4 and P-glycoprotein. This combination may be used to adjust the dose of sirolimus based on effect/concentration measurements;
with tacrolimus - serum concentrations of tacrolimus when taken orally may increase up to 5-fold due to inhibition of the metabolism of tacrolimus in the intestine via CYP3A4. No significant pharmacokinetic changes were observed with intravenous tacrolimus. Increased tacrolimus levels have been associated with nephrotoxicity. The dosage of oral tacrolimus should be reduced depending on the drug concentration
amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and/or S-amitriptyline may be measured at the start of combination therapy and after one week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted
carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the concentration of the latter in the blood serum by 30%. There is a risk of carbamazepine toxicity. Carbamazepine dosage adjustments may be necessary based on concentration/effect measurements.

special instructions

Fluconazole may cause prolongation of the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation/flutter were observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalances and concomitant therapy that contributes to the development of such disorders. Therefore, fluconazole should be used with caution in such patients with potentially proarrhythmic conditions.

Patients with liver, heart and kidney diseases are advised to consult a doctor before use.

When using Flunol® 50 mg or Flunol® 150 for vaginal candidiasis, patients should be warned that improvement in symptoms is usually observed after 24 hours, but sometimes takes several days for them to completely disappear.

Fluconazole is a strong CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Patients receiving treatment with fluconazole who are taking concomitant therapy with drugs with a narrow therapeutic window that are metabolized through CYP2C9 and CYP3A4 should be monitored.

Flunol® 50 or Flunol® 150 should be taken with caution by patients with renal dysfunction.

Pediatric population

Examples and cases of adverse events and laboratory abnormalities that were observed in children are comparable to those observed in adults.

Pregnancy and lactation

During pregnancy, the use of the drug should be avoided, except in patients with severe or potentially life-threatening fungal infection for whom fluconazole can be used if the expected benefit is higher than the possible risk to the fetus.

Use during breastfeeding

Fluconazole has been found in breast milk at plasma concentrations and is therefore not recommended for use in nursing mothers.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

Patients should be informed about the hazards associated with driving vehicles, servicing mechanical equipment, and other potentially hazardous activities.

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: supportive and symptomatic therapy is used, if necessary, gastric lavage. Since fluconazole is excreted primarily in the urine, forced diuresis is likely to increase the rate of elimination. A 3-hour hemodialysis session reduces the plasma concentration of fluconazole by approximately 50%.

Release form and packaging

7 capsules (for a dosage of 50 mg) or 1 or 2 capsules (for a dosage of 150 mg) are placed in a blister pack made of transparent polyvinyl chloride film and printed aluminum foil.

1 or 2 (for a dosage of 50 mg) or 1 (for a dosage of 150 mg) blister packs together with instructions for medical use in the state and Russian languages are placed in a cardboard pack with a hologram of the manufacturer.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 0C.

Keep out of the reach of children!

Shelf life

4 years

Do not use after expiration date

Conditions for dispensing from pharmacies

On prescription

The Republic of Kazakhstan

Almaty, st. Shevchenko 162 E.

Registration Certificate Holder

JSC "Nobel Almaty Pharmaceutical Factory"

The Republic of Kazakhstan

Address of the organization that accepts claims from consumers regarding the quality of products (products) on the territory of the Republic of Kazakhstan:

JSC "Nobel Almaty Pharmaceutical Factory"

Republic of Kazakhstan, Almaty, st. Shevchenko 162 E.

Phone number: (+7

Fax number: (+7

E-mail address

Flunol 150 mg No. 1 caps.

Instructions for medical use of the drug FLUNOL® 150 Trade name FLUNOL® 150 International nonproprietary name Fluconazole Dosage form Capsules, 150 mg Composition One capsule contains the active substance - fluconazole 150 mg, excipients: lactose monohydrate, corn starch, colloidal anhydrous silica (Aerosil 200), sodium lauryl sulfate, magnesium stearate, capsule shell composition: capsule body: titanium dioxide (E 171), gelatin, capsule cap: iron oxide (III) red (E 172), titanium dioxide (E 171), gelatin. Description Hard gelatin capsules size No. 1 with a matte white body and a matte pink cap. The contents of the capsule are a homogeneous white powder, odorless. Pharmacotherapeutic group Antifungal drugs for systemic use. Triazole derivatives. Fluconazole. ATC code J02AC01 Pharmacological properties Pharmacokinetics Fluconazole is well absorbed after oral administration, bioavailability is more than 90%. Eating does not affect the absorption of the drug. The maximum concentration is reached after 0.5 - 1.5 hours. Fluconazole penetrates well into body fluids. Levels of fluconazole in saliva and sputum approach its concentration in plasma. In patients with fungal meningitis, the level of fluconazole in the cerebrospinal fluid is about 80% of its plasma level. In the stratum corneum of the epidermis, dermis and sweat glands, high concentrations of fluconazole are achieved, which exceed serum concentrations. Fluconazole binds poorly to plasma proteins (12%). The half-life is 30 hours. Not metabolized. No fluconazole metabolites were detected in peripheral blood. Fluconazole is excreted primarily by the kidneys; approximately 80% of the dose taken is found unchanged in the urine. Pharmacodynamics FLUNOL®, a representative of triazole antifungal agents, is a selective inhibitor of ergosterol synthesis in the fungal membrane. Increases the permeability of the cell membrane, disrupts its growth and replication. Pharmacological effect - fungicidal. It has a specific effect on fungal enzymes dependent on cytochrome P450. Does not have antiandrogenic activity. Treatment with fluconazole 50 mg/day for 28 days did not affect blood testosterone concentrations in men or steroid concentrations in women of childbearing age. FLUNOL® is effective against superficial and systemic fungal infections caused by Candida spp., Cryptococcus neoformans, Coccidiodes immitis, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Histoplasma capsulatum. Indications for use - oropharyngeal candidiasis - acute or recurrent vaginal candidiasis - candidal balanitis - systemic candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis (infections of the peritoneum, endocardium, eyes, respiratory and urinary tract) - cryptococcosis, including cryptococcal meningitis and fungal infections of other localizations (lungs, skin) - skin mycoses: mycoses of the feet, smooth skin of the torso, pityriasis versicolor, skin infections caused by Candida species, onychomycosis - prevention of fungal infections in patients with malignant tumors against the background of chemotherapy or radiation therapy Method of administration and dosage Adults: - for oropharyngeal candidiasis, on the first day the drug is usually prescribed at 200 mg, then continued at 100 mg once a day (the use of FLUNOL® 100 capsules, 100 mg is recommended). Treatment is continued for 2 weeks to reduce the likelihood of relapse. — For vaginal candidiasis, take a single dose orally at a dose of 150 mg. To reduce the frequency of relapses of vaginal candidiasis, the drug can be used at a dose of 150 mg once a month. The duration of therapy is determined individually - it varies from 4 to 12 months. — For chronic recurrent vulvo-vaginal candidiasis (relapse rate 4 or more times a year), pulse therapy is recommended: 150 mg once a week for 1-3 months. — For candidal balanitis – 150 mg once. — For systemic candidiasis, candidemia and other forms of invasive candidal infection, take a dose of 400 mg on the first day, and then 200 mg once a day (the use of FLUNOL® 100 capsules, 100 mg is recommended). The duration of therapy depends on clinical and mycological effectiveness. — For cryptococcal meningitis and cryptococcal infections, take a dose of 400 mg on the first day, and then continue treatment at a dose of 200 mg once a day (the use of FLUNOL® 100 capsules, 100 mg is recommended). The duration of treatment for cryptococcal infections depends on the presence of clinical and mycological effect; For cryptococcal meningitis, treatment is usually continued for at least 6-8 weeks. — For mycosis of the skin, the recommended dose is 150 mg once a week. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy (up to 6 weeks) may be required. — For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until an uninfected nail grows out. Fingernails and toenails normally take 3-6 and 6-12 months to re-grow, respectively. — For pityriasis versicolor, 300 mg once a week for 2 weeks. — For the prevention of fungal infections in patients with malignant tumors, the recommended dose is 50-400 mg once a day, depending on the degree of risk of developing a fungal infection. For patients at high risk of generalized infection, for example, with severe or long-lasting neutropenia, the recommended dose is 400 mg once daily. Use in children As in adults, for similar infections, the duration of treatment depends on the clinical and mycological effect. The maximum daily dose for adults should not be exceeded in children. Fluconazole is taken every day in a single dose. For candidiasis of the mucous membranes, the dose is 3 mg/kg/day. On the first day, in order to more quickly achieve constant equilibrium concentrations, a loading dose of 6 mg/kg can be prescribed. 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 patients with immunodeficiency considered at risk due to neutropenia, receiving cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day, depending on the severity and duration of persistence of induced neutropenia. Use in the elderly In the absence of signs of renal failure, the drug is prescribed at the usual dose. Use in patients with renal failure With a single dose, no dose change is required. In patients, including children, with impaired renal function with repeated use of the drug, a loading dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indication) is set according to the following table: Creatinine clearance (ml/min) Interval between doses / percentage of recommended dose > 50 ≤50 (without dialysis) Regular dialysis 100% 50% 100% after each dialysis Regular dialysis patients should receive 100% of the recommended dose after each dialysis; on days when there is no dialysis, patients should receive a reduced dose according to their creatinine clearance. Side effects Common (from ≥1/100 to <1/10) - headache - abdominal pain, diarrhea, nausea, vomiting - increased levels of alkaline phosphatase, serum aminotransferase levels (ALT and AST) - rash Uncommon (from ≥1/10) 1,000 to ≤1/100) - insomnia, drowsiness - convulsions, dizziness, paresthesia, change in taste - vertigo - dyspepsia, flatulence, dry mouth - cholestasis, jaundice, increased bilirubin - itching, urticaria, increased sweating, dermatitis - myalgia - fatigue , malaise, weakness, increased body temperature Rarely (from ≥1/10,000 to ≤1/1,000) - agranulocytosis, leukopenia, neutropenia, thrombocytopenia - anaphylaxis, angioedema - hypertriglyceridemia, hypercholesterolemia, hypokalemia - tremor - tachycardia, ventricular fibrillation/flutter, QT prolongation - hepatotoxicity, including rare cases of death, liver failure, hepatocellular necrosis, hepatitis, hepatocellular injury - toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, facial edema, alopecia In patients with AIDS or cancer , during treatment with fluconazole and similar drugs, changes in blood counts, renal and liver function were observed, but the clinical significance of these changes and their relationship with treatment have not been established. Contraindications - hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole - simultaneous use of terfenadine during repeated doses of fluconazole at a dose of 400 mg / day or more - simultaneous use of drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme, such as cisapride, astemizole, erythromycin, pimozide and quinidine - hereditary lactose intolerance, Lapp-lactase enzyme deficiency, glucose-galactose malabsorption - pregnancy and lactation - children under 12 years of age Drug interactions When using fluconazole simultaneously: - with coumarin anticoagulants - fluconazole increases prothrombin time. Patients receiving coumarin anticoagulants should be under strict medical supervision; - with cisapride - cases of adverse cardiac events have been described, including paroxysms of ventricular tachycardia (AR); - with cyclosporine - it is recommended to control the concentration of cyclosporine in the blood, as it may increase; - with hydrochlorothiazide - leads to an increase in the concentration of fluconazole in the blood by 40%. However, this does not require a change in dosage regimen; - with ethinyl estradiol and levonorgestrel - fluconazole increases their areas under the concentration-time curve (AUC). However, this does not affect the effectiveness of the combined oral contraceptive drug; - with phenytoin - a significant increase in phenytoin concentrations may be observed. If it is necessary to use combined treatment with phenytoin, it is necessary to control the level of the latter and adequate dose selection to ensure therapeutic concentrations in the serum; - with rifampicin - leads to a decrease in AUC of fluconazole by 25% and T1/2 by 20%. In patients receiving concomitant rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole; - with oral hypoglycemic agents (sulfonylurea derivatives) - fluconazole prolongs their half-life. Frequent monitoring of blood glucose and appropriate reduction in the dose of sulfonylurea are recommended; - with antifungal drugs from the group of azole derivatives, with terfenadine and astemizole - the likelihood of developing serious arrhythmias with prolongation of the QT interval increases (if it is necessary to use such a combination, careful medical supervision is required); - with theophylline - it is possible to lengthen the half-life of theophylline from plasma and develop symptoms of its overdose; - with zidovudine - leads to an increase in the concentration of zidovudine in plasma. Patients receiving this combination should be monitored for side effects of zidovudine; - with antipyrine - fluconazole at a dose of 50 mg does not affect the metabolism of antipyrine; - with midazolam - fluconazole significantly increases the concentration of midazolam and psychomotor effects; - with triazolam - increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32% and t½ by 25-50%, due to inhibition of triazolam metabolism. Triazolam dosage adjustment may be required; - with benzodiazepines - careful monitoring is necessary in order to appropriately reduce the dose of the benzodiazepine; - with slow calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) - fluconazole can significantly increase the systemic exposure of calcium channel antagonists. Frequent monitoring for drug side effects is recommended; - with non-steroidal anti-inflammatory drugs (celecoxib, flurbiprofen, ibuprofen, naproxen, lornoxicam, meloxicam, diclofenac) - increases the Cmax and AUC of NSAIDs. Frequent monitoring for NSAID-related adverse effects and toxicities is recommended. NSAID dose adjustment may be required; - with cyclophosphamide - increases the levels of bilirubin and creatinine in the blood serum. The combination may be used before there is a risk of increased serum bilirubin and creatinine levels; - with fentanyl - fluconazole significantly delays the elimination of fentanyl. Elevated concentrations of fentanyl may lead to respiratory failure; - alfentanil: with simultaneous therapy with fluconazole, a decrease in clearance and volume of distribution is observed, as well as an extension of the elimination period of alfentanil. A possible mechanism of action is inhibition of the CYP3A4 enzyme by fluconazole. Alfentanil dosage adjustment may be required. - with halofantrine - fluconazole may increase plasma concentrations of halofantrine due to an inhibitory effect on CYP3A4; - with hydroxymethylglutaryl-A reductase (HMG-CoA reductase) inhibitors - the risk of myopathy and acute skeletal muscle necrosis (rhabdomyolysis) increases when fluconazole is prescribed concomitantly with HMG-CoA reductase inhibitors that are metabolized through CYP3A4, such as atorvastatin and simvastatin, or via CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. HMG-CoA reductase inhibitors should be discontinued if a significant increase in creatine kinase levels is observed or if myopathy/rhabdomyolysis is diagnosed or suspected; - with losartan - fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the angiotensin II receptor antagonism that occurs during treatment with losartan. Patients should constantly monitor blood pressure; - with methadone - the concentration of methadone in the blood serum increases, a dose adjustment of methadone may be required; - with vinca alkaloid - may increase plasma levels of vinca alkaloid (eg, vincristine and vinblastine) and lead to neurotoxicity due to inhibitory effects on CYP3A4; - with vitamin A - careful monitoring of patients is required in order to identify side effects associated with the central nervous system; - with voriconazole - simultaneous administration of voriconazole and fluconazole at any dose is not recommended. Concomitant use of oral voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) led to an increase in voriconazole concentration and AUC by an average of 57% (9% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively; - with cimetidine, antacids - there is no clinically significant effect on the absorption of fluconazole; - with prednisolone - patients on long-term treatment with fluconazole and prednisolone should be monitored for the development of adrenal insufficiency after discontinuation of fluconazole; - with rifabutin - increases serum rifabutin levels by up to 80%. Cases of uveitis have been reported in patients who were simultaneously prescribed fluconazole and rifabutin. Careful monitoring of the condition of patients receiving rifabutin and fluconazole simultaneously is necessary; - with saquinavir - increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55% and reduces the clearance of saquinavir by approximately 50% due to inhibition of the hepatic metabolism of saquinavir via CYP3A4 and inhibition of P-glycoprotein. Dose adjustments of saquinavir may be necessary; - with sirolimus - the plasma concentration of sirolimus increases, presumably by inhibiting the metabolism of sirolimus through CYP3A4 and P-glycoprotein. This combination may be used to adjust the dose of sirolimus based on effect/concentration measurements; - with tacrolimus - serum concentrations of tacrolimus when taken orally may increase up to 5-fold due to inhibition of the metabolism of tacrolimus in the intestine via CYP3A4. No significant pharmacokinetic changes were observed with intravenous tacrolimus. Increased tacrolimus levels have been associated with nephrotoxicity. The dosage of oral tacrolimus should be reduced based on drug concentrations; - amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and/or S-amitriptyline may be measured at the start of combination therapy and after one week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted; - carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the concentration of the latter in the blood serum by 30%. There is a risk of carbamazepine toxicity. Carbamazepine dosage adjustments may be necessary based on concentration/effect measurements. Special instructions Treatment must be continued until clinical and mycological remission of the disease occurs. Premature cessation of treatment leads to relapses. Treatment can begin before receiving the results of culture or other laboratory tests, with subsequent correction of fungicidal therapy based on the results of the studies. During treatment, it is necessary to monitor blood counts, kidney and liver function. If renal or liver dysfunction occurs, you should stop taking the drug. In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including death, mainly in patients with concomitant diseases. Patients whose liver function tests are impaired during treatment with fluconazole should be monitored for signs of 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. The hepatotoxic effect of fluconazole is usually reversible, and symptoms disappear after discontinuation of therapy. If skin rashes occur in patients with immunosuppression, careful observation is necessary, and if the skin reaction progresses, treatment should be discontinued (risk of developing Stevens-Johnson syndrome, Lyell's syndrome). People with AIDS are more likely to develop severe skin reactions. If a patient receiving treatment for a superficial fungal infection develops a rash that can be associated with fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme appear. In rare cases, anaphylactic reactions have been observed. Fluconazole may cause prolongation of the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation/flutter were observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalances and concomitant therapy that contributes to the development of such disorders. Therefore, such patients with potentially proarrhythmic conditions should use FLUNOL® with caution. Patients with liver, heart and kidney diseases are advised to consult a doctor before using FLUNOL®. When using Flunol® 150 mg for vaginal candidiasis, patients should be warned that improvement in symptoms is usually observed after 24 hours, but sometimes it takes several days for them to completely disappear and they should consult a doctor. Fluconazole is a strong CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Patients receiving treatment with fluconazole who are taking concomitant therapy with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. Flunol® 150 should be taken with caution in patients with renal dysfunction. Pediatric Population The examples and incidence of adverse events and laboratory abnormalities observed in children are comparable to those observed in adults. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous machinery Patients should be informed about the dangers associated with driving vehicles, servicing mechanical equipment and other potentially hazardous activities. Overdose Symptoms: hallucinations, paranoid behavior. Treatment: supportive and symptomatic therapy is used, if necessary, gastric lavage. Since fluconazole is excreted primarily in the urine, forced diuresis is likely to increase the rate of elimination. A 3-hour hemodialysis session reduces the plasma concentration of fluconazole by approximately 50%. Release form and packaging 1 or 2 capsules in a blister pack made of polyvinyl chloride film and printed aluminum foil. 1 blister pack together with instructions for medical use in the state and Russian languages are placed in a cardboard pack with a hologram of the manufacturer. Storage conditions: In a dry place, protected from light, at a temperature not exceeding 25 0C. Keep out of the reach of children! Shelf life 4 years Do not use after the expiration of the shelf life Conditions for dispensing from pharmacies By prescription Republic of Kazakhstan Almaty, st. Shevchenko 162 E. Owner of the registration certificate of Nobel Almaty Pharmaceutical Factory JSC, Republic of Kazakhstan Address of the organization that accepts claims from consumers regarding the quality of products (products) on the territory of the Republic of Kazakhstan: Nobel Almaty Pharmaceutical Factory JSC, Republic of Kazakhstan, Almaty, st. Shevchenko 162 E. Phone number: (+7 Fax number: (+7 Email address