Fucis®

INSTRUCTIONS 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, 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 exhibit clinically significant effects 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 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, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations (MICs) and the epidemiological cut-off value (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.

Pharmacokinetic/Pharmacodynamic Relationships.

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 not fully sufficient, correlation 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 azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by non-C. albicans Candida species, which often show reduced susceptibility (e.g., 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 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 (see 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-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.

Antifungal agent			Species-specific breakpoints, S ≤ / R > in mg/l				Non-species-specific breakpointsa S ≤ / R > in mg/l
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

S = sensitive;

R = resistant;

a – breakpoints not associated with a specific species, which were primarily defined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific distribution of minimal inhibitory concentrations. These were studied only in microorganisms for which no specific breakpoint exists;

• susceptibility testing is not recommended, as this species is not a target for antimicrobial 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 only to prevent misclassification of I strains as S strains. 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 adjusting the dosing regimen or increased 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 of the drug when 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 the 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 in the skin, exceeding serum levels, are achieved 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, fluconazole 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 completion of therapy.

Biotransformation.

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 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 of fluconazole. 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 their infants. In breast milk, fluconazole was found 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 average milk intake of 150 mL/kg/day), calculated based on the mean peak milk concentration, was 0.39 mg/kg/day, representing 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 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 (30–113) 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 oral fluconazole. Ten patients were concurrently taking 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 compared to those in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Also, 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 clearly 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 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 the prevention of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• 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 the medicinal product may be used in this patient group only when children are able to swallow the tablet safely, which is usually 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 the 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 via 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 marked 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 agents 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, a significant increase in terfenadine plasma levels occurs when these agents are 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. 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 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 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 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 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, as a consequence, 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 torsade de pointes type) and, as a consequence, 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. If 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 irradiation (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 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.

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; careful patient monitoring is required. 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 alfentanil 20 mcg/kg intravenously resulted in a two-fold 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 after 1 week of treatment. 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 results is unknown.

Anticoagulants: as with other azole antifungal agents, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported with concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. A two-fold 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 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 midazolam 7.5 mg orally increased AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Concomitant use 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 with concomitant use of fluconazole and triazolam.

If benzodiazepines need to be prescribed 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 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. Careful 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 agents 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, 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 agents 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 plasma concentration of ibrutinib and may increase the risk of toxicity. If combination cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily to continue inhibitor use, 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 plasma concentration 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, and 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 agents may be used concomitantly with cyclosporine dose reduction 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 with sirolimus dose adjustment based 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 via 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-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 plasma concentration 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 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 medicinal products to avoid phenytoin toxicity.

Prednisone: a case was reported of acute adrenal insufficiency in a liver transplant patient receiving prednisone, which occurred after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated metabolism of prednisone. 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. Uveitis has 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 hepatic saquinavir metabolism by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied, so they 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 and appropriate dose reduction of sulfonylurea derivatives are recommended when used concomitantly with fluconazole.

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 that cause 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 agents.

Tolvaptan: exposure to tolvaptan (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. If used concomitantly, the dose of tolvaptan 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 of central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri in a patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole concomitantly, 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 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 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 combination should be monitored for adverse reactions associated with zidovudine use. Dose reduction of zidovudine may be considered.

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, there are no recommendations regarding dosage regimens for the treatment of such infections.

Deep endemic mycoses. There is insufficient evidence of efficacy of fluconazole for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, there are no recommendations regarding dosage regimens for the treatment of such infections.

Renal system. Fluconazole should be administered 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 is rare. Adrenal insufficiency associated with concomitant prednisone therapy is described in the 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 administered 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, no clear relationship was observed with 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 abnormal liver function test results during fluconazole therapy 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 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 current (I_Kr). 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 conditions 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 have an increased risk of developing 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 susceptible to developing severe skin reactions when taking many medicinal products. If a patient with 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 should be discontinued if bullous eruptions or erythema multiforme develop.

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 concomitant fluconazole and medicinal products with 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. Close 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 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 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 potential.

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

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

For prolonged treatment courses, women of reproductive potential should consider using contraception throughout the 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 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 receiving cumulative doses ≤ 450 mg, compared to women who received 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 cardiac malformations associated with 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 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 to 800 mg/day) of 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 radiohumeral synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

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

High-dose fluconazole 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 be continued 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 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 did not affect fertility in male and female rats.

Ability to drive and use machines.

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 with this medicinal product. If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage.

The drug is administered orally. The intake of the drug is independent of food intake.

The daily dose of fluconazole depends on the type and severity of the fungal infection. If repeated administration is necessary, treatment of infections should be continued until clinical and laboratory signs of fungal activity have disappeared. Insufficient 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: 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. 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 cutaneous 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 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 count rises 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, tinea of smooth skin, 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.
• Tinea 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 the infected nail is replaced by healthy nail growth. Healthy nail regrowth on fingers and great toes usually requires 3–6 months and 6–12 months, respectively. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-term chronic infections, the nail shape 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. A single dose does not require dose adjustment. 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

Creatinine clearance (ml/min)	Percentage of recommended dose
> 50	100 %
≤ 50 (without hemodialysis)	50 %
Hemodialysis	100 % after each hemodialysis

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 data on the use of fluconazole in this patient population (see sections "Dosage and Administration" 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.

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 individual patient. Clinical data indicate that children have higher fluconazole clearance compared to adults. Administration of 100, 200, and 400 mg doses to adults and 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 applied.

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 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 relapse 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 may be used in this patient population only when children are able to safely swallow tablets, which is typically 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 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 for Use").

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

The following frequency classification was 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 ≥1/10000 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: convulsions, dizziness, paresthesia, 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 for Use").

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 for Use").

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

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

Skin and subcutaneous tissue disorders

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

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

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

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, except for genital candidiasis, are comparable to those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System 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 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.

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

INSTRUCTION

for medical use of the medicinal product

FUSYSÒ

(FUSYSÒ)

Composition:

Active ingredient: 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 score 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. The accumulation of 14-alpha-methyl-sterols correlates with the subsequent depletion of ergosterol in the fungal cell membrane and is likely responsible 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 has no 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 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. The minimal inhibitory concentrations (MICs) and epidemiological cut-off 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 such as 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, although not fully sufficient, 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 alterations in the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or the development of compensatory metabolic pathways.

Superinfections caused by non-albicans Candida species, which often exhibit 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 the treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant species (e.g., C. krusei) or 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 (see 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 04.02.2020). These breakpoints are categorized into non-species-specific breakpoints, primarily determined from 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.

Antifungal agent		Species-specific breakpoints, S ≤ / R > in mg/L					Non-species-specific breakpoints S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

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 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 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-dose dependent: a microorganism is categorized as "susceptible-dose dependent" when there is a high probability of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or achieving 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 absorption of the drug when 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 when a loading dose twice the normal 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 concentrations of fluconazole in the skin, exceeding serum levels, are achieved 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 completion of treatment, the concentration was still 5.8 µg/g. With a dose of 150 mg once weekly, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after administration of the next dose, the concentration remained at 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 completion of therapy.

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 administration in vaginal candidiasis, as well as 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 these patients. 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 their infants. 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 fluconazole dose received by the 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, 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 of fluconazole 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 mean birth weight was 0.9 kg (range 0.75–1.10 kg). Up to 5 intravenous injections of fluconazole at 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 and older) who received 50 mg fluconazole orally. 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. 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 those 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, tinea of smooth skin, tinea cruris; pityriasis versicolor and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis when other medicinal products are 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 of 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").

The tablet form of the drug may be administered to this patient category only when children are able to swallow the tablet safely, which is usually 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 the 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 via 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 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, when fluconazole was administered at doses of 400 mg daily or higher, a significant increase in terfenadine plasma levels occurred with concomitant use. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered 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 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 "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 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 "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 combination of these drugs 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. If concomitant use of fluconazole and amiodarone is necessary, caution is required, 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 irradiation (in bone marrow transplantation).

Rifampicin: concomitant use of fluconazole and rifampicin led to a 25 % decrease in AUC and a 20 % reduction in fluconazole elimination half-life. 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 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 of drugs should be used with caution; careful patient monitoring 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. The dose of amitriptyline or nortriptyline should be adjusted if 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 carefully 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 administration of midazolam led to 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 concomitantly 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 serum carbamazepine 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. Careful 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 can be used concomitantly, considering the possible 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, 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 patient monitoring for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels are required. If a significant increase in 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 prescribing information for statins.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentration of ibrutinib 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 times and exposure to hydroxymethylivacaftor (M1) by 1.9 times.

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

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentration of olaparib; 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 at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These drugs can 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 enzyme and P-glycoprotein. These drugs can be used concomitantly provided sirolimus dose is adjusted depending on concentration and effects of the drug.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5-fold with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus 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 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): with concomitant use of fluconazole, Cmax and AUC of flurbiprofen increased by 23 % and 81 %, respectively, compared to corresponding values with flurbiprofen alone. Similarly, with concomitant use of fluconazole and racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer increased by 15 % and 82 %, respectively, compared to corresponding values with racemic ibuprofen alone.

Fluconazole is potentially capable of increasing systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring of 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 leads to a 75 % increase in AUC24 of phenytoin and a 128 % increase in Cmin. Monitoring of phenytoin serum concentration is required with concomitant use of these drugs to avoid phenytoin toxic effects.

Prednisone: a case was reported in which a liver transplant patient developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole therapy while receiving prednisone. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving fluconazole and prednisone concomitantly for a prolonged period should be carefully monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

Rifabutin: fluconazole increases rifabutin serum concentration, leading to up to an 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 enzyme 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 are recommended with concomitant use with fluconazole.

Theophylline: administration of fluconazole at 200 mg for 14 days led to an 18 % decrease in average theophylline plasma clearance. Patients receiving theophylline at high doses 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.

Tolvaptan: exposure to tolvaptan (a CYP3A4 substrate) significantly increases (200% AUC; 80% Cmax) with concomitant use of fluconazole (a moderate CYP3A4 inhibitor), thereby increasing the risk of adverse reactions such as enhanced diuresis, dehydration, and acute renal failure. In case of concomitant use, the tolvaptan 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 in which a patient receiving all-trans retinoic acid (acid form of vitamin A) concomitantly with fluconazole experienced central nervous system adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of central nervous system 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) led to 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 voriconazole-associated adverse effects is required.

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

Azithromycin: no significant pharmacokinetic interactions were observed with concomitant single oral 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 at a dose of 50 mg, whereas with fluconazole at a dose of 200 mg daily, AUC of ethinylestradiol increased by 40 % and levonorgestrel by 24 %. This indicates 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, there are no recommendations regarding dosage regimens for the treatment of such infections.

Deep endemic mycoses. There is insufficient evidence of efficacy of fluconazole for the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, there are no recommendations regarding dosage regimens for the treatment of such 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 is rare. Cases of adrenal insufficiency associated with concomitant prednisone therapy are described in the 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 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, there was no clear correlation with total daily dose, duration of therapy, gender, 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 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, 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 (such as 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 during fluconazole use. These reports involved patients with severe underlying conditions 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. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely 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 superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or development of erythema multiforme.

Hypersensitivity. Anaphylactic reactions have been reported in rare cases (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 concomitant fluconazole and medicinal products with 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. Close 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 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 of different Candida species to fluconazole.

Excipients.

The product contains lactose. If the 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 childbearing potential.

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 childbearing potential should consider using contraception throughout the 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 increase in the 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 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 exceeding 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester found an 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 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 and short-term courses of fluconazole should not be used during pregnancy except when absolutely necessary.

High-dose and/or prolonged courses of fluconazole 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 dose of the standard dose of fluconazole (150 mg).

Breastfeeding is not recommended during repeated administration or high-dose fluconazole therapy.

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 drive and use machines.

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 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 administration of the drug is independent of food intake.

The daily dose of fluconazole depends on the type and severity of the fungal infection. If repeated administration is necessary, treatment of infections should be continued until clinical and laboratory signs of fungal infection activity have disappeared. Insufficient 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. In 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 its development: 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. The loading dose is 800 mg on the first day. The maintenance dose is 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 prolonged.
• 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 recurrent mucosal candidiasis in HIV patients at high risk of its development.

• 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 immunocompromised patients.

Prophylaxis of candidal infections 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 dose of 150 mg.
• 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 mycosis, 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.
• Tinea 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 on hands and great toes usually takes 3–6 months and 6–12 months, respectively. 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. 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 therapeutic indications. Subsequently, the daily dose (depending on the indication) should be calculated according to Table 1.

Table 1

Creatinine clearance (ml/min)	Percentage of recommended dose
> 50	100 %
≤ 50 (without hemodialysis)	50 %
Hemodialysis	100 % after each hemodialysis

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" 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 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 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 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 administered to this patient group only when children are able to safely swallow a tablet, 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 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 for Use").

The most commonly 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 frequency classification is used to describe the incidence 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, paresthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Rare: torsade de pointes, QT interval prolongation (see section "Special Warnings and Precautions for Use").

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 for Use").

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

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

Skin and subcutaneous tissue disorders

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

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

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

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, except for genital candidiasis, are comparable to those in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures 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 status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

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

INSTRUCTION

for medical use of the medicinal product

FUCISÒ

(FUSYSÒ)

Composition:

Active ingredient: 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 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 repeated administration of 50 mg fluconazole does 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 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.

Pharmacokinetic/pharmacodynamic relationships.

According to animal studies, there is a correlation between 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, 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 efficacy in vivo and in clinical practice.

In normally susceptible Candida species, the most common resistance mechanism involves the azole target enzymes 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 exhibiting 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 have been established for Candida species (see 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 from 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 MIC distributions, and species-specific breakpoints, most commonly associated with human infections. These breakpoints are listed below.

Antifungal agent		Species-specific breakpoints S ≤ / R > in mg/L					Non-species-related breakpoints S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

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 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 probability of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or 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 of the drug when 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 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.

After a dose of 50 mg once daily, fluconazole concentration reached 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a dose of 150 mg once weekly, fluconazole concentration was 23.4 µg/g on day 7 of treatment; seven 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 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 completion of therapy.

Biotransformation.

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 single-dose administration for 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, fluconazole dosage should be reduced in these patients. 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 their infants. In breast milk, fluconazole was detected at an average concentration of approximately 98% of that in maternal plasma. The average peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole received by an infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on the average 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 a single dose. 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 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, and 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 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. Also, 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, changes in pharmacokinetics in elderly patients are clearly 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, tinea of glabrous skin, 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").

The tablet form of the drug may be used in this patient population only when children are able to swallow the tablet 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 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 via 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 "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 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/day, no QTc interval prolongation was observed. However, when fluconazole was administered at doses of 400 mg/day or higher, a significant increase in plasma terfenadine levels occurred with concomitant use. 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 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 "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 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 "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 drugs 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 drugs 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 is required, 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.

No clinically significant effect on fluconazole absorption after oral administration has been 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, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide: in a pharmacokinetic interaction study, multiple-dose 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 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 drug combinations should be used with caution; close monitoring of patients is required. 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 component 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 μg/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 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 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 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 oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg 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 a patient undergoing fluconazole treatment needs to be prescribed benzodiazepines concomitantly, the dose of the latter should be reduced and appropriate patient monitoring should be established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and increases 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, and 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 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 potential risk of increased serum bilirubin and creatinine levels.

Fentanyl: one fatal case of fentanyl intoxication due to 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 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, close 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 prescribing information for statins.

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 its hydroxymetabolite (M1) increased exposure to ivacaftor by 3-fold and exposure to hydroxymetabolite (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. 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 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 with concomitant use of methadone and fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): with concomitant use of fluconazole, Cmax and AUC of flurbiprofen increased by 23 % and 81 %, respectively, compared to corresponding values with flurbiprofen alone. Similarly, with concomitant use of fluconazole and racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer increased by 15 % and 82 %, respectively, compared to corresponding values with 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 resulted in a 75 % increase in AUC24 of phenytoin and a 128 % increase in Cmin. Monitoring of phenytoin serum concentration is required with concomitant use of these drugs to avoid phenytoin toxicity.

Prednisone: a case was reported in which a liver transplant patient developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole therapy while receiving prednisone. 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 up to an 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 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, and tolbutamide) resulted in prolonged elimination half-life. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative dose are recommended with concomitant use with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days resulted in an 18 % decrease in the average plasma theophylline clearance. 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 drugs 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.

Tolvaptan: exposure to tolvaptan (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. In case of concomitant use, the tolvaptan 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 in which a patient receiving all-trans retinoic acid (the 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 central nervous system adverse reactions should be kept in mind.

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 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 adverse effects associated with voriconazole is required.

Zidovudine: fluconazole increases zidovudine Cmax and AUC by 84 % and 74 %, respectively, due to approximately 45 % reduction in zidovudine clearance 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/day, a 40 % increase in AUC of ethinylestradiol and a 24 % increase in levonorgestrel were observed. This indicates 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 fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, there are no dosage recommendations for treating such infections.

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

Renal system. Fluconazole 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 is rare. Cases of adrenal insufficiency associated with concomitant prednisone therapy are described in the subsection Effect of fluconazole on other medicinal products of the section "Interaction with other medicinal products and other forms of interaction".

Hepatobiliary system. Fluconazole 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 correlation with total daily dose, duration of therapy, sex, or age of the patient. Typically, fluconazole-induced hepatotoxicity is reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for signs 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 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 (such as 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 during 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 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. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also been reported. Patients with AIDS are more prone to developing severe skin reactions when taking many medicinal products. If a patient with 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, close monitoring is required, and fluconazole should be discontinued if bullous eruptions or erythema multiforme develop.

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 that have a narrow therapeutic window 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 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 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 medicine contains lactose. If the patient has been diagnosed with intolerance to certain sugars, medical advice should be sought before taking this medicine.

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 childbearing potential.

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

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

For prolonged treatment courses, women of childbearing potential 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 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 receiving cumulative doses ≤ 450 mg, compared to women who received 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 exceeding 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 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 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 infants were brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radio-humeral 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 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 150 mg dose of fluconazole.

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

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 did not affect fertility in male and female rats.

Ability to influence the ability to drive and use machines.

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

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

Dosage and Administration.

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. Insufficient 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. 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 prolonged.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic cutaneous 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 case 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 for 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 anticipated onset of neutropenia and continued for 7 days after neutrophil count rises 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 regimen 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 therapy with 150 mg once weekly for 6 months is recommended.

Dermatomycoses.

• Tinea pedis, tinea of glabrous skin, 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 the infected nail is replaced by a healthy one. Healthy nail regrowth on fingers and great toes usually takes 3–6 months and 6–12 months, respectively. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-term chronic infections, the nail shape may sometimes remain altered.

Special patient groups.

Geriatric 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 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

Creatinine clearance (ml/min)	Percentage of recommended dose
> 50	100 %
≤ 50 (without hemodialysis)	50 %
Hemodialysis	100 % after each hemodialysis

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" 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.

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 determine whether the adult or pediatric dosage is more appropriate 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), the 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 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 adult dosing).

Children.

The tablet formulation may be used in this patient population only when children are able to safely swallow tablets, 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 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 for Use").

The most commonly reported adverse reactions (from ≥1/100 to <1/10) were: 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 ≥1/1000 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, paraesthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

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

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 for Use").

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

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

Skin and subcutaneous tissue disorders

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

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

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

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 of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, 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, No. 4 or No. 10 in a blister pack in a cardboard box.

Tablets 100 mg, No. 4 or No. 10 in a blister pack in a cardboard box.

Tablets 150 mg, No. 2 or No. 4 in a blister pack in a cardboard box.

Tablets 200 mg, No. 4 or No. 10 in a blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and location of business activity.

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

INSTRUCTION

for medical use of medicinal product

FUCISÒ

(FUSYSÒ)

Composition:

Active ingredient: fluconazole;

1 tablet contains 150 mg of fluconazole;

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 beveled edges, with a score 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 repeated administration of 50 mg fluconazole does 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 (MICs) and the epidemiological cutoff value (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 relationship

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, though not fully sufficient, relationship 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 exhibiting high MIC values for fluconazole tends to be less effective.

Mechanism 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 azole target enzymes 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 have been established for Candida species (Supporting explanatory document EUCAST for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective 04.02.2020). These have been categorized into non-species-related 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.

Antifungal agent			Species-specific breakpoints, S ≤ / R > in mg/L				Non-species-related breakpoints S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

S = susceptible;

R = resistant;

a – breakpoints not associated with a specific species, which were primarily defined based on pharmacokinetic/pharmacodynamic information 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 only to prevent misclassification of I strains as S strains. 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 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 levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption following oral administration. Peak plasma concentrations are reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma 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. Concentrations in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, fluconazole concentrations in cerebrospinal fluid reach 80% of plasma concentrations.

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

Fluconazole concentration in nails after 4 months of 150 mg once weekly 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 treatment ended.

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.

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 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 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.

Plasma and breast milk concentrations of fluconazole 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 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 ingested by the 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, representing approximately 40% of the dose recommended for neonates (< 2 weeks old) 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 half-life of approximately 24 hours was observed after a single dose. 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 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 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.

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 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. 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"):

• Acute vaginal candidiasis when topical therapy is not appropriate;
• Candidal balanitis when topical therapy is not appropriate.

Treatment with Fucis® may be initiated prior to obtaining results of cultures and other laboratory tests; however, antimicrobial therapy should be adjusted accordingly once test results are available.

Official recommendations regarding the appropriate use of antifungal agents should be taken into account.

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 via 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 types of interactions.

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 levels of cisapride 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 have been conducted. When fluconazole was administered at a dose of 200 mg per day, no QTc interval prolongation was observed. However, when fluconazole was administered at doses of 400 mg per day or higher, a significant increase in terfenadine plasma levels occurred with concomitant use. 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 per 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, in rare cases, 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 relevant in vitro and in vivo studies have not been conducted. Increased pimozide plasma concentration may lead to QT interval prolongation and, in rare cases, 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 relevant in vitro and in vivo studies have not been conducted. Quinidine use has been associated with QT interval prolongation and, in rare cases, 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, as a consequence, 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 drugs 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 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. Caution is required when combining fluconazole and amiodarone, 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 intake of 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 escalation of fluconazole should be considered for patients receiving rifampicin.

Hydrochlorothiazide: in a pharmacokinetic interaction study, repeated multiple-dose 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 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, 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 administration of fluconazole 400 mg and alfentanil 20 mcg/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 after one week of treatment. 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: 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) associated with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. 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 200 mg and midazolam 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 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 benzodiazepine therapy is required in a patient undergoing fluconazole treatment, the dose of benzodiazepines 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 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: when fluconazole (200 mg daily) and celecoxib (200 mg) were used concomitantly, Cmax and AUC of celecoxib increased 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 can be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine levels.

Fentanyl: one 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 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). When 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 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 prescribing information for statins.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of ibrutinib and may increase the risk of toxicity. If the combination cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily to continue inhibitor use, 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-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 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, 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 1.8-fold. These drugs can 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 via CYP3A4 and P-glycoprotein. These drugs can 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 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 dose of tacrolimus 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 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 when used concomitantly with fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): when used concomitantly with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when fluconazole was used concomitantly with racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer increased 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 administration of 200 mg fluconazole and 250 mg phenytoin intravenously resulted in a 75% increase in phenytoin AUC24 and a 128% increase in Cmin. Monitoring of phenytoin serum concentration is required when these drugs are used concomitantly to avoid phenytoin toxicity.

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

Rifabutin: fluconazole increases rifabutin serum concentration, leading to up to an 80% increase in rifabutin AUC. Uveitis has been reported with 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, so they 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 the dose of sulfonylurea derivatives should be reduced accordingly when used concomitantly with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in theophylline plasma clearance. 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 when used concomitantly with medicinal products that cause 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.

Tolvaptan: exposure to tolvaptan (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 tolvaptan 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 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 can be used concomitantly, but the risk of central nervous system adverse reactions should be kept in mind.

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 decrease 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 drug combination should be monitored for zidovudine-related adverse reactions. Consideration may be given to reducing the zidovudine dose.

Azithromycin: no significant pharmacokinetic interactions were observed after single oral 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 the efficacy of fluconazole in the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, there are no dosage recommendations for the treatment of such infections.

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

Renal system. The drug 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 is rare. 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 the use of fluconazole, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was linked to fluconazole use, no clear relationship was observed with 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 therapy 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, 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 (such as amiodarone) may be potentiated due to 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 underlying conditions 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. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS) has also been reported. Patients with AIDS are more susceptible to developing severe skin reactions when using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of 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 erythema multiforme.

Hypersensitivity. Anaphylactic reactions have been reported rarely (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. Close 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 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 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 childbearing potential.

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 half-lives), should be observed before conception (see section "Pharmacokinetics").

For prolonged treatment courses, women of childbearing potential 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 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 receiving cumulative doses ≤ 450 mg, compared to women who received 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 exceeding 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- to 2-fold increased risk of congenital heart defects in infants compared to infants of mothers who 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 be continued after a single standard dose of fluconazole (150 mg).

Breastfeeding is not recommended during repeated administration of fluconazole or when high doses of fluconazole are used.

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 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.

Method of administration and dosage.

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

Adults.

The recommended dose is a single 150 mg dose.

Elderly patients.

In the absence of signs of renal impairment, the usual adult dose should be used for treatment of this patient group.

Renal impairment.

Fluconazole is primarily excreted unchanged in urine. Dose adjustment is not required for single-dose administration of fluconazole in this patient group.

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction due to insufficient data on fluconazole use in this patient population (see sections "Special precautions" and "Adverse reactions").

Children.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite adequate data on fluconazole use in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the standard adult dosage should be used.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Since fluconazole is primarily excreted in the urine, 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) associated with fluconazole use has been reported (see section "Special Warnings and Precautions for Use").

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.

To assess the frequency of adverse reactions, the following classification is used: 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: convulsions, dizziness, paraesthesia, taste disturbance.
Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

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

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 for Use").
Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special Warnings and Precautions for Use").
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders

Common: rash (see section "Special Warnings and Precautions for Use").
Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special Warnings and Precautions for Use").
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special Warnings and Precautions for Use").
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, except for genital candidiasis, are comparable to those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System 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.

1 tablet in a blister; 1 blister in a cardboard pack.

Prescription status.

Over-the-counter.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business activity.

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

INSTRUCTION

for medical use of the medicinal product

FUCISÒ

(FUSYSÒ)

Composition:

Active ingredient: fluconazole;

1 tablet contains 150 mg of fluconazole;

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 beveled 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 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 the various cytochrome P450 enzyme systems of 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 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 the epidemiological cutoff value (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 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, candidemia. Similarly, treatment of infections caused by strains with high MIC values for fluconazole is less effective.

Mechanism 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 result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by Candida spp. other than C. albicans, which often show 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 (Supporting explanatory document EUCAST for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective 04.02.2020). These have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific MIC distributions, and species-related breakpoints, typically associated with human infections. These breakpoints are listed below.

Antifungal agent			Species-specific breakpoints, S ≤ / R > in mg/L				Non-species-specific breakpoints S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

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 minimum inhibitory concentration distributions. These were studied only in microorganisms for which no species-specific breakpoint exists;

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

* All C. glabrata isolates fall within the intermediate (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 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 of the drug when administered orally. Peak plasma concentration is 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. 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 concentrations of fluconazole in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum.

After a dose of 50 mg once daily, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after completion of treatment, the concentration was still 5.8 µg/g. After a dose of 150 mg once weekly, fluconazole 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 was 4.05 µg/g in healthy volunteers and 1.8 µg/g in nail disease; fluconazole was detectable in nail samples up to 6 months after completion of therapy.

Biotransformation.

Fluconazole is minimally metabolized. After administration of a radiolabeled dose, only 11% of fluconazole is excreted in urine in altered form. 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 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 of fluconazole. 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 their infants. Fluconazole was detected in breast milk at an average concentration of approximately 98% of that in maternal plasma. The average 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 average milk intake of 150 mL/kg/day), calculated based on the average 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 preterm 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 average 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 a single dose. This value is comparable to the plasma elimination half-life of fluconazole 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 median age at first dose was 24 hours (range 9–36 hours), and median birth weight was 0.9 kg (range 0.75–1.10 kg). Up to 5 intravenous injections of fluconazole at 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 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 fluconazole orally. 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 in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, 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, the observed changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

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

• Acute vaginal candidiasis, when topical therapy is not appropriate;
• Candidal balanitis, when topical therapy is not appropriate.

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

Official recommendations regarding the appropriate use of antifungal agents should be taken into account.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the medicinal product.
• Concomitant administration of fluconazole and terfenadine to patients receiving repeated doses of fluconazole at 400 mg/day or higher (based on multiple-dose interaction study results).
• Concomitant administration 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 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 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 agents have been 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, a significant increase in terfenadine plasma levels occurs when both agents are administered together. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily together 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 "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, as a consequence, 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 "torsades de pointes" type) and, as a consequence, 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.

There is no clinically significant effect on fluconazole absorption following oral administration due to 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, 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 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 administered concomitantly with fluconazole. Therefore, such combinations should be used with caution; 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 administration of 400 mg fluconazole and 20 mcg/kg intravenous alfentanil 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 administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in: 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, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. 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 indandione derivatives concomitantly. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines of short duration, e.g., midazolam, triazolam: administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of 200 mg fluconazole and 7.5 mg oral midazolam resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of 200 mg fluconazole daily and 0.25 mg oral triazolam 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 administered concomitantly to a patient undergoing fluconazole therapy, the dose of the latter should be reduced and appropriate patient monitoring 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 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: when fluconazole (200 mg daily) and celecoxib (200 mg) were administered concomitantly, Cmax and AUC of celecoxib increased 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 leads to increased serum bilirubin and creatinine levels. These agents can be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine levels.

Fentanyl: a fatal case of fentanyl intoxication due to 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 statin metabolism). When 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 significant increases in creatine kinase levels occur, 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 statin prescribing information.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase ibrutinib plasma concentration and may increase toxicity risk. If combination cannot be avoided, ibrutinib dose should be reduced to 280 mg once daily to continue inhibitor use, 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-fold and to hydroxymethylivacaftor (M1) by 1.9-fold.

The dose of ivacaftor (alone or in combination) should be reduced according to its medical use instructions (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 administration of 200 mg fluconazole daily and 2.7 mg/kg/day cyclosporine, cyclosporine AUC increased 1.8-fold. These agents can 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 can 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 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-31 74), 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, lurasidone dose should be reduced as specified in its medical use instructions.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs): when used concomitantly with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, with concomitant use of fluconazole and racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer increased 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 NSAID-related adverse reactions and toxic effects is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic phenytoin metabolism. Multiple concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases phenytoin AUC24 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 was reported in which 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 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 up to an 80% increase in rifabutin AUC. Uveitis has been reported with 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 hepatic saquinavir metabolism 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) prolonged their elimination half-lives. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative doses are recommended when used concomitantly with fluconazole.

Theophylline: administration of 200 mg fluconazole for 14 days resulted in an 18% reduction in theophylline plasma clearance. 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 with concomitant use of medicinal products causing moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these agents.

Tolvaptan: exposure to tolvaptan (a CYP3A4 substrate) significantly increases (200% AUC; 80% Cmax) when administered concomitantly with fluconazole (a moderate CYP3A4 inhibitor), thereby increasing the risk of adverse reactions such as enhanced diuresis, dehydration, and acute kidney injury. In case of concomitant use, the tolvaptan dose should be reduced according to its instructions, 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 in which a patient receiving concomitant all-trans retinoic acid (the acid form of vitamin A) and fluconazole developed central nervous system adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These medicinal products can 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 voriconazole Cmax and AUCτ of 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 of approximately 45% with oral administration. Zidovudine elimination half-life 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. Consideration may be given to reducing the zidovudine dose.

Azithromycin: when azithromycin and fluconazole were administered concomitantly as single oral doses of 1200 mg and 800 mg, respectively, no significant pharmacokinetic interactions were observed.

Oral contraceptives: at a fluconazole dose of 50 mg, no effect on hormone levels was observed, whereas at a fluconazole dose of 200 mg daily, AUC of ethinylestradiol increased by 40% and levonorgestrel by 24%. This indicates 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 fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be made for the treatment of such infections.

Deep endemic mycoses. There is insufficient evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, no dosage recommendations can be made for the treatment of such 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 is rare. Adrenal insufficiency associated with concomitant prednisone therapy is described in the 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 impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been reported with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was associated with 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 therapy 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 current (I_Kr). QT interval prolongation caused by other medicinal products (such as amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported during fluconazole use. These reports involved patients with severe underlying diseases 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 enzyme of cytochrome P450 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 administered 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 prone to developing severe skin reactions when using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole should be discontinued in case of bullous eruptions or development of 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. It is also a moderate inhibitor of the CYP2C19 enzyme. Patients receiving concomitant fluconazole and medicinal products with 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. Close 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 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 failure. Therefore, it is recommended to consider the prevalence of resistance of various Candida species to fluconazole.

Excipients.

The medicinal product contains lactose. If a patient has 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 potential.

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 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 potential 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 administration 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 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 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 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 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 radioulnar 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 unless absolutely necessary.

High-dose fluconazole and/or prolonged treatment courses with fluconazole 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 be continued after a single standard dose of fluconazole (150 mg).

Breastfeeding is not recommended during repeated administration of fluconazole or when high doses of fluconazole are used.

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 influence the speed of reactions 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.

Method of administration and dosage.

The drug should be administered orally. The intake of the drug is not affected by food intake.

Adults.

The drug should be administered at a dose of 150 mg as a single dose.

Elderly patients.

In the absence of signs of impaired renal function, the usual adult dose should be used for treatment of this patient category.

Renal function impairment.

Fluconazole is predominantly excreted unchanged in the urine. Dose adjustment is not required for this category of patients when fluconazole is administered as a single dose.

Hepatic function impairment.

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

Children.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite comprehensive data on the use of fluconazole in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the usual adult doses should be used.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Since fluconazole is predominantly excreted in the urine, forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces the plasma concentration of fluconazole 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 for Use").

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.

To assess the frequency of adverse reactions, the following classification is used: 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 for Use")

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 for Use")
Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special Warnings and Precautions for Use")
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special Warnings and Precautions for Use")

Skin and subcutaneous tissue disorders

Common: rash (see section "Special Warnings and Precautions for Use")
Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special Warnings and Precautions for Use")
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special Warnings and Precautions for Use")
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 of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any 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 temperatures not exceeding 25°C.
Keep out of the reach of children.

Packaging.

1 tablet in a blister; 1 blister per cardboard pack.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business activity.

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

FUSYSÒ

(FUSYSÒ)

Composition:

Active ingredient: fluconazole;

1 tablet contains fluconazole 150 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 beveled edges and 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 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, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations (MICs) and the epidemiological cut-off value (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, correlation 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 azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by non-C. albicans Candida species, 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. (Refer to the accompanying explanatory document: EUCAST for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Tables of interpretative breakpoints for MICs, version 10.0, effective from 04.02.2020). These breakpoints are divided 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.

Antifungal agent	Species-specific breakpoints, S ≤ / R > in mg/L						Non-species-related breakpoints S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

S = sensitive;

R = resistant;

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

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

* All C. glabrata results 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: the microorganism is categorized as "susceptible with increased exposure" when there is a high probability of therapeutic success due to increased drug exposure achieved by dose regimen adjustments 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 absorption of the drug when 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 normal 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 was still 5.8 µg/g. With a 150 mg once-weekly dose, 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.

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.

Biotransformation.

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 detected.

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), 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.

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 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 average milk intake of 150 mL/kg/day), calculated based on mean peak milk concentration, was 0.39 mg/kg/day, representing 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 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 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 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. 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. 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. 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.

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 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. 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 are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

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

• Acute vaginal candidiasis when topical therapy is not appropriate;
• Candidal balanitis when topical therapy is not appropriate.

Treatment with Fucis® may be initiated before the results of cultures and other laboratory tests are available; however, after obtaining test results, antifungal therapy should be adjusted accordingly.

Official recommendations regarding appropriate use of antifungal agents should be taken into account.

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 caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these agents 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. 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. 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 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 "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 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 "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, as a consequence, 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 "torsade de pointes" type) and, as a result, 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. 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.

There is no clinically significant effect on fluconazole absorption following oral administration when taken concomitantly 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, 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 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; patients must 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 intravenous alfentanil 20 µg/kg resulted in a twofold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates dose adjustment of alfentanil.

Amitriptyline, nortriptyline: fluconazole enhances the effects 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.

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

Anticoagulants: as with other azole antifungal agents, bleeding events (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.

Benzodiazepines of short duration of action, 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 of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg oral triazolam increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed with 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 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 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 agents may be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine concentrations.

Fentanyl: one 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 agents is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If a significant increase in 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 statin prescribing information.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of ibrutinib 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, 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 plasma concentrations of olaparib; 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, AUC of cyclosporine increased by 1.8 times. These agents may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus: fluconazole may increase serum concentrations of everolimus by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These agents 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 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-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 plasma concentrations of lurasidone. 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.

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 NSAID-related adverse reactions and toxic effects is recommended. Dose adjustment of NSAIDs may be required.

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

Prednisone: a case has been reported where a patient after liver transplantation developed acute adrenal insufficiency on a background of prednisone use, following 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 up to an 80% increase in rifabutin AUC. Uveitis has 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 hepatic saquinavir metabolism 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) prolonged their elimination half-life. Frequent blood glucose monitoring is recommended, and sulfonylurea derivative doses should be appropriately reduced 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 appear.

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

Tolvaptan: exposure to tolvaptan (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. In case of concomitant use, 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: adverse reactions from the CNS in the form of pseudotumor cerebri were 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 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 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 voriconazole-associated adverse effects is required.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease 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 and zidovudine combination. Patients receiving this combination should be monitored for zidovudine-related adverse reactions. Consideration may be given to reducing the zidovudine dose.

Azithromycin: no significant pharmacokinetic interactions were observed after single oral 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 daily resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. This indicates 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 fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be made for the treatment of such infections.

Endemic deep mycoses. There is insufficient evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, no dosage recommendations can be made for the treatment of such infections.

Renal system. The drug 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 is rare. Adrenal insufficiency associated with concomitant prednisone therapy is described in the subsection Effect of fluconazole on other medicinal products in 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 reported with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was associated with fluconazole, no clear dependence on total daily dose, duration of therapy, gender, or patient age was observed. 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 signs 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 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 inward rectifier potassium ion currents (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to 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 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 using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole should be discontinued if bullous eruptions or erythema multiforme develop.

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

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. It 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. Close monitoring 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 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 of different Candida species to fluconazole.

Excipients.

The drug contains lactose. If a patient has 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 childbearing potential.

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 approximately 1 week (corresponding to 5–6 half-lives) should be observed before attempting pregnancy (see section "Pharmacokinetics").

For prolonged treatment courses, women of childbearing potential 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 who used 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 who received 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 exceeding 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy have yielded 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 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 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 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.

Lactation.

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 during repeated administration or high-dose fluconazole therapy.

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 did not affect fertility in male and female rats.

Ability to influence the ability to drive and use machines.

No studies on the effect of fluconazole on the ability to drive or operate machinery have 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.

Dosage and Administration.

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

Adults.

The drug should be administered at a dose of 150 mg as a single dose.

Elderly patients.

In the absence of signs of renal impairment, the usual adult dose should be used for treatment of this patient group.

Renal impairment.

Fluconazole is predominantly excreted unchanged in urine. When fluconazole is administered as a single dose, dose adjustment is not required in this patient group.

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction due to insufficient data on fluconazole use in this patient group (see sections "Special warnings and precautions for use" and "Side effects").

Children.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite adequate data on fluconazole use in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the usual adult doses should be used.

Overdose.

Symptoms: hallucinations and paranoid behavior.

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

Adverse reactions

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

The most frequently reported adverse reactions (from ≥1/100 to <1/10) are: 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 based on 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, paresthesia, taste disturbance
Rare: tremor

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

Rare: torsades de pointes, 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, except for genital candidiasis, are comparable to those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System 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 of children.

Packaging.

1 tablet in a blister; 1 blister per cardboard pack.

Availability category.

Over-the-counter.

Manufacturer.

LLC "GLEDPHARM LTD"

Manufacturer's address and location of its business activities.

54 Davydovskoho Hryhoriia Street, Sumy, Sumy Oblast, 40020, Ukraine