Instructions for use MYCOSYST®

Pharmacological properties of the drug Mikosist

fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1P-1,2,4-triazol-1-yl)-2-propanol) is an antifungal drug belonging to the group of bis -triazoles. The mechanism of antifungal action is due to the ability to disrupt the biosynthesis of ergosterol, which is necessary for the construction of the cell membrane of fungi. Effective against systemic infections caused by fungi of the genus Candida and Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis , fungi of the genus Microsporum and Trichophyton. The pharmacokinetics of Mikosist when administered orally and intravenously are the same. Well absorbed after oral administration. Eating food and antacids does not affect the absorption of fluconazole. Bioavailability - 90%. The maximum concentration in the blood plasma after oral administration is achieved within 1–2 hours, the half-life is about 30 hours. Simultaneous food intake does not affect the absorption of the drug, 90% of the equilibrium concentration level is achieved by the 4–5th day of treatment (when taken 1 time per day). On the 1st day of treatment, administration of a loading dose (2 times the usual daily dose) by the 2nd day allows one to achieve a level corresponding to 90% of the equilibrium concentration. 11–12% of the drug is bound to plasma proteins . It easily penetrates into the biological fluids of the body and through the BBB, so it can also be effectively used for intracranial infections. With meningitis caused by fungi, the concentration of the drug in the cerebrospinal fluid reaches approximately 80% of the level in the blood plasma. Concentrations of fluconazole in saliva and sputum are similar to its concentration in blood plasma. Higher concentrations are achieved in all layers of the skin than in blood serum. Fluconazole accumulates in the stratum corneum of the skin. When taken at a dose of 50 mg 1 time per day, the concentration of fluconazole after 12 days of treatment is 73 mcg/g, and 7 days after stopping treatment - 5.8 mcg/g; when taken at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum of the skin on the 7th day is 23.4 mcg/g, and 7 days after taking the second dose - 7.1 mcg/g. After 4 months of use at a dose of 150 mg once a week, the concentration of fluconazole is 4.05 mcg/g in healthy nails and 1.8 mcg/g in affected nails. 6 months after the end of therapy, fluconazole is still detected in the nails. It is excreted mainly in the urine (about 80% of the administered dose unchanged, 11% in the form of metabolites). The long half-life of fluconazole allows it to be prescribed once for vaginal candidiasis and taken once a day or once a week for course use for other indications.

Mikosist 150 mg No. 1 caps.

Instructions for medical use of the drug MIKOSIST® Trade name Mikosist® International nonproprietary name Fluconazole Dosage form Capsules 50 mg, 100 mg, 150 mg Composition One capsule contains the active substance - fluconazole 50 mg, 100 mg or 150 mg, excipients: colloidal silicon dioxide , magnesium stearate, talc, povidone, corn starch, lactose anhydrous composition of the gelatin capsule: body: titanium dioxide (E 171), gelatin cap: indigo carmine (E 132), titanium dioxide (E 171), gelatin. Description Hard opaque gelatin capsules, size No. 4, with a white body and a light blue cap (for a dosage of 50 mg). Hard opaque gelatin capsules, size No. 2, with a white body and a turquoise cap (for a dosage of 100 mg). Hard opaque gelatin capsules size No. 1, with a white body and a blue cap (for a dosage of 150 mg). The contents of the capsules are powder or dense powdery mass of white or almost white color. Pharmacotherapeutic group Antifungal drugs for systemic use. Triazole derivatives. Fluconazole ATC code J02A C01 Pharmacological properties Pharmacokinetics After oral administration, fluconazole is well absorbed, bioavailability is 90%. 1-2 hours after ingestion it reaches its maximum level in the blood plasma. Simultaneous food intake does not affect the absorption of the drug. A state of 90% equilibrium saturation occurs after taking 4-5 single doses. In the case of taking a double usual dose, the concentration in the blood plasma reaches a state of 90% equilibrium saturation on the second day. 11-12% of fluconazole is bound to plasma proteins. Fluconazole easily penetrates into biological fluids. With fungal meningitis, the concentration in the cerebrospinal fluid is 80% of the concentration in the blood. The concentration of fluconazole in saliva, sputum and plasma of healthy volunteers is the same. The concentration in all layers of the skin exceeds the concentration in the blood. During daily administration of 50 mg doses, the level of fluconazole in the stratum corneum after 12 days is 73 mcg/g, and 7 days after the end of treatment - 5.8 mcg/g. After a two-week course, consisting of a weekly dose of 150 mg of the drug, the concentration of fluconazole in the stratum corneum is 23.4 mcg/g, and after another 7 days - 7.1 mcg/g. For fungal nail infections, at the end of a 4-month course with weekly doses of 150 mg, the concentration of fluconazole in healthy volunteer nails is 4.05 mcg/g, while in the affected nails it is 1.8 mcg/g. The presence of fluconazole in the nail plates can be detected after 6 months from the end of therapy. The half-life is 30 hours, which is extended if renal function is impaired (up to 98 hours). Fluconazole is excreted mainly through the kidneys, the half-life (T1/2) is 30 hours, while 80% of the drug is found in the urine unchanged and 11% in the form of metabolites. Fluconazole clearance is proportional to creatinine clearance (CC). The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inversely proportional relationship between T1/2 and CC. After hemodialysis, the plasma concentration of fluconazole decreases by 50%. Due to the long half-life, a single dose of the drug provides sanitation of vaginal candidiasis, and for some other fungal infections, taking fluconazole once a week is sufficient. Pharmacodynamics Fluconazole, the active ingredient of the drug Mikosist®, belongs to triazoles and is a systemic antifungal drug. In fungi that are sensitive to it, fluconazole blocks cytochrome P450-dependent enzymes, leading to disruption of ergosterol synthesis in the cell membranes of fungi. As a broad-spectrum antifungal agent, Mikosist® capsules are effective against systemic infections caused by Candida and Cryptococcus neoformans. Penetrating the blood-brain barrier, it provides effective treatment of intracranial infections. In addition, it is effective against infections caused by Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis (including intracranial infections), as well as strains of Microsporum and Trichophyton. In animal trials, fluconazole was effective in the treatment of endemic infections caused by Blastomyces dermatitidis, Coccidioides immitis, including intracranial infections, and Histoplasma capsulatum in individuals with normal and compromised immunity. Candida krusei is resistant to fluconazole. 40% of Candida glabrata are primarily resistant to fluconazole. The drug Mikosist® capsules are characterized by a specific interaction with fungal cytochrome P450, so a 50 mg daily dose of the drug does not affect the testosterone concentration of adult men and the concentration of steroids in women of childbearing age. Indications for use Treatment in adults - systemic candidiasis (candidemia, disseminated candidiasis of the endocardium, in the peritoneal cavity, respiratory organs, genitourinary system) - candidiasis of the skin and mucous membranes: oropharyngeal, esophageal, non-invasive bronchopulmonary, urethritis, chronic atrophic candidiasis of the oral cavity ( thrush caused by dentures), candidal vaginitis (acute or recurrent), balanitis - cryptococcal meningitis - coccidioidomycosis - pityriasis versicolor - mycoses caused by dermatophytes (mycosis of the feet, smooth skin, when external therapy is ineffective) - onychomycosis, when other drugs cannot be used - endemic mycoses: coccidioidosis, paracoccidioidosis, sporotrichosis and histoplasmosis. Prevention in adults - relapse of cryptococcal meningitis in patients with HIV infection and in patients at high risk of its development. - candidiasis in patients receiving cytostatics or radiation therapy or in patients after hematopoietic stem cell transplantation or in patients with HIV infection (for example, oropharyngeal or esophageal candidiasis). - to reduce the incidence of recurrent vaginitis, balanitis with 4 or more episodes per year. Directions for use and dosage Capsules should be taken whole, with a small amount of water, before or after meals. Mikosist® can be used orally or intravenously; the method of administration depends on the patient’s condition. The transition from intravenous to oral administration and vice versa is carried out without changing the daily dose, i.e. the daily dose does not depend on the method of administration of the drug. Treatment can be started before receiving the results of mycobiological or laboratory tests; in the future, it may be necessary to select specific fungicidal therapy in accordance with the results obtained. The daily dose of fluconazole depends on the type of infection and its severity. Treatment should be continued until symptoms disappear completely and laboratory parameters normalize. The exception is acute vaginal candidiasis, for the treatment of which a single dose of 150 mg of Mikosist® capsules is sufficient. Premature cessation of treatment leads to relapse. Typically, cryptococcal meningitis and recurrent oropharyngeal candidiasis in HIV-infected patients require long-term treatment. Doses and duration for treatment and prophylaxis in adults Indications Doses Duration of treatment Cryptococcal infections - Treatment of cryptococcal meningitis Loading dose: 400 mg on the first day, then 200-400 mg once daily Typically for at least 6-8 weeks. For life-threatening conditions, the daily dose can be increased to 800 mg - Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of developing it 200 mg per day Unlimited with a daily dose of 200 mg Coccidioidomycosis from 200 to 400 mg From 11 to 24 months and longer depending on the patient's condition. A dose of 800 mg per day may be used to treat some types of infections, especially infections involving the meninges Invasive candidiasis Loading dose: 400 mg on the first day, then 400 mg once daily The usual recommended duration of treatment for candidemia is 2 weeks after the first negative result sowing and resolving symptoms of candidemia Mucosal candidiasis - Oropharyngeal candidiasis Saturation dose: 200-400 mg on the first day, then 100-200 mg once a day for 7-21 days until remission of oropharyngeal candidiasis. In patients with severe immunosuppression, the drug can be prescribed for a longer period of time - Esophageal candidiasis Saturation dose: 200-400 mg on the first day, then 100-200 mg once a day for 14-30 days until remission of esophageal candidiasis. In patients with severe immunodeficiency, the drug can be prescribed for a longer period of time - Candiduria 200-400 mg per day for 7-21 days. In patients with severe immunodeficiency, the drug can be prescribed for a longer period of time - Chronic atrophic candidiasis of the oral cavity 50 mg per day for 14 days - Chronic candidiasis of the skin and mucous membranes 50-100 mg per day Up to 28 days. Longer duration of treatment depends on the severity of the infection or immunodeficiency and the infection caused by it Prevention of relapse of mucosal candidiasis in patients with HIV infection in whom the risk of developing them is increased - Oropharyngeal candidiasis 100-200 mg per day or 200 mg 3 times a week Unlimited treatment period for patients with chronic immunodeficiency - Esophageal candidiasis 100-200 mg per day or 200 mg 3 times a week Unlimited treatment period for patients with chronic immunodeficiency Genital candidiasis - Acute candidal vaginitis - Candidal balanitis 150 mg Single dose - Treatment and prevention of recurrent vaginitis 4 or more episodes per year 150 mg every third day for a total of 3 doses (1st, 4th, 7th day), followed by a maintenance dose of 150 mg once a week for 6 months for a maintenance dose Dermatomycosis - mycosis of the feet, - mycosis of smooth skin, - mycosis of the legs, 150 mg once a week or 50 mg per day from 2 to 4 weeks, for the treatment of mycosis of the feet may require a treatment duration of up to 6 weeks - pityriasis versicolor 300-400 mg once a week from 1 up to 3 weeks 50 mg per day from 2 to 4 weeks - onychomycosis 150 mg once a week Treatment should be continued until the affected part of the nail is completely replaced by a healthy one. Typically, it takes 3-6 months for the nail plate of the fingers to grow and 6-12 months for the nail plate of the toes to grow. The rate of growth of the nail plate can vary greatly among individuals and slows down with age. In some cases, after effective treatment of a chronic infection, the nail plate may remain deformed. Prevention of candidal infections in patients with prolonged neutropenia 200-400 mg The drug is prescribed a few days before the probable onset of neutropenia, and after the number of neutrophils increases to 1000/mm³, treatment with fluconazole is continued for another 7 days In case of chronic renal failure In case of normal function kidneys are prescribed the usual doses. For a one-day course of treatment (in the case of vaginal candidiasis), the dose is not changed. In other cases, treatment should begin with a saturation dose, that is, with oral administration of 50-400 mg of the drug, according to the recommended daily dose for each individual indication). Further, with creatinine clearance > 50 ml/min, the usual recommended daily dose is used. If creatinine clearance is <50 ml/min, the usual daily dose should be halved, the dosage frequency should be 1 time per day. In patients on long-term hemodialysis, the usual recommended dose after each session. In hepatic impairment There is limited data on use in patients with impaired liver function, so fluconazole should be prescribed with caution in patients with impaired liver function. Use in elderly patients The dose should be adjusted according to renal function. Side effects Often >1/100 - <1/10 - headache - nausea, vomiting, abdominal pain, diarrhea - skin rashes - increased activity of liver enzymes (ALAT, ASAT, alkaline phosphatase) Not often >1/1000 - <1 /100 - anemia - taste disturbance, dizziness, sensory distortion, drowsiness, insomnia - vertigo - dry mouth, indigestion, bloating, constipation - cholestasis, jaundice - skin itching, increased sweating, urticaria, toxicderma - muscle pain - fatigue, feeling unwell, weakness, fever - increased bilirubin levels Rarely >1/10000 - <1/1000 - anaphylactic reaction, exfoliative dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, facial edema - ventricular fibrillation/flutter, increased QT interval - liver failure, hepatocellular necrosis, hepatitis, hepatocellular damage In HIV-infected patients, side effects are more common (21%) than in other patients (13%), however, the nature of the side effects is similar. Post-marketing studies - hypersensitivity reactions (Quincke's edema, toxic epidermal necrolysis) - leukopenia (neutropenia and agranulocytosis), thrombocytopenia - hypercholesterolemia, hypertriglyceridemia, hypokalemia - hepatitis, drug-induced liver damage - alopecia Contraindications - hypersensitivity to any of the components of the drug - hypersensitivity to others history of triazole derivatives - simultaneous use with terfenadine (during the use of high doses of fluconazole from 400 g and above) - simultaneous use with drugs that prolong the QT interval (pimozide, quinidine, cisapride, astemizole, erythromycin) - pregnancy and lactation - childhood up to 18 years of age (due to the content of a dye in the capsule) - hereditary intolerance to glucose, lactose, galactose, malabsorption syndrome. With caution. Impaired liver function parameters 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; simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day; potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders). Drug interactions Fluconazole is contraindicated in combination with the following drugs: - Cisapride Cardiac conditions, including torsades de pointes, have been reported in patients treated simultaneously with cisapride and fluconazole. Persons who have received fluconazole should not use cisapride. - Terfenadine (when using doses of fluconazole more than 400 mg; substrate of the CYP 3A4 enzyme) Since severe rhythm disturbances were observed with the combined use of terfenadine and azole derivatives, which were accompanied by a prolongation of the QT interval, a test of the combined effect of terfenadine and fluconazole was carried out. In one trial, fluconazole 200 mg was not shown to prolong the QT interval. Another trial, in which fluconazole was used at a dose of 400 and 800 mg, showed that fluconazole at a dose of 400 mg and above significantly increased the plasma concentration of concomitantly administered terfenadine. It is contraindicated to use terfenadine together with fluconazole at a dose of 400 mg or higher. When terfenadine is co-administered with fluconazole at a dose below 400 mg, the patient must be strictly monitored. - Astemizole (CYP 3A4 enzyme substrate) Overdose of astemizole is accompanied by prolongation of the QT interval, with severe cardiac arrhythmias, including torsades de pointes or cardiac arrest. Concomitant use of astemizole with fluconazole is contraindicated due to the potential for severe, sometimes fatal effects on the heart. - Pimozide Although no in vitro or in vivo studies have been conducted, coadministration of fluconazole and pimozide may result in inhibition of pimozide metabolism. Increased plasma concentrations of pimozide may lead to prolongation of the QT interval and, in rare cases, the development of torsade de pointes. Concomitant use of fluconazole and pimozide is contraindicated. - Quinidine Although no in vitro or in vivo studies have been conducted, coadministration of fluconazole and quinidine may result in inhibition of quinidine metabolism. Quinidine use has been associated with QT prolongation and rare cases of torsades de pointes. Concomitant use of fluconazole with quinidine is contraindicated. - Erythromycin Concomitant use of fluconazole and erythromycin may increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, consequently, sudden coronary death. Concomitant use of fluconazole and erythromycin is contraindicated. Drugs affecting the metabolism of fluconazole - Hydrochlorothiazide In healthy volunteers, hydrochlorothiazide increased the concentration of fluconazole by 40%. When using fluconazole and thiazide derivatives together, you should be aware of this interaction, but there is no need to change the dose or regimen of fluconazole. - Rifampicin (CYP450 enzyme inducer) When using fluconazole in patients receiving long-term therapy with rifampicin, the area under the absorption curve of fluconazole decreased by 25%, and the half-life decreased by 20%. When these drugs are used together, an increase in the dose of fluconazole may be necessary. The effect of fluconazole on the metabolism of other drugs Fluconazole significantly blocks the action of the cytochrome P450 isoenzyme, CYP 2C9 and, to a lesser extent, CYP 3A4. Fluconazole is also an inhibitor of the CYP2C19 isoenzyme. Because of this, in addition to the listed interactions, an increase in the plasma concentration of other drugs that are metabolized by CYP 2C9 or CYP 3A4 enzymes (for example: ergot alkaloids, quinidine) may be observed when used together with fluconazole. Because of this, it is necessary to use these drugs with caution jointly, and it is necessary to observe the patient. Inhibitory enzymes, the action of fluconazole can be observed for another 4-5 days after the interruption of the course of therapy, due to the long period of the half-life of fluconazole. -Alfentanil (the substrate of the CYP 3A4 enzyme) with a joint introduction of 400 mg of fluconazole and 20 μg/kg Alfentanil, intravenously, the area under the absorption curve Alfentanil increased by 50 %, and the clearance decreased by 55 %, in terms of inhibiting the CYP 3A4 enforcement. If these two drugs are used together, a dose adjustment may be necessary. -Amititriptylin, Nordriptylin fluconazole enhances the effect of amitriptyline and Nordriptylin: 5-nortritin and/or S-amitriptyline can be measured at the beginning of combined therapy and after a week. If necessary, the doses of amitriptyline/NORTRIPTILIN should be adjusted. - Azithromycin in an open randomized tripartite cross examination 18 healthy volunteers assessed the effect of azithromycin with a single administration of orally at a dose of 1200 mg on a pharmacokinetics of fluconazole with a single reception at a dose of 800 mg, as well as an assessment of the effect of fluconazole on the pharmaconetics of azithromycin. No significant pharmacokinetic interaction was found between fluconazole and azithromycin. - Benzodiazepines (short action) (CyP 3A4 enzyme substrate), for example, midazolas, triazolars with joint oral use of 7.5 mg of midazolam and 400 mg of fluconazole, noted a significant increase in the area under the absorption curve and psychomotor actions of midazolam. The joint use of 100 mg of fluconazole and 0.25 mg of triazolam increased the area under the triazolam curve and the period of prestige. They noted a more pronounced and continued effect of triazolam when it was jointly used with fluconazole. If the patient who received fluconazole should be used, benzodiazepines should be used, you need to think about reducing the dose of benzodiazepine and must be monitored for the patient. - Karbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the concentration of the latter in serum by 30%. There is a risk of carbamazepine toxicity. It may be required to correction of the dose of carbamazepine depending on the measurements of concentration/ effect. - Calcium channel blockers (calcium antagonist) (CYP 3A4 enzyme substrate) some calcium antagonists, dihydropyridine derivatives (nifedipine, Israpid, Nicardipin, Verapamil, amlodipine and felodipine) are metabolized by the CYP 3A4 enzyme. The scientific literature reported peripheral edema, and an increase in the concentration of calcium antagonists with the joint use of Itraconazole with Felodipin, Israpidin or Nifedipin. This interaction can also be observed when using fluconazole with calcium antagonists. - Celecoxib (CyP 2C9 enzyme substrate) in one clinical test, with a joint use of 200 mg of celloxib and 200 mg of fluconazole, an increase in the maximum concentration of 68 % and an increase in the area under the Celecoxib curve by 134 %. This interaction was noted due to the blocking of the action of the CYP 2C9 enzyme and thus, a decrease in the splitting of the celloxib. With the joint use of these drugs, the dose of coacoxib must be reduced by 50 %. - Cyclosporin (substrate of the CYP 3A4 enzyme) Fluconazole significantly increases the concentration and AUC cyclosporine. During the joint use of fluconazole in a dose of 200 mg per day and cyclosporine (2.7 mg/kg/day), AUC cyclosporine increased 1.8 times. This combination can be used by reducing the dose of cyclosporin depending on its concentration. - Cyclophosphamide: combined therapy of cyclophosphamide and fluconazole leads to an increase in the levels of bilirubin and creatinine in serum. The combination can be used before there is a risk of increasing bilirubin and creatinine in blood serum. -Daninosine the joint use of didanosine and fluconazole practically did not affect the pharmacokinetics or the effectiveness of didanosine. Despite this, it is advisable to regularly monitor the effectiveness of fluconazole. It is more advisable to conduct a course of fluconazole therapy before the use of didanosine. - Fentaninel was registered by one fatal case of the likely interaction of fentanyl and fluconazole. In addition, in a randomized cross examination with twelve healthy volunteers, it was demonstrated that the fluconazole significantly slowed the elimination of fentanil. Increased concentrations of fentanyl may cause respiratory depression. Patients should be carefully observed due to the potential risk of respiratory depression. You may need a dose of fentanyl. - Galofantrin (substrate of the CYP 3A4 enzyme) preparations blocking the CYP 3A4 enzyme can lead to blocking the breakdown of the halophany. The joint use of fluconazole and halophantrin can increase the risk of cardiotoxicity (lengthening of the QT, Torsades de Pointes interval) and, accordingly, the risk of sudden heart death. This combination should be avoided. -Inhibitors of the GMG-CoA-Creductase (the substrate of the CYP 2C9 or CYP 3A4 enzyme) with the joint use of fluconazole with the inhibitors of the GMG-CoA reductase inhibitors metabolized by the CYP 3A4 enzyme (e. and rabdomyoliasis. It is necessary to monitor the patients to detect signs of myopathy or acute necrosis of the skeletal muscles (rabdomyolysis), and it is necessary to regularly control the level of creatineineine blood plasma. The course of therapy with the inhibitor of the GMG-CoA eductase should be interrupted if the level of creatineineine is significantly increased or signs of myopathy or rabdomysis are noted. - oral anticoagulants derivatives of kumarin (the substrate of the CYP 2C9 enzyme), the prothrombin time can increase (2 times, probably due to the inhibiting of warfarin metabolism with the participation of CYP2C9), therefore it is necessary to regularly control the prothrombin time. According to observations, complications with bleeding may be noted, such as: bruises, nosebleeds, gastrointestinal bleeding, hematuria, Melena. You may need a correction of the dose of warfarin. - Lozartan (the substrate of the CYP 2C9 enzyme) Fluconazole inhibits the transformation of Losartan into an active metabolite, which is largely responsible for the antagonism of the Angiotensin II receptor. Therefore, with the joint use of these drugs, it is necessary to monitor patients, and regularly monitor blood pressure. - Methadone Fluconazole can increase the serum concentration of methadone. Methadone dose adjustment may be required. - oral contraceptives when studying healthy women 50 mg of fluconazole did not affect the level of active substances, oral combined, contraceptive means. 200 mg of fluconazole increased the area under the concentration-time curve (AUC) ethinyl estradiol and levonorgestrel by 40 and 24 %, respectively. Based on these studies, repeated doses of fluconazole do not affect the action of oral contraceptive means. - non -steroidal anti -inflammatory drugs (NSAIDs) CMAX and AUC Flurbiprofen, simultaneously with fluconazole, increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg). Although specific studies have not been conducted, fluconazole may increase the systemic effects of other NSAIDs metabolized by CYP2C9 (for example, naproxen, lornoxicam, meloxicam, diclofenac). Close monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. NSAID dose adjustment may be required. -Fenitoin (the substrate of the CYP 2C enzyme) with a joint repeated introduction of 200 mg of fluconazole intravenously and 250 mg of phenytein noted an increase in the area under the concentration curve of phenytoin by 75 %, and the maximum concentration of 128 %. If it is necessary to jointly use these drugs, the level of phenytoin should be regularly monitored and the dose of phenytoid should be reduced to avoid an overdose of phenytoid. - Prednisolone (substrate of the CYP 3A4 enzyme) in one patient who received prednisone after the kidney transplant, a crisis of addison disease was noted at the end of three -month fluconazole therapy. The take -off of fluconazole probably caused an increase in the activity of the CyP 3A4 enzyme. Patients who conduct a long joint course of therapy with fluconazole and prednisolone should be controlled on the appearance of signs of insufficiency of the adrenal cortex, when the fluconazole is taken away. - Rifabutin (substrate of the CYP 3A4 enzyme) with the joint use of fluconazole and rifabutin, the concentration of rifabutin increases by 80 %. Uveitis has been reported in patients receiving rifabutin and fluconazole together and these patients should be closely monitored. With joint use, the symptoms of rifabutin toxicity should be taken into account. -Sakquinavir due to inhibiting the metabolism of saquinavir in the liver through the influence of Surza4 and inhibiting P-glycoprotein, fluconazole increases the AUC of Squynavir by about 50%, CMAX saquinavir by approximately 55%and reduces its clearance by about 50%. You may need a correction of the dosage of the saquinavir. - oral antidiabetic agents derivatives of sulfonylmochevins (the substrate of the CYP 2C enzyme) with the joint use of fluconazole and derivatives of sulfonylmochevina (chlorpropamide, glibenclamide, glypizide and tolbutamide), and healthy volunteers noted an increase in half -life. These drugs can be used together, but it is necessary to take into account the possibility of hypoglycemia. A corresponding reduction in the dose of sulfonyl gross preparations is recommended. - Takrolimus and Sirolimus (the substrate of the CYP 3A4 enzyme), with the joint use of takrolimus and fluconazole, noted an increase in the concentration of the blood of the Takrolimus by 5 times. Nephrotoxicity was also noted with the joint use of fluconazole and tacrolimus. The dose of orally as orally takrolimus should be reduced depending on its concentration. Fluconazole increases the serum concentration of the syarolimus allegedly inhibiting its metabolism via CYP3A4 and P-glycoprotein. This combination can be used with the correction of the dose of the sylolymus, depending on the effect / measurement of concentration.

Indications for use of the drug Mikosist

Systemic candidiasis - candidemia, disseminated candidiasis (endocardium, abdominal organs, respiratory tract, genitourinary system, eyes); candidiasis of the mucous membranes - oropharyngeal, non-invasive bronchopulmonary and esophageal, candiduria, chronic atrophic candidiasis of the oral cavity (thrush caused by dentures); acute or recurrent vaginal candidiasis; prophylactic use to reduce the frequency of relapses of vaginal candidiasis (≥3 episodes per year); candidal balanitis; skin candidiasis. Diseases caused by dermatophytes when topical use of antifungal agents is ineffective: mycoses of the feet, trunk, legs, pityriasis versicolor, onychomycosis. Endemic mycoses: coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in patients with normal immune status. Systemic lesions caused by fungi of the genus Cryptococcus , in particular mycoses of the respiratory tract, skin and mucous membranes, cryptococcal meningitis; prevention of relapse of cryptococcal infection in patients with AIDS. Prevention of mycoses in patients receiving cytostatic or radiation therapy. For the treatment of patients who have undergone organ transplantation and are receiving antibiotics, cytostatic and immunosuppressive therapy, or in cases where there is a risk of fungal infection for other reasons.

Mycosyst®

The drug is taken orally.

When transferring from intravenous administration to taking capsules and vice versa, there is no need to change the daily dose.

Use in adults

For cryptococcal infections, the usual dose of fluconazole is 400 mg once a day on the first day of treatment, then 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on clinical effectiveness confirmed by mycological examination, and usually ranges from 6 to 8 weeks.

The recommended duration of treatment for the treatment of cryptococcal meningitis is 10-12 weeks after a negative microbiological test result on a cerebrospinal fluid sample.

To prevent relapse of cryptococcal meningitis in patients with AIDS, after completing the full course of primary therapy, fluconazole is prescribed to the patient at a dose of at least 200 mg per day for a long period.

For candidemia, disseminated candidiasis and other invasive candidal infections, the daily dose of fluconazole is 400 mg on the first day and 200 mg on subsequent days. If necessary, the dose of the drug can be increased to 400 mg/day. The duration of treatment depends on clinical effectiveness.

For severe systemic candidiasis, the dose may be increased to 800 mg per day. The duration of therapy depends on clinical effectiveness. Should be continued for at least 2 weeks after a negative blood culture has been obtained or after symptoms have resolved.

For oropharyngeal candidiasis, including patients with immunocompromised patients, the usual dose of fluconazole is 50-100 mg once daily for 7-14 days. To prevent relapses of oropharyngeal candidiasis in patients with AIDS after completing the full course of primary therapy - 150 mg once a week. If necessary, treatment can be extended, especially in severe immune disorders.

For atrophic candidiasis of the oral cavity associated with wearing dentures, fluconazole is usually prescribed 50 mg once a day for 14 days in combination with antiseptic agents for treating the denture.

For other candidiasis infections, for example, esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the daily dose is 50-100 mg for 14-30 days.

For severe candidiasis of the mucous membranes - 100-200 mg per day:

To prevent fungal infections in patients with malignant neoplasms, the dose of fluconazole should be 50 mg once daily as long as the patient is at increased risk due to cytostatic or radiation therapy.

For vaginal candidiasis - 150 mg once. To reduce the frequency of relapses, use 150 mg once a month for 4-12 months, sometimes more frequent use may be required.

For balanitis caused by Candida spp., fluconazole is prescribed as a single dose of 150 mg orally.

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg once a day, depending on the degree of risk of developing a fungal infection. If there is a high risk of generalized infection, for example in patients with expected severe or long-lasting neutropenia, the recommended dose is 400 mg 1 time per day. Fluconazole is prescribed several days before the expected onset of neutropenia; after the number of neutrophils increases to more than 1000/mm3, treatment is continued for another 7 days.

For mycoses of the skin (including candidiasis), including mycoses of the feet and skin of the groin area, the recommended dose is 150 mg once a week or 50 mg once a day. 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 pityriasis versicolor - 300 mg once a week for 2 weeks, some patients require a third dose of 300 mg per week, while in some cases a single dose of 300 mg is sufficient; An alternative treatment regimen is to use 50 mg once a day for 2-4 weeks.

For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced with a healthy one. Fingernails and toenails normally take 3-6 months and 6-12 months to re-grow, respectively.

For deep endemic mycoses, it may be necessary to use the drug at a dose of 200-400 mg per day for 2 years. The duration of therapy is determined individually; it can be 11-24 months for coccidioidosis; 2-17 months for paracoccidioidosis and 3-17 months for histoplasmosis.

Use in children

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

For candidiasis of the mucous membranes, the recommended dose of fluconazole is 3 mg/kg per day. On the first day, a loading dose of 6 mg/kg may be prescribed in order to more quickly achieve equilibrium concentration.

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

For the prevention of fungal infections in children with reduced immunity, in whom the risk of developing infection is associated with neutropenia developing in; as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg per day, depending on the severity and duration of persistence of induced neutropenia.

In newborns, fluconazole is excreted more slowly, so in the first 2 weeks of life the drug is prescribed at the same dose (in mg/kg) as in older children, but with an interval of 72 hours. For children aged 3-4 weeks of life, the same dose is administered at intervals of 48 hours.

Use in elderly patients

In the absence of renal dysfunction, the usual drug dosage recommendations should be followed. For patients with impaired renal function (creatinine clearance <50 ml/min), the dosage regimen should be adjusted as indicated below.

Use in patients with renal failure

Fluconazole is excreted primarily by the kidneys unchanged. With a single dose of fluconazole, no dose changes are required. If a course of treatment is necessary in patients (including children) with impaired renal function, a “loading” dose of 50 mg to 400 mg should initially be administered. Subsequently, the daily dose (depending on the indication) is determined according to the following table:

Use of the drug Mikosist

Orally or as an intravenous infusion (maximum rate of administration - 10 ml/min), depending on the patient’s condition. The daily dose does not change depending on the method of application. 100 ml of infusion solution contains 200 mg of fluconazole in 0.9% sodium chloride solution. Intravenous infusion is compatible with the following infusion solutions: 20% glucose solution, Ringer's solution, potassium chloride solution in glucose (composition: in 1000 ml of water for injection - 3.8 g of potassium chloride, 33.75 g anhydrous glucose, 5 g of 0.1-N hydrochloric acid), sodium bicarbonate solution (composition: 13 g of sodium bicarbonate in 1000 ml of water for injection), isotonic sodium chloride solution. For adults, the daily dose is determined individually, taking into account the nature and severity of the infection. Treatment is continued until clinical and hematological remission (with the exception of acute vaginal candidiasis, which is usually curable with a single dose of 150 mg). Premature cessation of treatment leads to relapses. Cryptococcal meningitis in patients with AIDS, as well as recurrent oropharyngeal candidiasis, usually require long-term treatment. For candidemia, disseminated candidiasis and other invasive forms of candidiasis, Mikosist is usually prescribed at a dose of 400 mg on the 1st day of therapy, and then 200 mg/day. Depending on the clinical picture, the daily dose can be increased to 400 mg. The duration of treatment depends on the patient's condition. For cryptococcal meningitis and other cryptococcal infections, 400 mg is prescribed on the 1st day, then 200–400 mg once a day. The duration of treatment depends on the clinical and mycological picture, and for cryptococcal meningitis it should be at least 6–8 weeks. To prevent cryptococcal meningitis in AIDS patients after treatment, 200 mg/day can be prescribed continuously. For oropharyngeal candidiasis, the daily dose is 50–100 mg for 7–14 days. For patients with severe immunodeficiency conditions, the drug can be prescribed for a longer period. For atrophic candidiasis of the oral cavity, the usual daily dose is 50 mg for 14 days while carrying out local treatment. For other mucosal candidiasis, for example, esophagitis, non-invasive bronchopulmonary candidiasis, candiduria, mucocutaneous candidiasis, a dose of 50–100 mg/day is usually prescribed for 14–30 days. In case of severe lesions of the mucous membranes caused by fungi of the genus Candida, the daily dose can be increased to 100 mg. To prevent relapses of candidiasis in patients with reduced immunity, the drug is prescribed in a daily dose of 50–400 mg. For mycoses of the feet, trunk, and legs caused by dermatophytes, and skin candidiasis, the recommended dose is 150 mg once a week or 50 mg/day. Treatment is carried out for 2–4 weeks, but for mycoses of the feet a 6-week course may be required. For the treatment of pityriasis versicolor, the recommended dose is 50 mg/day for 2–4 weeks. For onychomycosis, the recommended dose is 150 mg once a week until the infected nail is completely replaced with a healthy one. Nail growth usually takes 3–6 months; toenail growth takes longer, up to 6–12 months. The rate of nail growth is uneven; in old age it slows down. For paracoccidioidomycosis, histoplasmosis, sporotrichosis, Mikosist is used at a dose of 200–400 mg/day for 1–2 years. For coccidioidomycosis, the dose is determined individually and treatment lasts 1–2 years. For acute vaginal candidiasis, use 150 mg of fluconazole once. For chronic, often recurrent vaginal candidiasis, the course of treatment can be repeated: 150 mg/month for several months. In case of renal failure, the dose should be reduced depending on the degree of dysfunction. With a single administration of the drug (vaginal candidiasis), the dose should not be changed. For continuous therapy in patients with reduced renal function, treatment should begin with a loading dose of 50–400 mg. Then the frequency of use or dose is changed taking into account creatinine clearance:

In elderly patients with normal renal function, the drug can be prescribed at the usual adult dose. In case of renal failure (creatinine clearance ≤50 ml/min), the dose should be reduced. For children , as well as for adults, the dose and duration of treatment are set individually depending on the clinical and mycological effect. Fluconazole is used daily, once a day. The daily dose should not exceed the maximum dose for adults. For candidiasis of the mucous membranes, 6 mg/kg is prescribed on the 1st day, then 3 mg/kg/day. For systemic candidiasis or cryptococcal infection, the recommended dose is 6–12 mg/kg, depending on the severity of the disease. For prophylactic purposes, the drug is prescribed to children with neutropenia in a daily dose of 3–12 mg/kg. If renal function is impaired, the daily dose for children should be reduced in accordance with the instructions for adults. For children in the first weeks of life, the drug is prescribed in the same dose (in mg/kg) as for older children, but every 3 days, that is, with an interval of 72 hours, since fluconazole is excreted slowly in newborns. For children aged 3–4 weeks, the same dose is administered every 2 days, that is, with an interval of 48 hours.

Instructions for use MYCOSYST®

The use of fluconazole in combination with the following drugs is contraindicated

Cisapride:

in patients who were simultaneously treated with cisapride and fluconazole, adverse reactions from the heart were noted, incl. paroxysms of ventricular tachycardia. In a controlled clinical study, it was shown that co-administration of 200 mg fluconazole 1 time / day and 20 mg cisapride 4 times / day led to a significant increase in the concentration of cisapride in the blood plasma and an increase in the QTc interval. Concomitant use of fluconazole and cisapride is contraindicated.

Terfenadine

(when using fluconazole doses greater than 400 mg; CYP3A4 enzyme substrate):

• because When terfenadine and azole derivatives were used together, severe rhythm disturbances were observed, which were accompanied by a prolongation of the QT interval; a study was conducted on the combined effect of terfenadine and fluconazole. One study using fluconazole 200 mg did not demonstrate QT prolongation. In another study in which fluconazole was used at a dose of 400 mg and 800 mg, it was proven that fluconazole at a dose of 400 mg and above significantly increased the concentration of concomitantly administered terfenadine in the blood plasma. The use of terfenadine in combination with fluconazole at a dose of 400 mg or higher is contraindicated. When terfenadine is used together with fluconazole at a dose below 400 mg, it is necessary to strictly monitor the patient's condition.

Astemizole:

Co-administration of astemizole and fluconazole may reduce the clearance of astemizole. This leads to an increase in pimozide plasma concentrations, which can cause an increase in the QT interval and, in rare cases, torsade de pointes (TdP). The combined use of astemizole and fluconazole is contraindicated.

Pimozide:

Although no in vitro or in vivo studies have been conducted, coadministration of fluconazole and pimozide may result in inhibition of pimozide metabolism. An increase in the concentration of pimozide in the blood plasma can lead to a prolongation of the QT interval and, in rare cases, the development of torsade de pointes (TdP). Concomitant use of fluconazole and pimozide is contraindicated.

Quinidine:

Although no in vitro or in vivo studies have been conducted, coadministration of fluconazole and quinidine may result in inhibition of quinidine metabolism. The use of quinidine has been associated with prolongation of the QT interval and rare cases of torsade de pointes (TdP). Concomitant use of fluconazole with quinidine is contraindicated.

Erythromycin:

Concomitant use of fluconazole and erythromycin may increase the risk of cardiotoxicity (QT prolongation, torsade de pointes) and, consequently, sudden coronary death. Concomitant use of fluconazole and erythromycin is contraindicated.

Concomitant use with the following drugs is not recommended

Halofantrine

(fluconazole, due to its inhibitory effect on CYP3A4, may increase the plasma concentration of halofantrine. Concomitant use of fluconazole and halofantrine may increase the risk of cardiotoxicity (QT prolongation, torsade de pointes) and, accordingly, the risk of sudden cardiac death. This combination should be avoided.

Amiodarone:

simultaneous use of fluconazole with amiodarone may lead to prolongation of the QT interval. Concomitant use of fluconazole with amiodarone is contraindicated. For this reason, caution should be exercised when using these two drugs together, especially if the dose of fluconazole is high (800 mg).

When used together with the following drugs, caution and dosage adjustment is required

Effect of other drugs on fluconazole

Hydrochlorothiazide:

in healthy volunteers, hydrochlorothiazide increased fluconazole concentrations by 40%. When using fluconazole and thiazide derivatives together, you should be aware of this effect, but there is no need to change the dose or regimen of fluconazole.

Rifampicin (inducer of CYP450 isoenzymes):

when using fluconazole in patients receiving long-term therapy with rifampicin, the AUC of fluconazole decreased by 25%, T1/2 decreased by 20%. When these drugs are used together, an increase in the dose of fluconazole may be necessary.

Interaction studies have shown that coadministration of fluconazole with food, cimetidine, antacids, or after total irradiation before bone marrow transplantation does not have a clinically significant effect on the absorption of fluconazole.

Effect of fluconazole on the metabolism of other drugs

Fluconazole significantly blocks the action of the CYP2C9 isoenzyme and, to a lesser extent, CYP3A4. Because of this, in addition to the above interactions, an increase in the plasma concentration of other drugs that are metabolized by CYP2C9 or CYP3A4 isoenzymes (for example, ergot alkaloids, quinidine) may be observed when used together with fluconazole. Therefore, these drugs should be used together with caution and the patient's condition should be monitored. The enzyme inhibitory effect of fluconazole can be observed for another 4-5 days after interruption of the course of therapy, due to the long half-life of fluconazole.

Amphotericin B:

The combined use of fluconazole and amphotericin B in infected mice with normal and reduced immune status showed the following results:

• little cumulative antifungal effect was observed in the treatment of systemic infections caused by Candida albicans; in the treatment of intracranial infections caused by Cryptococcus neoformans, no drug interactions were identified;
• Antagonism between fluconazole and amphotericin B was observed in the treatment of systemic infections caused by Aspergillus fumigatus. The clinical significance of the results obtained in these studies is unknown.

Alfentanil:

When coadministered with 400 mg fluconazole and 20 mcg/kg alfentanil IV, the AUC of alfentanil increased by 50% and clearance decreased by 55%, likely due to inhibition of the CYP3A4 isoenzyme. If these two drugs are used together, a dose adjustment may be necessary.

Amitriptyline, nortriptyline:

There are a number of reports of increased concentrations of amitriptyline and nortriptyline, and toxicity with tricyclic antidepressants, when amitriptyline was used together with fluconazole. When fluconazole and nortriptyline (the active metabolite of amitriptyline) were administered together, an increase in nortriptyline in the blood plasma was noted. Due to the risk of amitriptyline toxicity, amitriptyline plasma levels should be monitored and a dose adjustment of amitriptyline may be necessary.

Anticoagulants
(CYP2C9 substrate):
Based on post-marketing experience, as with other azole antifungals, hemorrhages (bruising, epistaxis, hematuria, melena) associated with prolongation of prothrombin time have been reported in patients receiving fluconazole concomitantly with warfarin. When fluconazole and warfarin are co-administered, the prothrombin time can be extended by 2 times, probably due to inhibition of the metabolism of warfarin with the participation of CYP2C9. In patients receiving coumarin anticoagulants concomitantly with fluconazole, prothrombin time should be carefully monitored. Warfarin dose adjustment may be required.

Benzodiazepines (short-acting) (CYP3A4 substrate), eg midazolam, triazolam:

Co-administration of midazolam and fluconazole leads to an increase in midazolam concentrations and psychomotor agitation. Co-administration of 200 mg fluconazole and 7.5 mg oral midazolam increased the AUC and T1/2 of midazolam by 3.7 and 2.2 times, respectively. Co-administration of 200 mg of fluconazole per day and 0.25 mg of triazolam orally increased the AUC and T1/2 of triazolam by 4.4 and 2.3 times, respectively. When fluconazole and triazolam were taken together, potentiation and prolongation of the effects of triazolam were observed. If benzodiazepines must be used in a patient receiving fluconazole, consider reducing the benzodiazepine dose and monitor the patient's condition.

Calcium channel blockers
(calcium antagonist)
(CYP3A4 enzyme substrate):

• Some calcium antagonists, dihydropyridine derivatives (nifedipine, israpidine, nicardipine, amlodipine, verapamil and felodipine) are metabolized by the CYP3A4 isoenzyme. Peripheral edema and increased concentrations of calcium antagonists have been reported in the scientific literature when itraconazole is co-administered with felodipine, israpidine or nifedipine. This interaction may also occur when fluconazole is used with calcium antagonists.

Carbamazepine:

Fluconazole inhibits the metabolism of carbamazepine; an increase in serum carbamazepine concentrations of 30% was observed. This leads to an increased risk of increased carbamazepine toxicity. Depending on changes in concentration and associated effects, dosage adjustments of carbamazepine may be necessary. Close monitoring for the development of adverse events is recommended.

Celecoxib

(CYP2C9 isoenzyme substrate):

• In one clinical study, coadministration of 200 mg celecoxib and 200 mg fluconazole resulted in a 68% increase in plasma Cmax and a 134% increase in celecoxib AUC. This interaction was observed due to inhibition of the activity of the CYP2C9 isoenzyme and thus a slowdown in the metabolism of celecoxib. When these drugs are used together, the dose of celecoxib should be reduced by 50%.

Cyclophosphamide:

combination therapy with cyclophosphamide and fluconazole leads to an increase in bilirubin and creatinine in the blood serum. This combination can be used taking into account the risk associated with increased levels of bilirubin and creatinine in the blood plasma.

Didanosine:

Concomitant use of didanosine and fluconazole did not affect the pharmacokinetics or efficacy of didanosine. Despite this, it is advisable to regularly monitor the effectiveness of fluconazole. It may be beneficial if a course of fluconazole therapy is given before didanosine is used.

Fentanyl:

One fatal case of a possible interaction between fentanyl and fluconazole has been reported. The author considered that the patient died due to intoxication caused by fentanyl. Additionally, in a randomized crossover study with 12 healthy volunteers, it was demonstrated that fluconazole significantly delayed the elimination of fentanyl. Increased concentrations of fentanyl may cause respiratory depression.

HMG-CoA reductase inhibitors

(substrate of the CYP2C9 or CYP3A4 isoenzyme) When fluconazole is co-administered with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (for example, simvastatin, atorvastatin) or the CYP2C9 isoenzyme (fluvastatin), the risk of myopathy and rhabdomyolysis increases. Due to the interaction between fluvastatin and fluconazole, the AUC of fluvastatin may increase by 200%. Fluconazole and HMG-CoA reductase inhibitors should be used with caution. In this case, it is proposed to reduce the dose of the HMG-CoA reductase inhibitor. Patients should be monitored for signs of myopathy or acute necrosis of skeletal muscle (rhabdomyolysis), and plasma CPK levels should be regularly monitored. The course of therapy with an HMG-CoA reductase inhibitor should be interrupted if CPK levels increase significantly or signs of myopathy or rhabdomyolysis are observed.

Immunosuppressants

(eg, cyclosporine, everolimus, sirolimus and tacrolimus).
Cyclosporine:
Fluconazole significantly increases the plasma concentration and AUC of cyclosporine.
When taking fluconazole at a dose of 200 mg/day and cyclosporine (2.7 mg/kg body weight per day) together, an increase in the AUC of cyclosporine by 1.8 times was observed. Taking this combination is possible if the dose of cyclosporine is reduced depending on the concentration of cyclosporine. Everolimus:
Although there are no in vivo or in vitro studies, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.
Sirolimus:
Fluconazole increases plasma concentrations of sirolimus primarily by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein.
Taking this combination is possible if the dose of sirolimus is adjusted, taking into account the concentration dependence of the effect. Tacrolimus:
Fluconazole, due to its inhibition of tacrolimus metabolism by CYP3A4 in the intestine, may increase tacrolimus serum concentrations up to 5-fold after oral administration. With intravenous administration of tacrolimus, no significant changes in pharmacokinetic parameters were observed. Increasing tacrolimus concentrations were associated with increased nephrotoxicity. When taken orally, the dose of tacrolimus should be reduced depending on its concentration in the blood.

Losartan

(CYP2C9 enzyme substrate):

• Fluconazole inhibits the conversion of losartan to the active metabolite, which is largely responsible for angiotensin II receptor antagonism. When losartan is used together with fluconazole, the concentration of losartan increases and the concentration of the active metabolite decreases. Therefore, when using these drugs together, it is necessary to monitor patients and regularly monitor blood pressure.

Methadone:

Fluconazole may increase serum concentrations of methadone. Methadone dose adjustment may be required.

NSAIDs:

Cmax and AUC of flurbiprofen when coadministered with fluconazole increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg).

Although specific studies have not been conducted, fluconazole may increase the systemic effects of other NSAIDs metabolized by CYP2C9 (for example, naproxen, lornoxicam, meloxicam, diclofenac). Close monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. NSAID dose adjustment may be required.

Oral contraceptives:

Two studies were conducted to study the pharmacokinetics of fluconazole when administered multiple times in combination with combined oral contraceptives. Fluconazole 200 mg increased the AUC of ethinyl estradiol and levonorgestrel by 40% and 24%, respectively. Thus, repeated use of fluconazole at these doses probably does not affect the effectiveness of combined oral contraceptives.

Phenytoin

(CYP2C isoenzyme substrate):

• with co-administration of 200 mg fluconazole and 250 mg phenytoin intravenously, an increase in phenytoin AUC by 75% and Cmax by 128% was noted. If it is necessary to use these drugs together, plasma phenytoin concentrations should be regularly monitored and the dose of phenytoin should be reduced to avoid phenytoin overdose.

Prednisolone

(CYP3A4 isoenzyme substrate):

• One patient receiving prednisolone after a kidney transplant experienced an Addison's disease crisis upon completion of three months of fluconazole therapy. Withdrawal of fluconazole probably caused an increase in CYP3A4 enzyme activity. Patients receiving long-term concomitant therapy with fluconazole and prednisolone should be monitored for signs of adrenal insufficiency when fluconazole is discontinued.

Rifabutin

(CYP3A4 isoenzyme substrate):

• when fluconazole and rifabutin are used together, the concentration of rifabutin increases (by 80%). Uveitis has been reported in patients receiving rifabutin and fluconazole together and these patients should be closely monitored.

Oral hypoglycemic agents, sulfonylurea derivatives

(CYP2C isoenzyme substrate):

• with the combined use of fluconazole and sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide) an increase in T1/2 was noted in healthy volunteers. These drugs can be used together, but the possibility of hypoglycemia should be considered. In the case of co-administration, it is necessary to monitor the glucose level in the blood; if necessary, the dose of the drug, which is a sulfourea derivative, should be reduced.

Saquinavir:

Due to inhibition of the hepatic metabolism of saquinavir through its effect on CYP3A4 and P-glycoprotein inhibition, fluconazole increases the AUC of saquinavir by approximately 50%, the Cmax of saquinavir by approximately 55%, and reduces its clearance by approximately 50%. Dose adjustment of saquinavir may be necessary.

Theophylline:

in placebo-controlled drug interaction studies, fluconazole 200 mg/day administered for 14 days reduced theophylline clearance by 18%. Therefore, when using theophylline in high doses together with fluconazole, patients must be carefully monitored, and if signs of theophylline overdose or toxicity appear, its dose must be reduced.

Tofacitinib:

The effect of tofacitinib is enhanced when co-administered with drugs that both moderately inhibit CYP3A4 and strongly inhibit CYP2C19 (for example, fluconazole). Dose adjustment of tofacitinib may be necessary.

Trimetrexate:

fluconazole interferes with the metabolism of trimetrexate, which leads to an increase in the concentration of trimetrexate in the blood plasma. If it is necessary to use these drugs together, trimetrexate levels should be regularly monitored and the patient should be monitored for signs of trimetrexate toxicity.

Vinca alkaloids:

Although this aspect has not been studied, fluconazole may increase plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) and cause nephrotoxicity, which is likely due to an inhibitory effect on CYP3A4.

Vitamin A:

There has been one case report in a patient receiving concomitant therapy with trans-retinoid acid (the acid form of vitamin A) and fluconazole. The patient developed undesirable manifestations in the form of a false brain tumor, which disappeared after stopping fluconazole. You can use this combination of drugs, but you must be aware of the possibility of undesirable effects associated with the central nervous system.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4):

co-administration of voriconazole (400 mg orally every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg orally on day 1, then 200 mg every 24 hours for 4 days) in 6 healthy men resulted in an average increase in voriconazole Cmax and AUC of 57% (90% CI: 20%, 107%) and 79% (90% CI:

• 40%, 128%) respectively. In a subsequent clinical study of 8 healthy men, administration of voriconazole and fluconazole at a lower dose or frequency did not eliminate or reduce this effect. Concomitant use of voriconazole and fluconazole at any dose is not recommended.

Zidovudine:

fluconazole increases the Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% reduction in the clearance of orally administered zidovudine. T1/2 of zidovudine increases by approximately 128% when coadministered with fluconazole. Therefore, patients receiving this combination should be monitored for adverse reactions to zidovudine. A dose reduction of zidovudine may also be necessary.

Azithromycin:

In an open-label, randomized, three-way crossover study of 18 healthy volunteers, the effect of azithromycin at a single oral dose of 1200 mg on the pharmacokinetics of fluconazole at a single dose of 800 mg was assessed, as well as the effect of fluconazole on the pharmacokinetics of azithromycin. No significant pharmacokinetic interaction was found between fluconazole and azithromycin.

Ivacaftor:
Co-administration of fluconazole with ivacaftor (cystic fibrosis transmembrane regulator) increases the concentration of ivacaftor by 3 times, and the concentration of hydroxymethyl-ivacfactor (M1) by 1.9 times. For patients taking moderate CYP3A inhibitors such as fluconazole and erythromycin, it is recommended that the dose of ivacaftor be reduced to 150 mg/day.

Side effects of the drug Mikosist

Nausea, vomiting, lower abdominal pain, flatulence, diarrhea, skin rash, headache. In some patients, primarily with a severe underlying disease (oncological pathology, AIDS), kidney and liver damage and hematopoietic disorders are possible, but their cause-and-effect relationship with taking fluconazole has not been established. Skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous rash, erythema multiforme) are most likely in patients with acquired immunodeficiency conditions; If a skin rash appears, treatment with fluconazole should be discontinued. In AIDS patients taking fluconazole, seizures, leukopenia, thrombocytopenia and alopecia were noted, but a cause-and-effect relationship with the drug has not been established. Like other azole derivatives, anaphylactic reactions may occur during treatment with fluconazole. If symptoms suggestive of liver damage occur, fluconazole should be discontinued. The hepatotoxic effect of fluconazole is usually reversible; symptoms disappear after cessation of therapy.

Interactions of the drug Mikosist

Despite the lack of data on chemical incompatibility, mixing the drug with other infusion solutions is not recommended. When used simultaneously with indirect anticoagulants, it can cause an increase in prothrombin time (on average by 12%). Fluconazole may inhibit the metabolism of oral antidiabetic drugs (sulfonylureas) leading to hypoglycemia. Thiazide diuretics may increase plasma fluconazole levels by approximately 40%. Fluconazole may significantly increase plasma levels of phenytoin, so phenytoin levels should be monitored when used concomitantly. When prescribing fluconazole to patients receiving long-term rifampicin, the AUC for fluconazole decreased by 25% and the half-life by 20%, which may require an increase in the dose of the drug. When using fluconazole concomitantly with cyclosporine, it is recommended to monitor the level of cyclosporine in the blood plasma. Fluconazole may reduce the clearance of theophylline by an average of 18%, which may require a dose reduction of the latter. Azole derivatives when combined with terfenadine can cause the development of arrhythmias. With simultaneous use of fluconazole with cidovudine, the AUC for the latter may increase by 20–74%, which requires monitoring its concentration in the blood.