Difluzol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIFLUZOL® (DIFLUZOL®)

Composition:

Active ingredient: fluconazole;

1 capsule contains fluconazole, calculated as 100% substance – 150 mg;

Excipients: calcium stearate, sodium starch glycolate (type A);

Capsule shell composition: gelatin, patent blue V (E131), quinoline yellow (E104), titanium dioxide (E171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size №1, body turquoise-colored, cap green-colored.

Contents of capsules – powder white or almost white, odorless.

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.

Interaction studies 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 species of Candida (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 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 molds such as 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 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 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 of infections caused by strains with high minimal inhibitory concentrations to fluconazole is less effective.

Mechanism of Resistance.

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

In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may 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 species (C. krusei) or emerging species (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 (Supporting 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-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on MIC distribution within specific species, and species-specific breakpoints, most commonly associated with human infections. These breakpoints are listed below.

S = sensitive;

R = resistant;

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

-- susceptibility testing not recommended, as this species is not a target for 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 strains. I – susceptible dose-dependent: a microorganism is categorized as "susceptible dose-dependent" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or increasing drug concentration at the site of infection.

Pharmacokinetics.

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

Absorption.

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

Distribution.

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

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, specifically in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. After a daily dose of 50 mg, 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 weekly dose of 150 mg, fluconazole concentration on day 7 of treatment was 23.4 µg/g; seven days after the next dose, the concentration remained at 7.1 µg/g.

Fluconazole concentration in nails after 4 months of weekly 150 mg 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 drug, only 11% of fluconazole is excreted in urine in altered form. Fluconazole is a selective 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.

Renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 hours to 98 hours. Therefore, this patient group requires a reduced dose 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%.

Lactation.

Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours after a single 150 mg dose of Diflucan 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 maternal plasma levels. The mean peak concentration in breast milk, measured 5.2 hours after dosing, was 2.61 mg/L. 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 recommended dose for neonates (< 2 weeks old) or 13% of the recommended dose for infants for treatment of mucosal candidiasis.

Children.

Pharmacokinetic data were evaluated in 113 children across 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 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This 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 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. 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 to 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. Volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

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 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 in younger volunteers. Therefore, pharmacokinetic changes in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

Difluzol® 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.

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

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

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or any of the excipients of the drug.
• Concomitant administration of fluconazole and terfenadine to patients receiving fluconazole repeatedly at doses of 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).

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. A controlled study demonstrated that 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. In one study, administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased plasma terfenadine levels when administered concomitantly. 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. The resulting increase in plasma astemizole 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 and quinidine: Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although relevant in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to the development of paroxysmal ventricular tachycardia of the torsade de pointes type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

Erythromycin: Concomitant use of erythromycin and fluconazole may 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 of medicinal products 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 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. Fluconazole should be used with caution together with amiodarone, especially when high-dose fluconazole (800 mg) is prescribed.

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

• Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole simultaneously with food intake, cimetidine, antacids, or total body irradiation for bone marrow transplantation has no clinically significant effect on fluconazole absorption.

Rifampicin: Concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% shortening of 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 administration of hydrochlorothiazide to healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40%. Such interaction parameters do not require changes in fluconazole dosing regimen for patients receiving diuretics concomitantly.

• Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to observed/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 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 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 the abrocitinib instructions for medical use.

Alfentanil: During concomitant administration of alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in AUC was observed, possibly due to CYP3A4 inhibition. Alfentanil dose adjustment may be necessary.

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. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: Concomitant administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice showed the following results: 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 study results is unknown.

Anticoagulants: As with other azole antifungal agents, cases of bleeding (hematomas, 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. Anticoagulant dose adjustment may be necessary.

Benzodiazepines of short duration of action, 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 administration of fluconazole 200 mg and oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in midazolam 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 triazolam AUC and elimination half-life, 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 established.

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

Calcium channel blockers: Some calcium antagonists (nifedipine, isradipine, amlodipine, 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: With concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. With concomitant use of celecoxib and 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 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. In addition, a study in healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, patient status should be closely monitored. Fentanyl dose adjustment 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 [reduced hepatic statin metabolism]), increases the risk of myopathy and rhabdomyolysis (dose-dependent). If concomitant use of these drugs is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If creatine kinase levels are significantly elevated, and myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be necessary, as indicated in the statin instructions for medical use.

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 (2 capsules) to continue inhibitor use, and continuous clinical monitoring should be ensured.

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class): Concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased ivacaftor exposure threefold and hydroxymethylivacaftor (M1) exposure 1.9-fold. Dose reduction of ivacaftor (as monotherapy or in combination) is required, as specified in the ivacaftor instructions for medical use (as monotherapy or in combination).

Olaparib: Moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentrations; their concomitant use is not recommended. If such a combination cannot be avoided, olaparib intake should be limited 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 according to its concentration.

Everolimus: Although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase everolimus serum concentration due to CYP3A4 inhibition.

Sirolimus: Fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism by the CYP3A4 enzyme and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted according to its concentration and effects.

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

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

Lurasidone: Moderate CYP3A4 inhibitors, such as fluconazole, may increase lurasidone plasma concentration. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in the lurasidone instructions for medical use.

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 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 values with racemic ibuprofen alone.

Although specific studies have not been conducted, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring of adverse reactions and toxic manifestations associated with NSAIDs is recommended. NSAID dose adjustment may be needed.

Phenytoin: Fluconazole inhibits hepatic phenytoin metabolism. Multiple concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin results in a 75% increase in phenytoin AUC24 and a 128% increase in Cmin. Serum phenytoin concentration should be monitored when these drugs are used concomitantly to avoid phenytoin toxicity.

Prednisone: A case was reported where a patient after liver transplantation developed acute adrenal insufficiency on a background of prednisone use, occurring after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients who have been receiving fluconazole and prednisone concomitantly for a prolonged period 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 saquinavir metabolism in the liver by the CYP3A4 enzyme and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied, so they may be more pronounced. Saquinavir dose adjustment may be necessary.

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

Theophylline: In a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in 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 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: Tolvaptan exposure significantly increased (200% AUC, 80% Cmax) when tolvaptan, a CYP3A4 substrate, was administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute kidney injury. If co-administered, the tolvaptan dose should be reduced according to the instructions for medical use and the patient should be regularly checked for any adverse reactions associated with tolvaptan.

Vinca alkaloids: Although relevant studies have not been conducted, fluconazole, likely through CYP3A4 inhibition, may cause increased plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: A case was reported where a patient receiving all-trans retinoic acid (acid form of vitamin A) concomitantly with fluconazole experienced central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri; this effect disappeared after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS 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) to 8 healthy male volunteers 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 administered after fluconazole, monitoring for voriconazole-associated adverse effects should be conducted.

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

Azithromycin: In an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effect of azithromycin and fluconazole on each other's pharmacokinetics was evaluated after single oral administration at doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives: Two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives were conducted. With fluconazole 50 mg, no effect on hormone levels was observed, whereas with fluconazole 200 mg daily, a 40% increase in ethinylestradiol AUC and a 24% increase in levonorgestrel AUC were observed. This indicates that multiple administration of fluconazole at the specified doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to studies on fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, 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 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, no dosage recommendations can be made for treating such infections.

Renal system. Fluconazole should be administered with caution in patients with renal impairment (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. Adrenal insufficiency associated with concomitant prednisone therapy is described in the section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products".

Hepatobiliary system. Fluconazole should be administered with caution in patients with hepatic impairment. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was linked to fluconazole, no clear dependence on daily dose, duration of therapy, sex, 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 should be sought.

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., 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 conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval.

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 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 syndrome) 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 possibly 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 and a potent inhibitor of the CYP2C19 enzyme. Patients receiving concomitant fluconazole and medicinal products with a narrow therapeutic window metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

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

Candidiasis. Studies have demonstrated an increasing prevalence of infections caused by Candida species other than C. albicans. These are often naturally resistant (e.g., C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after treatment failure. Therefore, physicians prescribing fluconazole are advised to consider the prevalence of resistance among different Candida species.

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 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 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 of pregnancy 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 congenital malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg, compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI: 1.23–3.17) for doses > 450 mg.

Available epidemiological studies on the risk of cardiac malformations associated with fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies, including several thousand pregnant women who received fluconazole during the first trimester, found a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use or use of topical azoles.

Cases of 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. Malformations observed in these children include 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 unless absolutely necessary.

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

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg). Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole therapy. The benefit of breastfeeding for the child's development and health, the mother's clinical need for the medicinal product, and the potential adverse effects of the drug or the mother's underlying condition on the infant should be carefully evaluated.

Fertility.

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

Ability to affect driving and use of machinery.

Studies on the effect of the medicinal product Difluzol® on the ability to drive or operate machinery have not been conducted.

Patients should be informed about the possibility of developing dizziness or seizures during Difluzol® use. If such symptoms occur, driving or operating machinery is not recommended.

Dosage and Administration.

Capsules should be swallowed whole. The administration of the drug is independent of food intake.

Adults.

The drug is administered orally as a single 150 mg dose.

Elderly patients.

In the absence of signs of impaired renal function, this category of patients should receive the standard adult dose.

Renal impairment.

Fluconazole is primarily excreted unchanged in urine. When administered as a single dose, dosage adjustment is not required in this category of patients.

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction, as there is insufficient information regarding the use of fluconazole in this patient group (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Children.

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

Overdose.

Cases of fluconazole overdose have been reported, with concomitant hallucinations and paranoid behavior.

In case of overdose, symptomatic and supportive therapy should be initiated, and gastric lavage should be performed if necessary. Fluconazole is substantially excreted in urine; forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Side effects

Summary of safety profile

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

The most commonly reported adverse reactions were: headache, abdominal pain, diarrhoea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels, and rash.

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

Blood and lymphatic system disorders

Uncommon: anaemia
Rare: agranulocytosis, leucopenia, thrombocytopenia, neutropenia

Immune system disorders

Rare: anaphylaxis

Metabolism and nutrition disorders

Uncommon: decreased appetite
Rare: hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia

Psychiatric disorders

Uncommon: insomnia, somnolence

Nervous system disorders

Common: headache
Uncommon: convulsions, paraesthesia, dizziness, taste disturbance
Rare: tremor

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

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

Gastrointestinal disorders

Common: abdominal pain, nausea, diarrhoea, vomiting
Uncommon: constipation, dyspepsia, flatulence, dry mouth

Hepatobiliary disorders

Common: increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels (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: drug eruption (including fixed drug eruption), urticaria, pruritus, increased sweating (see section "Special precautions")
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic oedema, facial swelling, alopecia (see section "Special precautions")
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

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 clinical trials involving children were comparable to those observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorisation is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with local regulatory requirements.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.

Packaging.

Capsules 150 mg, 1 capsule in a blister, 1 or 2 blisters in a pack; 2 capsules in a blister, 1 blister in a pack.

Prescription status.

Over-the-counter – 150 mg capsules, 1 capsule per pack.
Prescription only – 150 mg capsules, 2 capsules per pack.

Manufacturer.

JSC "Kievmedpreparat"

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine