Fucis®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUSYSÒ (FUSYSÒ)

Composition:

Active substance: fluconazole;

1 tablet contains fluconazole 50 mg or 100 mg or 150 mg or 200 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K30, talc, magnesium stearate, sodium starch glycolate (type A), sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with bevelled edges, with a break line on one side.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action.

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, which is an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent depletion of ergosterol in the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

A study of interaction with antipyrine demonstrated that single or repeated administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro Susceptibility.

Fluconazole demonstrates in vitro antifungal activity against clinically relevant Candida species, including C. albicans, C. parapsilosis, and C. tropicalis. C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations (MICs) and epidemiological cutoff values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those for C. albicans.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Relationship between Pharmacokinetic and Pharmacodynamic Properties.

According to animal studies, there is a correlation between the minimal inhibitory concentration (MIC) and efficacy in experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between AUC and fluconazole dose (approximately 1:1). There is also a direct, but suboptimal, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment outcomes for infections caused by strains with high MIC values for fluconazole are less favorable.

Mechanisms of Resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high MIC values against fungal strains possessing one or more resistance mechanisms, which negatively impacts in vivo efficacy and clinical outcomes.

In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may be due to mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by Candida species other than C. albicans, often with reduced susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant species (e.g., C. krusei) or newly emerging species (e.g., C. auris).

EUCAST (European Committee on Antimicrobial Susceptibility Testing) Breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species. (Refer to the accompanying explanatory document: EUCAST for Fluconazole (2020) – Version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal Agents, Tables of Breakpoints for Interpretation of MICs, Version 10.0, effective 04.02.2020). These breakpoints are categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific MIC distributions, and species-specific breakpoints, typically associated with human infections. These breakpoints are listed below.

S = sensitive;

R = resistant;

a – breakpoints not related to a specific species, which are primarily based on pharmacokinetic/pharmacodynamic data and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a specific breakpoint;

• susceptibility testing is not recommended, as this species is not a target for medical therapy;

* All C. glabrata values fall into category I. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S strains. I – susceptible dose-dependent: a microorganism is categorized as "susceptible dose-dependent" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or increasing drug concentration at the site of infection.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption when the drug is administered orally. Peak plasma concentration is reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 with once-daily dosing, or by day 2 of treatment if a loading dose twice the standard daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to total body water. Plasma protein binding is low (11–12%).

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum.

With a 50 mg once-daily dose, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration remained at 5.8 µg/g. With a 150 mg once-weekly dose, the concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

Fluconazole concentration in nails after 4 months of 150 mg once-weekly dosing was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disorders; fluconazole was detectable in nail samples up to 6 months after therapy completion.

Metabolism.

Fluconazole is minimally metabolized. After administration of a radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent inhibitor of the CYP2C19 isoenzyme.

Excretion.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for single-dose administration in vaginal candidiasis and once-weekly dosing for other indications.

Pharmacokinetics in renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, this patient group requires dose reduction. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Pharmacokinetics during lactation.

Plasma and breast milk fluconazole concentrations were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of approximately 98% of maternal plasma levels. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily fluconazole dose ingested by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean peak milk concentration, was 0.39 mg/kg/day, corresponding to approximately 40% of the recommended dose for neonates (age < 2 weeks) or 13% of the recommended dose for infants for treatment of mucosal candidiasis.

Pharmacokinetics in children.

Pharmacokinetic parameters in children were evaluated in five studies: two single-dose studies, two multiple-dose studies, and one study in preterm neonates. After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, and the volume of distribution was approximately 880 mL/kg. A longer plasma elimination half-life of approximately 24 hours was observed after single-dose administration. This value is comparable to the elimination half-life observed after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 preterm infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours), and mean birth weight was 0.9 kg (range 0.75–1.10 kg). Up to 5 intravenous doses of fluconazole 6 mg/kg were administered every 72 hours. Mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. Volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13, respectively.

Pharmacokinetics in elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently taking diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher compared to those in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Thus, pharmacokinetic changes in elderly patients appear to be primarily dependent on renal function parameters.

Clinical characteristics.

Indications.

Fucis® is indicated for the treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

• cryptococcal meningitis (see section "Special precautions for use");
• coccidioidomycosis (see section "Special precautions for use");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic cutaneous and mucosal candidiasis;
• chronic atrophic oral candidiasis (denture-related stomatitis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
• candidal balanitis, when topical therapy is not appropriate;
• dermatomycoses, including tinea pedis, tinea of glabrous skin, tinea cruris; pityriasis versicolor and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

Fucis® is indicated for prophylaxis of the following conditions in adults:

• prevention of recurrence of cryptococcal meningitis in patients at high risk of developing it;
• prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prophylaxis of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation) (see section "Pharmacological properties. Pharmacodynamics").

Children.

Fucis® is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prophylaxis of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section "Special precautions for use").

The tablet formulation of Fucis® may be administered to this patient population only when children are able to swallow tablets safely, which is generally possible from the age of 5 years.

Treatment with Fucis® may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted accordingly once results are obtained.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the medicinal product.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on multiple-dose interaction study results).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin); see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction".

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride: cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsade de pointes" type, have been reported in patients receiving fluconazole and cisapride concomitantly. Concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in plasma cisapride levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias associated with QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these agents have been conducted. When fluconazole was administered at a dose of 200 mg/day, no QTc interval prolongation was observed. However, at fluconazole doses of 400 mg/day or higher, a significant increase in terfenadine plasma levels occurs when both agents are administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg/day concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide: concomitant use of fluconazole with pimozide may lead to inhibition of pimozide metabolism, although corresponding in vitro and in vivo studies have not been conducted. Increased pimozide plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole with pimozide is contraindicated (see section "Contraindications").

Quinidine: concomitant use of fluconazole and quinidine may lead to inhibition of quinidine metabolism, although corresponding in vitro and in vivo studies have not been conducted. Quinidine use has been associated with QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole with quinidine is contraindicated (see section "Contraindications").

Erythromycin: concomitant use of fluconazole with erythromycin may increase the risk of cardiotoxicity (QT interval prolongation and paroxysmal ventricular tachycardia of the "torsade de pointes" type) and, consequently, sudden cardiac death. Concomitant use of fluconazole and erythromycin is contraindicated (see section "Contraindications").

Concomitant use of fluconazole and the following medicinal products is not recommended.

Halofantrine: fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsade de pointes" type) and, consequently, sudden cardiac death. The combination of these medicinal products should be avoided (see section "Special precautions for use").

Concomitant use of fluconazole and the following medicinal products requires caution.

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. Caution is required when fluconazole and amiodarone are used concomitantly, especially when fluconazole is used at high doses (800 mg).

Concomitant use of fluconazole and the following medicinal products requires caution and dose adjustment.

Effect of other medicinal products on fluconazole.

Clinically significant effects on fluconazole absorption following oral administration are not observed with concomitant food intake, cimetidine, antacids, or whole-body irradiation (in bone marrow transplantation).

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in fluconazole elimination half-life. Therefore, dose escalation of fluconazole should be considered for patients receiving rifampicin.

Hydrochlorothiazide: in a pharmacokinetic interaction study, repeated concomitant use of hydrochlorothiazide in healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40 %. Such interaction parameters do not require changes in fluconazole dosing regimen for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to observed/documentarily confirmed interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution, and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long elimination half-life (see section "Contraindications").

Abrocitinib: fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155%. When used concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to its prescribing information.

Alfentanil: concomitant use of fluconazole 400 mg and alfentanil 20 µg/kg intravenously resulted in a twofold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates dose adjustment of alfentanil.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and one week after initiation. Dose adjustment of amitriptyline or nortriptyline may be required if necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in the following outcomes: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two agents in systemic Aspergillus fumigatus infection. The clinical significance of these findings is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported during concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indandione derivatives concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and midazolam 7.5 mg orally increased AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If benzodiazepines need to be administered concomitantly to a patient undergoing fluconazole therapy, their dose should be reduced and appropriate patient monitoring should be established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and increases serum carbamazepine levels by 30 %. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be required depending on its concentration and effect.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4 enzyme. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib: concomitant use of fluconazole (200 mg/day) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68 % and 134 %, respectively. When celecoxib is used concomitantly with fluconazole, a halving of the celecoxib dose may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These agents may be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine concentrations.

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. Fluconazole significantly slows fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, patient status should be closely monitored. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), dose-dependently increases the risk of myopathy and rhabdomyolysis (due to reduced hepatic statin metabolism). If concomitant use of these agents is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If creatine kinase levels are significantly elevated, or if myopathy/rhabdomyolysis is suspected or diagnosed, HMG-CoA reductase inhibitors should be discontinued. Lower doses of HMG-CoA reductase inhibitors may be required according to statin prescribing information.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase ibrutinib plasma concentration and may increase the risk of toxicity. If combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily to continue inhibitor therapy, with continuous clinical monitoring.

Ivacaftor (alone or in combination with drugs of the same therapeutic class): concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, with hydroxymethylivacaftor (M1) increased exposure to ivacaftor by 3 times and exposure to hydroxymethylivacaftor (M1) by 1.9 times.

The dose of ivacaftor (alone or in combination) should be reduced according to its medical prescribing information (alone or in combination).

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase olaparib plasma concentration; concomitant use is not recommended. If use of this combination cannot be avoided, the olaparib dose should be reduced to 200 mg twice daily.

Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, and tacrolimus).

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day were used concomitantly, cyclosporine AUC increased by 1.8 times. These agents may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus: fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These agents may be used concomitantly provided sirolimus dose is adjusted based on concentration and effect.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5 times with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced based on tacrolimus concentration.

Losartan: fluconazole inhibits the conversion of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous blood pressure monitoring in patients is recommended.

Lurasidone: moderate CYP3A4 inhibitors such as fluconazole may increase lurasidone plasma concentration. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in its medical prescribing information.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary when used concomitantly with fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): concomitant use of fluconazole increased Cmax and AUC of flurbiprofen by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, concomitant use of fluconazole with racemic ibuprofen (400 mg) increased Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer by 15 % and 82 %, respectively, compared to racemic ibuprofen alone.

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant use of 200 mg fluconazole and 250 mg phenytoin intravenously increases AUC24 of phenytoin by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration is required when these medicinal products are used concomitantly to avoid phenytoin toxicity.

Prednisone: a case has been reported of acute adrenal insufficiency in a liver transplant patient receiving prednisone, occurring after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after fluconazole discontinuation.

Rifabutin: fluconazole increases rifabutin serum concentration, leading to an up to 80 % increase in rifabutin AUC. Cases of uveitis have been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this combination.

Saquinavir: fluconazole increases AUC and Cmax of saquinavir by approximately 50 % and 55 %, respectively, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: concomitant use of fluconazole with oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) resulted in prolonged elimination half-life. Frequent blood glucose monitoring is recommended, and sulfonylurea derivative dose should be reduced accordingly when used concomitantly with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days reduced the average plasma clearance of theophylline by 18 %. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity occur.

Tofacitinib: the effect of tofacitinib increases when used concomitantly with medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these agents.

Vasopressin receptor antagonists (tolvaptan): exposure to tolvaptan (a CYP3A4 substrate) increases significantly (200% AUC; 80% Cmax) when used concomitantly with fluconazole (a moderate CYP3A4 inhibitor), thereby increasing the risk of adverse reactions such as increased diuresis, dehydration, and acute renal failure. When used concomitantly, the tolvaptan dose should be reduced according to its prescribing information, and patients should be monitored for adverse reactions.

Vinca alkaloids: fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: a case has been reported of CNS adverse reactions in the form of pseudotumor cerebri in a patient receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole, which resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in Cmax and AUCτ of voriconazole by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is required.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a reduction in zidovudine clearance of approximately 45 % after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole-zidovudine combination. Patients receiving this combination should be monitored for zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered.

Azithromycin: no significant pharmacokinetic interactions were observed after single oral concomitant administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.

Oral contraceptives: no effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg/day resulted in a 40 % increase in AUC of ethinylestradiol and a 24 % increase in levonorgestrel. This suggests that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. It is known that when fluconazole is used to treat dermatophytosis in children, its efficacy does not exceed that of griseofulvin, and the overall efficacy rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. Evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, no dosage recommendations are available for treating these infections.

Deep endemic mycoses. Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, no dosage recommendations are available for treating these infections.

Renal system. Fluconazole should be used with caution in patients with impaired renal function (see section "Dosage and administration").

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it occurs rarely. Adrenal insufficiency associated with concomitant prednisone therapy is described in subsection Effect of fluconazole on other medicinal products of section "Interaction with other medicinal products and other forms of interaction".

Hepatobiliary system. Fluconazole should be used with caution in patients with hepatic impairment. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was linked to fluconazole, no clear relationship was observed with the total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for progression to more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole treatment should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole causes QT interval prolongation by inhibiting the inward rectifier potassium ion current (I_Kr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported with fluconazole use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other QT-prolonging drugs. Patients with hypokalemia and severe heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Fluconazole should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 cytochrome P450 enzyme is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole treatment. Drug reaction with eosinophilia and systemic symptoms (DRESS) has also been reported. Patients with AIDS are more prone to developing severe skin reactions when taking various medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole, further treatment with the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, close monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. Rare cases of anaphylactic reactions have been reported (see section "Contraindications").

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a moderate inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with medicinal products that have a narrow therapeutic index and are metabolized by CYP2C9, CYP2C19, or CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine. Close monitoring of the patient is required when terfenadine is used concomitantly with fluconazole at doses below 400 mg daily (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Candidiasis. Studies have shown an increasing prevalence of Candida species other than C. albicans. These species are often intrinsically resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy due to treatment failure. Therefore, it is recommended to consider the prevalence of resistance among different Candida species to fluconazole.

Excipients.

The medicinal product contains lactose. If a patient has an intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

One tablet of Fucis® contains less than 1 mmol of sodium (23 mg), i.e., the product is practically sodium-free.

Use during pregnancy or breastfeeding.

Women of reproductive age.

Before initiating treatment, the patient should be informed about the potential risk to the fetus.

After a single dose, a washout period of fluconazole, which is approximately 1 week (corresponding to 5–6 elimination half-lives), should be observed before conception (see section "Pharmacokinetics").

For prolonged treatment courses, women of reproductive age should consider using contraception throughout the entire treatment period and for 1 week after the last dose.

Pregnancy.

Observational studies indicate an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand pregnant women who received fluconazole treatment with a cumulative dose ≤ 150 mg during the first trimester show no increased overall risk of fetal malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a fluconazole dose of 150 mg orally and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester found a 1.8- to 2-fold increased risk of cardiac malformations in infants compared to infants whose mothers did not use fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high-dose (400–800 mg/day) fluconazole for 3 months or longer during pregnancy for the treatment of coccidioidomycosis. Among the congenital malformations observed in these infants were brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

Standard doses and short-term fluconazole treatment should not be used during pregnancy unless absolutely necessary.

High-dose and/or prolonged fluconazole treatment should not be used during pregnancy except for the treatment of life-threatening infections.

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg).

Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole.

The benefit of breastfeeding for the child's development and health, the mother's clinical need for Fucis®, and any potential adverse effects of Fucis® or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Fertility.

Fluconazole had no effect on fertility in male and female rats.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Studies on the effect of fluconazole on the ability to drive vehicles or operate machinery have not been conducted.

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during treatment. If such symptoms occur, driving vehicles or operating machinery is not recommended.

Administration and Dosage.

The drug is administered orally. The drug may be taken regardless of food intake.

The daily dose of fluconazole depends on the type and severity of the fungal infection. When repeated administration is required, treatment of infections should be continued until clinical and laboratory signs of fungal infection activity have disappeared. Inadequate duration of treatment may lead to recurrence of the active infectious process.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg once daily. The duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of developing it: the recommended dose is 200 mg once daily for an indefinite period.

Coccidioidomycosis. The recommended dose is 200–400 mg once daily. The duration of treatment is 11–24 months or longer, depending on the patient's condition. For treatment of certain forms of infection, especially meningitis, a dose of 800 mg once daily may be appropriate.

Invasive candidiasis. The loading dose is 800 mg on the first day. Maintenance dose – 400 mg once daily. The recommended duration of treatment for candidemia is usually 2 weeks after the first negative blood culture results and disappearance of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. The duration of treatment is 7–21 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. The duration of treatment is 14–30 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Candiduria: the recommended dose is 200–400 mg once daily for 7–21 days. For patients with severe immunodeficiency, the duration of treatment may be extended.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic candidiasis of skin and mucous membranes: the recommended dose is 50–100 mg once daily. The duration of treatment is up to 28 days, but may be extended depending on the severity and type of infection or in case of immunosuppression.

Prevention of recurrence of mucosal candidiasis in HIV-infected patients at high risk of developing it.

• Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100–200 mg once daily or 200 mg three times weekly. The duration of treatment is indefinite for patients with suppressed immunity.

Prophylaxis of candidiasis in patients with prolonged neutropenia. The recommended dose is 200–400 mg once daily. Treatment should be initiated several days before the expected onset of neutropenia and continued for 7 days after neutrophil counts rise above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: the recommended dose is 150 mg as a single dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more episodes per year): the recommended regimen is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After this, a maintenance dose of 150 mg once weekly should be given for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous candidiasis, tinea cruris, cutaneous candidiasis: the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg once daily for 2–4 weeks.
• Dermatophytic onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued until a healthy nail replaces the infected one. Healthy nail regrowth typically requires 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-standing chronic infections, nail appearance may sometimes remain altered.

Special patient groups.

Elderly patients.

Dosage should be adjusted according to renal function (see below).

Patients with renal impairment.

Fluconazole is primarily excreted unchanged in urine. No dose adjustment is required for single-dose administration. For patients (including children) with impaired renal function requiring multiple dosing, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on therapeutic indications. Subsequently, the daily dose (depending on the indication) should be calculated according to Table 1.

Table 1

Patients undergoing regular hemodialysis should receive 100% of the recommended dose after each hemodialysis session. On days when hemodialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Patients with hepatic impairment.

Fluconazole should be used with caution in patients with hepatic impairment, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children.

The maximum daily dose of 400 mg should not be exceeded.

As with similar infections in adults, the duration of treatment depends on clinical and mycological response. The drug should be administered once daily.

Dosing recommendations for children with renal impairment are provided above. The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should determine whether the adult or pediatric dose is optimal for the patient. Clinical data indicate that children have a higher fluconazole clearance compared to adults. Administration of doses of 100, 200, and 400 mg once daily to adults and doses of 3, 6, and 12 mg/kg once daily to children results in comparable systemic exposure.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Available information is presented in the section "Adverse reactions." If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose may be administered on day 1 to achieve steady-state concentration more rapidly.

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg/day depending on the severity of the disease.

Maintenance therapy for prevention of recurrence of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg/day once daily, depending on the severity of the disease.

Prophylaxis of candidiasis in immunocompromised patients: dosage is 3–12 mg/kg once daily depending on the severity and duration of induced neutropenia (see doses for adults).

Children.

The tablet formulation of the drug may be used in this patient population only when children are able to safely swallow a tablet, which is generally possible from the age of 5 years.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Fluconazole is primarily excreted in urine; therefore, forced diuresis may enhance its elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse Reactions

A drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with fluconazole use (see section "Special precautions").

The most commonly reported adverse reactions (from ≥1/100 to <1/10) include: headache, abdominal pain, diarrhea, nausea, vomiting, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase in blood, and rash.

The following frequency classification is used to assess the incidence of adverse reactions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.

Uncommon: convulsions, dizziness, paraesthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Rare: paroxysmal ventricular tachycardia of the "torsades de pointes" type, QT interval prolongation (see section "Special precautions").

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased levels of ALT, AST, alkaline phosphatase in blood (see section "Special precautions").

Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special precautions").

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special precautions").

Skin and subcutaneous tissue disorders

Common: rash (see section "Special precautions").

Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special precautions").

Rare: toxic epidermal necrolysis, Stevens–Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special precautions").

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: fatigue, malaise, asthenia, fever.

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in children during clinical trials, except for genital candidiasis, are comparable to those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

Tablets 50 mg, pack of 4 or 10 in a blister pack within a cardboard box.

Tablets 100 mg, pack of 4 or 10 in a blister pack within a cardboard box.

Tablets 150 mg, pack of 2 or 4 in a blister pack within a cardboard box.

Tablets 200 mg, pack of 4 or 10 in a blister pack within a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTION

for medical use of the medicinal product

FUCISÒ

(FUSYSÒ)

Composition:

Active substance: fluconazole;

1 tablet contains 50 mg, 100 mg, 150 mg, or 200 mg of fluconazole;

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K30, talc, magnesium stearate, sodium starch glycolate (type A), sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with bevelled edges, with a break line on one side.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation mediated by cytochrome P450, an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Studies on interaction with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole do not affect antipyrine metabolism.

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against clinically prevalent Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and epidemiological cut-off values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those against C. albicans.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationships.

According to animal studies, there is a correlation between the minimal inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between AUC and fluconazole dose (approximately 1:1). There is also a direct, albeit insufficient, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains with high MIC values for fluconazole is less effective.

Mechanisms of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high MIC values against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo and clinical efficacy.

In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may be due to mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by Candida spp. other than C. albicans, which often have reduced susceptibility (C. glabrata) or are resistant (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for the treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant (C. krusei) or emerging (C. auris) Candida species.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species. (Accompanying explanatory document: EUCAST document for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective date 04.02.2020). These have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific minimal inhibitory concentration distributions, and species-specific breakpoints, most commonly associated with human infections. These breakpoints are listed below.

S = susceptible;

R = resistant;

a – breakpoints not associated with a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific distribution according to minimal inhibitory concentration. These were studied only in microorganisms lacking a specific breakpoint;

• susceptibility testing is not recommended, as this species is not a target of antimicrobial therapy;

* All C. glabrata isolates fall within the I category. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S. I – susceptible with increased exposure: a microorganism is categorized as "susceptible with increased exposure" when there is a high probability of therapeutic success due to increased drug exposure achieved by adjustment of dosing regimen or higher drug concentration at the site of infection.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption following oral administration. Peak plasma concentration is reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma drug concentration is proportional to the dose. Steady-state 90% concentration is achieved by day 4–5 with once-daily multiple dosing, or by day 2 of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

The volume of distribution approximates total body water. Plasma protein binding is low (11–12%).

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum.

With a dose of 50 mg once daily, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration remained at 5.8 µg/g. With a dose of 150 mg once weekly, the concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

Fluconazole concentration in nails after 4 months of 150 mg once weekly dosing was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after therapy completion.

Metabolism.

Fluconazole is minimally metabolized. After administration of radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent inhibitor of the CYP2C19 isoenzyme.

Elimination.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for single-dose treatment in vaginal candidiasis and once-weekly dosing for other indications.

Pharmacokinetics in renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, dose reduction is required in this patient group. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Pharmacokinetics during lactation.

Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. In breast milk, fluconazole was detected at an average concentration of approximately 98% of that in maternal plasma. The mean peak concentration in breast milk, observed 5.2 hours after dosing, was 2.61 mg/L. The daily fluconazole dose received by an infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on the mean peak milk concentration, was 0.39 mg/kg/day, corresponding to approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Pharmacokinetics in children.

Pharmacokinetic parameters in children were evaluated in five studies: two single-dose studies, two multiple-dose studies, and one study in premature neonates. After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, an AUC of approximately 38 µg*h/mL per 1 mg/kg dose was observed. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, and the volume of distribution was approximately 880 mL/kg. A longer plasma elimination half-life of approximately 24 hours was observed after single-dose administration. This value is comparable to the plasma elimination half-life observed after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours), and mean birth weight was 0.9 kg (range 0.75–1.10 kg). Up to 5 intravenous doses of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and 47 hours (27–68) on day 13. The area under the curve (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13, respectively.

Pharmacokinetics in elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Similarly, creatinine clearance (74 mL/min), percentage of fluconazole excreted unchanged in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, pharmacokinetic changes in elderly patients are evidently dependent on renal function parameters.

Clinical characteristics.

Indications.

Fucis® is indicated for the treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

• cryptococcal meningitis (see section "Special precautions");
• coccidioidomycosis (see section "Special precautions");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic candidal skin and mucosal infections;
• chronic atrophic oral candidiasis (denture stomatitis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
• candidal balanitis, when topical therapy is not appropriate;
• dermatomycoses, including tinea pedis, cutaneous fungal infections, tinea cruris; pityriasis versicolor and cutaneous candidal infections when systemic therapy is indicated;
• dermatophytic onychomycosis when use of other medicinal products is not appropriate.

Fucis® is indicated for the prevention of the following conditions in adults:

• prevention of recurrence of cryptococcal meningitis in patients at high risk of developing it;
• prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidal infections in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation) (see section "Pharmacological properties. Pharmacodynamics").

Children.

Fucis® is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for the prevention of candidal infections in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section "Special precautions").

The tablet form of the drug may be used in this patient population only when children are able to swallow tablets safely, which is generally possible from the age of 5 years.

Treatment with Fucis® may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted appropriately once results are obtained.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the drug.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole at repeated doses of 400 mg/day or higher (based on results of multiple-dose interaction studies).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin); see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction".

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride: cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients receiving fluconazole and cisapride concomitantly. Concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in plasma cisapride levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. When fluconazole was administered at a dose of 200 mg daily, no QTc interval prolongation was observed. However, at fluconazole doses of 400 mg daily or higher, terfenadine plasma levels were significantly increased when both drugs were used concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. This increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide: concomitant use of fluconazole with pimozide may inhibit pimozide metabolism, although relevant in vitro and in vivo studies have not been conducted. Increased pimozide plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole with pimozide is contraindicated (see section "Contraindications").

Quinidine: concomitant use of fluconazole and quinidine may inhibit quinidine metabolism, although relevant in vitro and in vivo studies have not been conducted. Quinidine use has been associated with QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole with quinidine is contraindicated (see section "Containdications").

Erythromycin: concomitant use of fluconazole and erythromycin may increase the risk of cardiotoxicity (QT interval prolongation and paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden cardiac death. Concomitant use of fluconazole and erythromycin is contraindicated (see section "Contraindications").

Concomitant use of fluconazole and the following medicinal products is not recommended.

Halofantrine: fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these drugs may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden cardiac death. The combination of these drugs should be avoided (see section "Special precautions").

Concomitant use of fluconazole and the following medicinal products requires caution.

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. If concomitant use of fluconazole and amiodarone is necessary, caution should be exercised, especially when using high-dose fluconazole (800 mg).

Concomitant use of fluconazole and the following medicinal products requires caution and dose adjustment.

Effect of other medicinal products on fluconazole.

There is no clinically significant effect on fluconazole absorption following oral administration when co-administered with food, cimetidine, antacids, or whole-body irradiation (in bone marrow transplantation).

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in fluconazole elimination half-life. Therefore, dose adjustment of fluconazole should be considered for patients receiving rifampicin.

Hydrochlorothiazide: in a pharmacokinetic interaction study, multiple-dose co-administration of hydrochlorothiazide in healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40%. Such interaction parameters do not require changes in fluconazole dosing regimen for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution, and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long elimination half-life (see section "Contraindications").

Abrocitinib: fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155%. When used concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to its prescribing information.

Alfentanil: concomitant use of fluconazole 400 mg and intravenous alfentanil 20 mcg/kg resulted in a twofold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates dose adjustment of alfentanil.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and one week after initiation. Dose adjustment of amitriptyline or nortriptyline may be necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in: a slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these findings is unknown.

Anticoagulants: as with other azole antifungal agents, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported during concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants or indandione derivatives. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and oral midazolam 7.5 mg increased AUC and elimination half-life by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg increased triazolam AUC and elimination half-life by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use with fluconazole.

If benzodiazepines must be prescribed to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism, increasing carbamazepine serum levels by 30%. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its concentration and effect.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, verapamil, felodipine) are metabolized by CYP3A4. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib: concomitant use of fluconazole (200 mg/day) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. When celecoxib is used concomitantly with fluconazole, a 50% reduction in celecoxib dose may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole increases serum bilirubin and creatinine levels. These drugs may be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine levels.

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. Fluconazole significantly slows fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, close patient monitoring is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin, simvastatin) or by CYP2C9 (fluvastatin) increases the risk of myopathy and rhabdomyolysis in a dose-dependent manner (due to reduced hepatic statin metabolism). If concomitant use of these drugs is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If significant elevation of creatine kinase occurs, or if myopathy/rhabdomyolysis is suspected or diagnosed, HMG-CoA reductase inhibitors should be discontinued. Lower doses of HMG-CoA reductase inhibitors may be required according to statin prescribing instructions.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of ibrutinib and may increase the risk of toxicity. If combination therapy cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily to continue inhibitor therapy, with continuous clinical monitoring.

Ivacaftor (alone or in combination with drugs of the same therapeutic class): concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, with its hydroxymethyl metabolite (M1) increased exposure to ivacaftor by 3 times and exposure to hydroxymethylivacaftor (M1) by 1.9 times.

The dose of ivacaftor (alone or in combination) should be reduced according to its medical prescribing information (alone or in combination).

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of olaparib; concomitant use is not recommended. If use of this combination cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily.

Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, tacrolimus).

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. Concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in an 1.8-fold increase in cyclosporine AUC. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus: fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted based on concentration and drug effects.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced based on tacrolimus concentration.

Losartan: fluconazole inhibits the conversion of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan therapy. Continuous monitoring of blood pressure in patients is recommended.

Lurasidone: moderate CYP3A4 inhibitors such as fluconazole may increase plasma concentrations of lurasidone. If concomitant use cannot be avoided, the dose of lurasidone should be reduced as specified in its medical prescribing information.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary during concomitant use.

Nonsteroidal anti-inflammatory drugs (NSAIDs): concomitant use with fluconazole increased Cmax and AUC of flurbiprofen by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, concomitant use of fluconazole with racemic ibuprofen (400 mg) increased Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer by 15% and 82%, respectively, compared to racemic ibuprofen alone.

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse reactions and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant use of 200 mg fluconazole and 250 mg intravenous phenytoin increased phenytoin AUC24 by 75% and Cmin by 128%. Monitoring of phenytoin serum concentration is required during concomitant use to avoid phenytoin toxicity.

Prednisone: a case of acute adrenal insufficiency was reported in a liver transplant patient receiving prednisone after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely enhanced CYP3A4 activity, leading to accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after fluconazole discontinuation.

Rifabutin: fluconazole increases rifabutin serum concentration, increasing rifabutin AUC by up to 80%. Uveitis has been reported during concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this drug combination.

Saquinavir: fluconazole increases saquinavir AUC and Cmax by approximately 50% and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: concomitant use of fluconazole with oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, tolbutamide) prolonged their elimination half-life. Frequent blood glucose monitoring and appropriate dose reduction of sulfonylurea derivatives are recommended during concomitant use with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days reduced the average plasma clearance of theophylline by 18%. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity occur.

Tofacitinib: the effect of tofacitinib increases when used concomitantly with medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the dose of tofacitinib to 5 mg once daily when used in combination with these drugs.

Conivaptan: exposure to conivaptan (a CYP3A4 substrate) significantly increases (200% AUC; 80% Cmax) when used concomitantly with fluconazole (a moderate CYP3A4 inhibitor), thereby increasing the risk of adverse reactions such as enhanced diuresis, dehydration, and acute renal failure. When used concomitantly, the dose of conivaptan should be reduced according to its prescribing information, and patients should be monitored for adverse reactions.

Vinca alkaloids: fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine, vinblastine), leading to neurotoxic effects.

Vitamin A: a case of CNS adverse reactions in the form of pseudotumor cerebri was reported in a patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole concomitantly, which resolved after discontinuation of fluconazole. These drugs may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in voriconazole Cmax and AUCτ by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for voriconazole-associated adverse effects is required.

Zidovudine: fluconazole increases zidovudine Cmax and AUC by 84% and 74%, respectively, due to a reduction in zidovudine clearance by approximately 45% after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128% after concomitant use of fluconazole and zidovudine. Patients receiving this drug combination should be monitored for zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered.

Azithromycin: no significant pharmacokinetic interactions were observed after single oral co-administration of azithromycin 1200 mg and fluconazole 800 mg.

Oral contraceptives: no effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily increased AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that repeated use of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytia. It is known that when fluconazole is used to treat dermatophytia in children, its efficacy does not exceed that of griseofulvin, and the overall efficacy rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytia.

Cryptococcosis. Evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, dosage regimen recommendations for treating such conditions are not available.

Deep endemic mycoses. Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, dosage regimen recommendations for treating such conditions are not available.

Renal system. The drug should be used with caution in patients with impaired renal function (see section "Method of administration and dosage").

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it occurs rarely. Adrenal insufficiency associated with concomitant prednisone therapy is described in subsection Effect of fluconazole on other medicinal products of section "Interaction with other medicinal products and other forms of interaction".

Hepatobiliary system. The drug should be used with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was associated with fluconazole use, there was no clear dependence on total daily dose, duration of therapy, sex, or patient age. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormalities in liver function tests during fluconazole treatment should be closely monitored for the development of more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole therapy should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole causes QT interval prolongation by inhibiting the inward rectifier potassium ion current (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported during fluconazole use. These reports involved patients with severe illnesses and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and severe heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Fluconazole should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 cytochrome P450 enzyme is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS) has also been reported. Patients with AIDS are more prone to developing severe skin reactions when taking many medicinal products. If a patient with a superficial fungal infection develops a rash that may be related to fluconazole use, further treatment with the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole therapy should be discontinued in case of bullous eruptions or development of erythema multiforme.

Hypersensitivity. In rare cases, anaphylactic reactions have been reported (see section "Contraindications").

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a moderate inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with medicinal products having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine. Careful monitoring of the patient is required when terfenadine is used concomitantly with fluconazole at doses below 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Candidiasis. Studies have shown an increasing prevalence of Candida species other than C. albicans. These species are often intrinsically resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy due to treatment inefficacy. Therefore, it is recommended to consider the prevalence of resistance among different Candida species to fluconazole.

Excipients.

The product contains lactose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

One tablet of the medicinal product Fucis® contains less than 1 mmol of sodium (23 mg), i.e., the product is practically sodium-free.

Use during pregnancy or breastfeeding.

Women of reproductive age.

Before initiating treatment, the patient should be informed about the potential risk to the fetus.

After a single dose, a washout period of fluconazole of approximately 1 week (corresponding to 5–6 half-lives) should be observed before conception (see section "Pharmacokinetics").

For prolonged treatment courses, women of reproductive age should consider using contraception throughout the entire treatment period and for 1 week after the last dose.

Pregnancy.

Observational studies indicate an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand pregnant women who received fluconazole treatment with a cumulative dose ≤ 150 mg during the first trimester show no increased overall risk of fetal malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the risk of congenital heart defects following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester revealed a 1.8- to 2-fold increased risk of congenital heart defects in infants compared to infants whose mothers did not use fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400 to 800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Among the congenital malformations observed in these children were brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radiohumeral synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

Standard doses of fluconazole and short-term treatment courses should not be used during pregnancy except when absolutely necessary.

High-dose fluconazole and/or prolonged treatment courses should not be used during pregnancy except for the treatment of life-threatening infections.

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard 150 mg dose of fluconazole.

Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole use.

The benefit of breastfeeding for the infant's development and health, the mother's clinical need for Fucis®, and any potential adverse effects of Fucis® or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Fertility.

Fluconazole had no effect on fertility in male and female rats.

Ability to drive and operate machinery.

Studies on the effect of fluconazole on the ability to drive or operate machinery have not been conducted.

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during treatment. If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage.

The drug is administered orally. The drug may be taken regardless of food intake.

The daily dose of fluconazole depends on the type and severity of the fungal infection. When repeated administration is required, treatment of infections should be continued until clinical and laboratory signs of active fungal infection have disappeared. Inadequate duration of treatment may lead to recurrence of active infection.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg once daily. The duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of developing it: the recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis. The recommended dose is 200–400 mg once daily. The duration of treatment is 11–24 months or longer, depending on the patient's condition. For treatment of certain forms of infection, especially meningitis, a dose of 800 mg once daily may be appropriate.

Invasive candidiasis. Loading dose is 800 mg on the first day. Maintenance dose – 400 mg once daily. The recommended duration of treatment for candidemia is usually 2 weeks after the first negative blood culture results and resolution of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. The duration of treatment is 7–21 days (until remission is achieved), but may be prolonged in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. The duration of treatment is 14–30 days (until remission is achieved), but may be prolonged in patients with severe immunodeficiency.
• Candiduria: the recommended dose is 200–400 mg once daily for 7–21 days. For patients with severe immunodeficiency, the duration of treatment may be prolonged.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic skin and mucosal candidiasis: the recommended dose is 50–100 mg once daily. The duration of treatment is up to 28 days, but may be extended depending on the severity and type of infection or in the presence of immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV-infected patients at high risk of developing it.

• Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100–200 mg once daily or 200 mg three times weekly. The duration of treatment is indefinite in immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia. The recommended dose is 200–400 mg once daily. Treatment should be initiated several days before the expected onset of neutropenia and continued for 7 days after neutrophil count increases above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: the recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more recurrences per year): the recommended dose is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After that, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous candidiasis, tinea cruris, cutaneous candidiasis: the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg once daily for 2–4 weeks.
• Dermatophytic onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued until a healthy nail replaces the infected one. Healthy nail regrowth usually takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-term chronic infections, nail appearance may sometimes remain altered.

Special patient groups.

Elderly patients.

Dosage should be adjusted according to renal function (see below).

Patients with renal impairment.

Fluconazole is primarily excreted unchanged in urine. Dose adjustment is not required for single-dose administration. For patients (including children) with impaired renal function requiring multiple-dose therapy, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the therapeutic indication. Subsequently, the daily dose (depending on the indication) should be calculated according to Table 1.

Table 1

Patients undergoing regular hemodialysis should receive 100 % of the recommended dose after each hemodialysis session. On days when hemodialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Patients with hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction, as there is insufficient data regarding the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children.

The maximum daily dose of 400 mg should not be exceeded.

As with similar infections in adults, duration of treatment depends on clinical and mycological response. The drug should be administered once daily.

Dosage recommendations for children with renal impairment are provided above. The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or pediatric dosage is optimal for the patient. Clinical data indicate that children have higher fluconazole clearance compared to adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg once daily to children results in comparable systemic exposure.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Available information is provided in the section "Adverse reactions." If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose may be administered on day 1 to achieve steady-state concentrations more rapidly.

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg/day depending on the severity of the disease.

Maintenance therapy for prevention of recurrence of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg/day once daily, depending on disease severity.

Prophylaxis of candidiasis in immunocompromised patients: dosage is 3–12 mg/kg once daily depending on the severity and duration of induced neutropenia (see adult dosing).

Children.

The tablet formulation of the medicinal product may be used in this patient population only when children are able to swallow tablets safely, which is usually possible at the age of 5 years.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Fluconazole is primarily excreted in the urine; therefore, forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50 %.

Adverse Reactions

A drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with fluconazole use (see section "Special Warnings and Precautions").

Most frequently (from ≥1/100 to <1/10) reported adverse reactions include: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase levels in blood, and rash.

The following classification is used to assess the frequency of adverse reactions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1,000 to <1/100), rare (from ≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.

Uncommon: seizures, dizziness, paraesthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Rare: paroxysmal ventricular tachycardia of the "torsades de pointes" type, QT interval prolongation (see section "Special Warnings and Precautions").

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased levels of ALT, AST, alkaline phosphatase in blood (see section "Special Warnings and Precautions").

Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special Warnings and Precautions").

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special Warnings and Precautions").

Skin and subcutaneous tissue disorders

Common: rash (see section "Special Warnings and Precautions").

Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special Warnings and Precautions").

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special Warnings and Precautions").

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever.

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in children during clinical trials, apart from genital candidiasis, were comparable to those in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets 50 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Tablets 100 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Tablets 150 mg, pack of 2 or 4 in a blister pack in a cardboard box.

Tablets 200 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.

INSTRUCTIONS

for medical use of the medicinal product

FUCISÒ

(FUSYSÒ)

Composition:

Active substance: fluconazole;

One tablet contains fluconazole 50 mg or 100 mg or 150 mg or 200 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K30, talc, magnesium stearate, sodium starch glycolate (type A), sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round tablets with bevelled edges, with a break line on one side.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation mediated by cytochrome P450, an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

A drug interaction study with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole do not affect antipyrine metabolism.

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and epidemiological cut-off values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those against C. albicans.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationships.

According to animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between AUC and fluconazole dose (approximately 1:1). There is also a direct, but suboptimal, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidaemia. Similarly, treatment of infections caused by strains with high MIC values for fluconazole is less effective.

Mechanisms of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high MIC values against fungal strains possessing one or more resistance mechanisms, which negatively impacts its efficacy in vivo and in clinical practice.

In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by Candida spp. other than C. albicans, often with reduced susceptibility (C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for the treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant (C. krusei) or emerging (C. auris) Candida species.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole against Candida species have been established. (Accompanying explanatory document: EUCAST for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Tables of breakpoints for interpretation of MICs, version 10.0, effective 04.02.2020). These breakpoints are divided into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific distribution of minimum inhibitory concentrations, and species-related breakpoints, most commonly associated with human infections. These breakpoints are listed below.

S = susceptible;

R = resistant;

a – breakpoints not associated with a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic data and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a species-specific breakpoint;

• susceptibility testing is not recommended, as this species is not a target for drug therapy;

* All C. glabrata isolates fall into the I category. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S. I – susceptible with increased exposure: a microorganism is categorized as "susceptible with increased exposure" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjustment of the dosing regimen or higher drug concentrations at the site of infection.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect drug absorption following oral administration. Peak plasma concentrations are reached within 0.5–1.5 hours after dosing on an empty stomach. Drug concentration in plasma is proportional to the dose. Steady-state 90% concentration is achieved by day 4–5 with once-daily dosing, or by day 2 of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to total body water. Plasma protein binding is low (11–12%).

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, including the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum.

After a daily dose of 50 mg, fluconazole concentrations in the stratum corneum reached 73 µg/g after 12 days of treatment and remained at 5.8 µg/g 7 days after treatment ended. With a weekly dose of 150 mg, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration remained at 7.1 µg/g.

Nail concentrations of fluconazole after 4 months of weekly 150 mg dosing were 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after therapy completion.

Biological transformation.

Fluconazole is minimally metabolized. After administration of a radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent inhibitor of the CYP2C19 isoenzyme.

Elimination.

The plasma elimination half-life of fluconazole is approximately 30 hours. The drug is primarily excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for single-dose administration in vaginal candidiasis and once-weekly dosing for other indications.

Pharmacokinetics in renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, dose reduction of fluconazole is required in this patient group. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Pharmacokinetics during lactation.

Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. In breast milk, fluconazole was detected at an average concentration of approximately 98% of that in maternal plasma. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole received by the infant via breast milk (assuming an average milk intake of 150 mL/kg/day), calculated based on the mean peak milk concentration, was 0.39 mg/kg/day, corresponding to approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Pharmacokinetics in children.

Pharmacokinetic parameters in children were evaluated in five studies: two single-dose studies, two multiple-dose studies, and one study in premature neonates. After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, the AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, and the volume of distribution was approximately 880 mL/kg. A longer plasma elimination half-life of approximately 24 hours was observed after single-dose administration. This value is comparable to the plasma elimination half-life observed after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The median age at first dose was 24 hours (range 9–36 hours), and the mean birth weight was 0.9 kg (range 0.75–1.10 kg). Up to 5 intravenous injections of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and to 47 hours (27–68) on day 13. The area under the curve (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7 and to 1328 (1040–1680) on day 13, respectively.

Pharmacokinetics in elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg fluconazole orally. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, pharmacokinetic changes in elderly patients are evidently dependent on renal function parameters.

Clinical characteristics.

Indications.

Fucis® is indicated for the treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

• cryptococcal meningitis (see section "Special precautions for use");
• coccidioidomycosis (see section "Special precautions for use");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic candidal skin and mucosal infections;
• chronic atrophic oral candidiasis (denture-related candidiasis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
• candidal balanitis when topical therapy is not appropriate;
• dermatomycoses, including tinea pedis, cutaneous fungal infections, tinea cruris; pityriasis versicolor and cutaneous candidal infections when systemic therapy is indicated;
• dermatophytic onychomycosis when use of other medicinal products is not appropriate.

Fucis® is indicated for prophylaxis of the following conditions in adults:

• prevention of recurrence of cryptococcal meningitis in patients at high risk of developing it;
• prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prophylaxis of candidal infections in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation) (see section "Pharmacological properties. Pharmacodynamics").

Children.

Fucis® is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prophylaxis of candidal infections in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section "Special precautions for use").

Administration of the drug in tablet form to this patient category is possible only when children are able to swallow tablets safely, which is generally feasible from the age of 5 years.

Treatment with Fucis® may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted accordingly once test results are obtained.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the drug.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on results of multiple-dose interaction studies).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin); see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction".

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride: cases of cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients receiving fluconazole and cisapride concomitantly. Concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in cisapride plasma levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. When fluconazole was administered at a dose of 200 mg daily, no QTc interval prolongation was observed. However, when fluconazole was administered at doses of 400 mg daily or higher, a significant increase in terfenadine plasma levels occurred with concomitant use of these drugs. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. This increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide: concomitant use of fluconazole with pimozide may lead to inhibition of pimozide metabolism, although appropriate in vitro and in vivo studies have not been conducted. Increased pimozide plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole with pimozide is contraindicated (see section "Contraindications").

Quinidine: concomitant use of fluconazole and quinidine may lead to inhibition of quinidine metabolism, although appropriate in vitro and in vivo studies have not been conducted. Quinidine use has been associated with QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole with quinidine is contraindicated (see section "Contraindications").

Erythromycin: concomitant use of fluconazole with erythromycin may increase the risk of cardiotoxicity (QT interval prolongation and paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden coronary death. Concomitant use of fluconazole and erythromycin is contraindicated (see section "Contraindications").

Concomitant use of fluconazole and the following medicinal products is not recommended.

Halofantrine: fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden cardiac death. The use of this combination should be avoided (see section "Special precautions for use").

Concomitant use of fluconazole and the following medicinal products requires caution.

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. When concomitant use of fluconazole and amiodarone is necessary, caution should be exercised, especially when fluconazole is used at high doses (800 mg).

Concomitant use of fluconazole and the following medicinal products requires caution and dose adjustment.

Effect of other medicinal products on fluconazole.

Clinically significant effects on fluconazole absorption after oral administration are not observed with concomitant food intake, cimetidine, antacids, or whole-body radiation therapy (in bone marrow transplantation).

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide: in a pharmacokinetic interaction study, multiple concomitant use of hydrochlorothiazide in healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40 %. Such interaction parameters do not require changes in fluconazole dosing regimen for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of isoenzyme CYP2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution; careful monitoring of patients is required. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long elimination half-life (see section "Contraindications").

Abrocitinib: fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155%. When used concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to its prescribing information.

Alfentanil: concomitant use of fluconazole at a dose of 400 mg and alfentanil at a dose of 20 µg/kg intravenously resulted in a twofold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates dose adjustment of alfentanil.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and one week after initiation. Dose adjustment of amitriptyline or nortriptyline may be necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in: a slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these results is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported with concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indandiones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole at a dose of 200 mg/day and 0.25 mg triazolam orally resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam.

If benzodiazepines need to be prescribed to a patient undergoing fluconazole treatment, their dose should be reduced and appropriate patient monitoring should be established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and causes a 30 % increase in carbamazepine serum levels. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its concentration and effect.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib: concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68 % and 134 %, respectively. When celecoxib is used concomitantly with fluconazole, a halving of the celecoxib dose may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs may be used concomitantly, considering the possible risk of increased bilirubin and creatinine levels in serum.

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. Fluconazole significantly slows fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful patient monitoring is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), dose-dependently increases the risk of myopathy and rhabdomyolysis (due to reduced hepatic metabolism of statins). If concomitant use of these drugs is necessary, careful monitoring for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels are required. If significant elevation of creatine kinase levels occurs, or if myopathy/rhabdomyolysis is suspected or detected, HMG-CoA reductase inhibitors should be discontinued. Lower doses of HMG-CoA reductase inhibitors may be required according to the statin prescribing information.

Ibrutinib: moderate CYP3A4 inhibitors, such as fluconazole, increase ibrutinib plasma concentration and may increase the risk of toxicity. If combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily to continue inhibitor use and ensure continuous clinical monitoring.

Ivacaftor (alone or in combination with drugs of the same therapeutic class): concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, with hydroxymethylivacaftor (M1) increased exposure to ivacaftor by 3-fold and exposure to hydroxymethylivacaftor (M1) by 1.9-fold.

The dose of ivacaftor (alone or in combination) should be reduced according to its medical prescribing information (alone or in combination).

Olaparib: moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentration; concomitant use is not recommended. If use of this combination cannot be avoided, the olaparib dose should be reduced to 200 mg twice daily.

Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, and tacrolimus).

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. With concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These drugs may be used concomitantly provided cyclosporine dose is reduced depending on its concentration.

Everolimus: fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted depending on concentration and drug effects.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5-fold with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced depending on tacrolimus concentration.

Losartan: fluconazole inhibits the conversion of losartan to its active metabolite (E-31 74), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure in patients is recommended.

Lurasidone: moderate CYP3A4 inhibitors, such as fluconazole, may increase lurasidone plasma concentration. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in its medical prescribing information.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary with concomitant use of methadone and fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): concomitant use with fluconazole increased Cmax and AUC of flurbiprofen by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, concomitant use of fluconazole with racemic ibuprofen (400 mg) increased Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer by 15 % and 82 %, respectively, compared to racemic ibuprofen alone.

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse reactions and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant use of 200 mg fluconazole and 250 mg phenytoin intravenously increases AUC24 of phenytoin by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration is required with concomitant use of these drugs to avoid phenytoin toxicity.

Prednisone: a case was reported where a liver transplant patient developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole therapy while on prednisone. Discontinuation of fluconazole likely caused increased CYP3A4 activity, leading to accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

Rifabutin: fluconazole increases rifabutin serum concentration, leading to an up to 80 % increase in rifabutin AUC. Cases of uveitis have been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this drug combination.

Saquinavir: fluconazole increases AUC and Cmax of saquinavir by approximately 50 % and 55 %, respectively, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: concomitant use of fluconazole with oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) led to prolonged elimination half-life. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative dose when used concomitantly with fluconazole are recommended.

Theophylline: administration of fluconazole 200 mg for 14 days resulted in an 18 % decrease in the average plasma clearance of theophylline. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity appear.

Tofacitinib: the effect of tofacitinib increases with concomitant use of medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these drugs.

Tomivosertib: exposure to tomivosertib (a CYP3A4 substrate) significantly increases (200% AUC; 80% Cmax) when used concomitantly with fluconazole (a moderate CYP3A4 inhibitor), thereby increasing the risk of adverse reactions such as increased diuresis, dehydration, and acute renal failure. If used concomitantly, the tomivosertib dose should be reduced according to its prescribing information, and the patient should be monitored for adverse reactions.

Vinca alkaloids: fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: a case was reported where a patient receiving all-trans retinoic acid (acid form of vitamin A) concomitantly with fluconazole developed central nervous system adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These drugs may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg every 24 hours for 4 days) resulted in an average increase in Cmax and AUCτ of voriconazole by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is required.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a decrease in zidovudine clearance by approximately 45 % with oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole-zidovudine combination. Patients receiving this drug combination should be monitored for adverse reactions associated with zidovudine use. Consideration may be given to reducing the zidovudine dose.

Azithromycin: no significant pharmacokinetic interactions were observed with single oral concomitant administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.

Oral contraceptives: no effect on hormone levels was observed with fluconazole 50 mg, whereas with fluconazole 200 mg daily, AUC of ethinylestradiol increased by 40 % and levonorgestrel by 24 %. This suggests that repeated use of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. It is known that when fluconazole is used to treat dermatophytosis in children, its efficacy does not exceed that of griseofulvin, and the overall efficacy rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. There is insufficient evidence of efficacy of fluconazole for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, dosage recommendations for treatment of such infections are not available.

Deep endemic mycoses. There is insufficient evidence of efficacy of flucon游戏副本азолу for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, dosage recommendations for treatment of such infections are not available.

Renal system. The drug should be used with caution in patients with impaired renal function (see section "Administration and dosage").

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rare. Adrenal insufficiency associated with concomitant treatment with prednisone is described in subsection Effect of fluconazole on other medicinal products of section "Interaction with other medicinal products and other forms of interaction".

Hepatobiliary system. The drug should be used with caution in patients with impaired liver function. Use of fluconazole has been associated with rare cases of development of severe hepatotoxicity, including fatal outcomes, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was associated with fluconazole use, there was no clear dependence on the total daily dose of the drug, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormalities in liver function tests during fluconazole treatment should be closely monitored for the development of more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole treatment should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole causes QT interval prolongation by inhibiting the inward rectifier potassium ion current (Ikr). QT interval prolongation caused by other medicinal products (such as amiodarone) may be potentiated due to inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the torsades de pointes type have been reported during fluconazole use. These reports involved patients with severe underlying diseases and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and severe heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Fluconazole should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 cytochrome P450 enzyme is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also been reported. Patients with AIDS are more susceptible to developing severe skin reactions when taking many medicinal products. If a patient with a superficial fungal infection develops a rash that may be related to fluconazole use, further treatment with the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. In rare cases, anaphylactic reactions have been reported (see section "Contraindications").

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a moderate inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with medicinal products having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine. Careful monitoring of the patient is required when terfenadine is used concomitantly with fluconazole at doses less than 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Candidiasis. Studies have shown an increasing prevalence of Candida species other than C. albicans. These species are often naturally resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy due to treatment inefficacy. Therefore, it is recommended to consider the prevalence of resistance of different Candida species to fluconazole.

Excipients.

The product contains lactose. If a patient has a known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

One tablet of the medicinal product Fucis® contains less than 1 mmol of sodium (23 mg), i.e., the product is practically sodium-free.

Use during pregnancy or breastfeeding.

Women of reproductive age.

Before initiating treatment, the patient should be informed about the potential risk to the fetus.

After administration of a single dose, a washout period of fluconazole, which is approximately 1 week (corresponding to 5–6 elimination half-lives), should be observed before conception (see section "Pharmacokinetics").

For prolonged treatment courses, women of reproductive age should consider using contraception throughout the entire treatment period and for 1 week after the last dose.

Pregnancy.

Observational studies indicate an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand pregnant women who received fluconazole treatment at a cumulative dose ≤ 150 mg during the first trimester show no increased overall risk of fetal malformations. In one large observational cohort study, oral use of fluconazole during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women who received cumulative doses ≤ 450 mg, compared to women who received topical azoles, and approximately 4 additional cases per 1000 women who received cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester revealed an 1.8–2-fold increased risk of cardiac malformations in infants compared to infants whose mothers did not use fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Among the congenital malformations observed in these children were brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

Standard doses and short-term courses of fluconazole should not be used during pregnancy unless absolutely necessary.

High-dose fluconazole and/or prolonged treatment courses should not be used during pregnancy except for the treatment of life-threatening infections.

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg).

Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole treatment.

The benefit of breastfeeding for the infant's development and health, the mother's clinical need for Fucis® and any potential adverse effects of Fucis® or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Fertility.

Fluconazole had no effect on fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of fluconazole on the ability to drive or operate machinery have not been conducted.

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during treatment. If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage

The drug is administered orally. The drug may be taken regardless of food intake.

The daily dose of fluconazole depends on the type and severity of the fungal infection. When repeated administration is required, treatment of infections should be continued until clinical and laboratory signs of fungal activity have disappeared. Inadequate duration of treatment may lead to recurrence of the active infectious process.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg once daily. Duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of developing it: the recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis. The recommended dose is 200–400 mg once daily. Duration of treatment is 11–24 months or longer, depending on the patient's condition. For treatment of certain forms of infection, especially meningitis, a dose of 800 mg once daily may be appropriate.

Invasive candidiasis. Loading dose is 800 mg on the first day. Maintenance dose – 400 mg once daily. The recommended duration of treatment for candidemia is usually 2 weeks after the first negative blood culture and resolution of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. Duration of treatment is 7–21 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. Duration of treatment is 14–30 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Candiduria: recommended dose is 200–400 mg once daily for 7–21 days. For patients with severe immunodeficiency, duration of treatment may be prolonged.
• Chronic atrophic candidiasis: recommended dose is 50 mg once daily for 14 days.
• Chronic cutaneous and mucosal candidiasis: recommended dose is 50–100 mg once daily. Duration of treatment is up to 28 days, but may be extended depending on severity and type of infection or in case of immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV-infected patients at high risk of developing it.

• Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg once daily or 200 mg three times weekly. Duration of treatment is indefinite for immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia. Recommended dose is 200–400 mg once daily. Treatment should be initiated several days before anticipated onset of neutropenia and continued for 7 days after neutrophil count rises above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more recurrences per year): recommended dose is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After that, maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

• Tinea pedis, tinea of glabrous skin, tinea cruris, cutaneous candidiasis: recommended dose is 150 mg once weekly or 50 mg once daily. Duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg once daily for 2–4 weeks.
• Dermatophytic onychomycosis: recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced by a healthy one. Healthy nail regrowth usually takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-standing chronic infections, nail appearance may remain altered.

Special patient groups.

Elderly patients.

Dosage should be adjusted according to renal function (see below).

Patients with renal impairment.

Fluconazole is predominantly excreted unchanged in the urine. No dose adjustment is required for single-dose administration. For patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the therapeutic indication. Subsequently, the daily dose (depending on the indication) should be calculated according to Table 1.

Table 1

Patients undergoing regular hemodialysis should receive 100 % of the recommended dose after each hemodialysis session. On days when hemodialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Patients with hepatic impairment.

Fluconazole should be administered with caution to patients with hepatic impairment, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children.

The maximum daily dose of 400 mg should not be exceeded.

As with similar infections in adults, the duration of treatment depends on the clinical and mycological response. The drug should be administered once daily.

Dosage recommendations for children with renal impairment are provided above. The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or pediatric dosage is optimal for the patient. Clinical data indicate that children have a higher clearance of fluconazole compared to adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg once daily to children results in comparable systemic exposure.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Available information is presented in the section "Adverse reactions". If there is a compelling need to use the drug in adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose may be administered on the first day to achieve steady-state concentration more rapidly.

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg/day depending on the severity of the disease.

Maintenance therapy for prevention of relapse of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg/day once daily, depending on the severity of the disease.

Prophylaxis of candidiasis in patients with immunodeficiency: dosage is 3–12 mg/kg once daily depending on the severity and duration of induced neutropenia (see adult dosing).

Children.

The tablet formulation may be used in this patient population only when children are able to safely swallow a tablet, which is generally possible at the age of 5 years and older.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Fluconazole is primarily excreted in the urine; therefore, forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50 %.

Adverse Reactions

A drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with fluconazole use (see section "Special precautions").

The most frequently reported adverse reactions (from ≥1/100 to <1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase in blood, and rash.

The following classification is used to assess the frequency of adverse reactions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.

Uncommon: seizures, dizziness, paresthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Rare: paroxysmal ventricular tachycardia of the torsade de pointes type, QT interval prolongation (see section "Special precautions").

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased levels of ALT, AST, alkaline phosphatase in blood (see section "Special precautions").

Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special precautions").

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special precautions").

Skin and subcutaneous tissue disorders

Common: rash (see section "Special precautions").

Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special precautions").

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special precautions").

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever.

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in children during clinical trials, apart from genital candidiasis, are comparable to those in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

Tablets 50 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Tablets 100 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Tablets 150 mg, pack of 2 or 4 in a blister pack in a cardboard box.

Tablets 200 mg, pack of 4 or 10 in a blister pack in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriya St., 54.