Diflazon®

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

Composition:

Active substance: fluconazole;

1 capsule contains fluconazole 150 mg;

Excipients: lactose monohydrate, maize starch, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate;

Capsule shell: titanium dioxide (E 171), patent blue V dye (E 131), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: capsules with light blue body and cap, filled with powder ranging from white to almost white.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole and tetrazole 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 the subsequent loss of ergosterol from 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 did not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily showed no 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 the most common Candida species (including Candida albicans, Candida parapsilosis, and Candida tropicalis). Candida glabrata shows reduced susceptibility to fluconazole, whereas Candida krusei and Candida auris are resistant to fluconazole.

The minimal inhibitory concentration (MIC) and epidemiological cut-off values (ECOFF) of fluconazole for Candida guilliermondii are higher than those for Candida albicans.

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

Pharmacokinetic/pharmacodynamic relationships

According to animal studies, there is a correlation between minimal inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between area under the curve (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 minimal inhibitory concentrations (MICs) to 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 generally susceptible Candida species, the most commonly observed resistance mechanism involves alterations in the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from gene mutations, overexpression of the target enzyme, drug efflux mechanisms, or development of compensatory metabolic pathways.

Superinfections with non-albicans Candida species, which often exhibit reduced susceptibility (e.g., Candida glabrata) or resistance to fluconazole (e.g., Candida krusei, Candida auris), have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms have not been fully elucidated for some Candida species with intrinsic resistance (e.g., Candida krusei) or for newly emerging species (e.g., Candida auris).

Breakpoints (according to recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST))

Based on the analysis of pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole against Candida species have been established (EUCAST document on fluconazole rationale (2020) - version 2; European Committee on Antimicrobial Susceptibility Testing, antifungal agents, tables of breakpoints for interpretation of MICs, version 10.0, effective from 04.02.2020). These breakpoints are 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.

S = susceptible;
R = resistant;

α – breakpoints not associated with a specific species, which were largely determined based on pharmacokinetic/pharmacodynamic information and do not depend on the distribution of minimal inhibitory concentration for species where no specific breakpoint exists;

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

* = All Candida glabrata isolates belong to category I. MIC against Candida glabrata should be interpreted as resistant if it exceeds 16 mg/L. The susceptible category (≤ 0.001 mg/L) allows avoiding misclassification of "I" isolates as "S". I – Susceptible, dose-dependent: the microorganism belongs to the "susceptible, dose-dependent" category when there is a high likelihood of therapeutic success due to increased exposure of the agent through adjustment of dosing regimen or increased 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 drug administration. Plasma drug concentration is proportional to dose. Steady-state concentration reaches 90% by the second day 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 investigated 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 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 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 radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes (see section "Interaction with other medicinal products and other forms of interaction"). Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme.

Elimination

The plasma half-life (T½) of fluconazole is approximately 30 hours. The majority of the drug is eliminated 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 T½ of the drug allows 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), T½ increases from 30 hours 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%.

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 mean peak concentration in breast milk was 2.61 mg/L, occurring 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, equals 0.39 mg/kg/day, which is approximately 40% of the dose recommended for newborns (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Children

Pharmacokinetic data were evaluated in 113 children across 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 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, mean plasma T½ of fluconazole ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer plasma T½ of approximately 24 hours was observed after single-dose administration. This value is comparable to the plasma elimination half-life of fluconazole after single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole at 6 mg/kg were administered every 72 hours. Mean T½ 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 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 T½ 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. 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.

Diflazon® 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 Diflazon® may be initiated before the results of cultures 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 to any of the excipients of the medicinal product.
• Concomitant use of fluconazole and terfenadine in patients receiving repeated doses of fluconazole at 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. 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 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 agents were conducted. In one study, administration of fluconazole 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 doses of 400 mg daily or higher significantly increased plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg 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 "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide and quinidine: concomitant use of fluconazole with pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although appropriate 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 "torsades de pointes" type. Concomitant use of fluconazole with pimozide or quinidine is contraindicated (see section "Contraindications").

Erythromycin: concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden fatal outcome. 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 potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, consequently, sudden fatal outcome. The use of this combination of medicinal products should be avoided (see section "Special precautions for use").

Concomitant use of fluconazole and the following medicinal products requires caution

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. 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 co-administration of food, cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on the absorption of orally administered fluconazole.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the half-life (T½) of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the dose of fluconazole.

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

• Effect of fluconazole on other medicinal products

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

Abrocitinib

Fluconazole (an 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 the instructions for use of abrocitinib.

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 AUC10 was observed, possibly due to inhibition of CYP3A4. Adjustment of the alfentanil dose may be necessary.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of concentrations of 5-nortriptyline and/or S-amitriptyline 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 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 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 during concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants concomitantly. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines of short duration of action, e.g., midazolam, triazolam: administration of fluconazole after oral administration of 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 half-life by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally increased AUC and half-life by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If benzodiazepines must 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, 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: during concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg), 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 levels of bilirubin and creatinine. These medicinal products may be used concomitantly, considering the risk of increased serum bilirubin and creatinine concentrations.

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study involving 12 healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, patient status should be closely monitored. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4, such as atorvastatin and simvastatin, or HMG-CoA reductase inhibitors metabolized by CYP2C9, such as fluvastatin (which reduces hepatic statin metabolism), increases the risk (dose-dependent) of myopathy and rhabdomyolysis. If concomitant use of these medicinal products is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If creatine kinase levels are significantly elevated, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. A reduction in the dose of HMG-CoA reductase inhibitors may be required according to the information on statin use.

Ibrutinib. Moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of ibrutinib and may increase the risk of toxicity. If such a combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) for the duration of the inhibitor use, and close clinical monitoring should be ensured.

Ivacaftor (alone or in combination with medicinal products of the same therapeutic class). Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3 times and to hydroxymethylivacaftor (M1) by 1.9 times. The dose of ivacaftor (alone or in combination) should be reduced according to the information on ivacaftor use (alone or in combination).

Olaparib: moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of olaparib; 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. During 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 medicinal products may be used concomitantly provided the cyclosporine dose is reduced depending on its concentration.

Everolimus: although in vitro and in vivo studies have not been conducted, fluconazole may increase serum concentrations of everolimus by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via the CYP3A4 enzyme and P-glycoprotein. These medicinal products may be used concomitantly provided the sirolimus dose is adjusted depending on its concentration and effects.

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

Losartan: fluconazole inhibits the metabolism 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 concentrations. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in the lurasidone use information.

Metadone: fluconazole may increase metadone serum concentration. Dose adjustment of metadone may be necessary during concomitant use with fluconazole.

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

Although specific studies have not been conducted, fluconazole may potentially increase 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 phenytoin metabolism. Repeated concomitant administration of 200 mg fluconazole and 250 mg phenytoin intravenously increases phenytoin AUC24 by 75% and Cmin by 128%. Serum phenytoin concentration should be monitored during concomitant use of these medicinal products to avoid phenytoin toxicity.

Prednisone: a case has been reported in which a patient after liver transplantation developed acute adrenal insufficiency while 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 fluconazole and prednisone concomitantly for a prolonged period should be closely monitored to prevent the development of adrenal insufficiency after discontinuation of fluconazole.

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

Saquinavir: fluconazole increases AUC and Cmax of saquinavir 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 and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: fluconazole prolongs the half-life (T½) of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea derivative dose are recommended during concomitant use with fluconazole.

Theophylline: in a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days resulted in an 18% reduction 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 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 tofacitinib dose to 5 mg once daily when used in combination with these medicinal products.

Concomitant use of tolvaptan. Exposure to tolvaptan significantly increases (200% in AUC; 80% in Cmax) when tolvaptan, a CYP3A4 substrate, is used concomitantly with fluconazole, a moderate CYP3A4 inhibitor, with a risk of significantly increased adverse reactions, especially diuresis, dehydration, and acute kidney injury. When used concomitantly, the tolvaptan dose should be reduced according to the tolvaptan prescribing information, and patients should be closely monitored for any adverse reactions related to tolvaptan.

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

Vitamin A: a case has been reported in which a patient receiving all-trans retinoic acid (the 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 considered.

Voriconazole (inhibitor of CYP2C9 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 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 related to voriconazole is recommended.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a reduction in zidovudine clearance of approximately 45% after oral administration. The half-life (T½) of zidovudine 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 adverse reactions related to zidovudine use. 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. When fluconazole was administered at a dose of 50 mg, no effect on hormone levels was observed, whereas administration of fluconazole at a dose of 200 mg daily resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. 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.

Dermatophytia. According to studies on fluconazole for the treatment of dermatophytia in children, fluconazole does not exceed griseofulvin in efficacy, and the overall efficacy rate is less than 20%. Therefore, Diflazon® should not be used for the treatment of dermatophytia.

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

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

Renal system. The drug should be administered with caution to 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 section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products."

Hepatobiliary system. The drug should be administered with caution to 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 has been linked to fluconazole use, there was no clear dependence on the total daily dose, duration of therapy, patient's sex, or 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 treatment should be closely monitored for progression to more severe liver damage.

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 prolongs the QT interval by inhibiting the rectifier potassium channel (Ikr). QT interval prolongation due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported during Diflazon® use. These reports involved patients with severe illnesses and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and progressive heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Diflazon® 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 skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

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

Cytochrome P450. Fluconazole is a moderate inhibitor of the CYP2C9 and CYP3A4 enzymes. It is also a potent inhibitor of the CYP2C19 enzyme. Patients receiving Diflazon® concomitantly with medicinal products having a narrow therapeutic window that are metabolized by 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 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 increased prevalence of infections caused by Candida species other than Candida albicans. These are often inherently resistant (e.g., Candida krusei and Candida auris) or exhibit reduced susceptibility to fluconazole (Candida glabrata). Such infections may require alternative antifungal therapy due to lack of response to fluconazole. Therefore, the prevalence of resistance among different Candida species to fluconazole should be considered.

Excipients. The drug contains lactose. This drug should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Women of reproductive age

Before initiating treatment, the patient should be informed about the potential risk to the fetus. After a single dose, a washout period of fluconazole, which is 1 week (corresponding to 5–6 elimination half-lives), should be observed before conception (see section "Pharmacokinetics").

For longer treatment courses, contraception should be considered for women of reproductive age throughout the entire treatment period and for 1 week after the last dose.

Pregnancy

Observational study data 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 receive fluconazole or used topical azoles during the same period.

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg of fluconazole during the first trimester do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, the effect of oral fluconazole during the first trimester was associated with a slight increase in the risk of musculoskeletal abnormalities, 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 exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) with a 150 mg oral dose of fluconazole and 1.98 (95% CI: 1.23–3.17) with doses exceeding 450 mg of fluconazole.

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 of pregnancy revealed a 1.8–2-fold increased risk of cardiac malformations in infants compared to infants whose mothers did not receive fluconazole and/or used topical azoles.

Reports describe congenital malformations in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Congenital abnormalities in newborns include auricular dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis.

A causal relationship between fluconazole use and these cases 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 potentially life-threatening infections.

Period of breastfeeding

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

Fertility

Fluconazole does not affect fertility in male and female rats.

Ability to influence reaction rate when driving or operating machinery.

Studies on the effect of Diflazon® 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 Diflazon® use (see section "Adverse reactions"). If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

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

Adults

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

Elderly Patients

In the absence of signs of renal impairment, elderly patients should receive the standard adult dose.

Patients with Renal Impairment

Fluconazole is primarily excreted unchanged in the urine. Dose adjustment is not required for a single dose of fluconazole.

Patients with Hepatic Impairment

Fluconazole should be used with caution in patients with hepatic impairment, as there is insufficient information regarding its use in this patient population (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. The currently 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.

Overdose.

There have been reports of fluconazole overdose leading to hallucinations and paranoid behavior.

In case of overdose, symptomatic and supportive therapy should be administered, and gastric lavage should be performed if necessary.

Fluconazole is substantially excreted in the urine; forced diuresis may accelerate its elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse Reactions.

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

The most frequently reported adverse reactions (>1/10) are: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels, rash.

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

Blood and lymphatic system disorders

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.

Uncommon: seizures, paresthesia, dizziness, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

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

Gastrointestinal disorders

Common: abdominal pain, nausea, diarrhea, 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 for use").

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

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

Skin and subcutaneous tissue disorders

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

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

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

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions for use").

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 are comparable to those in adults.

If severe adverse effects occur, treatment should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients 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. 5 years.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of reach and sight of children.

Packaging.

1 capsule in a blister; 1 blister per cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

INSTRUCTIONS

for medical use of the medicinal product

Diflazon®

(Diflazon®)

Composition:

Active substance: fluconazole;

1 capsule contains fluconazole 50 mg, or 100 mg, or 150 mg;

Excipients: lactose monohydrate, maize starch, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate;

Capsule shell: titanium dioxide (E 171), patent blue V (E 131), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties:

50 mg capsules: capsules with white body and light blue cap, filled with powder ranging from white to almost white;

100 mg capsules: capsules with white body and blue cap, filled with powder ranging from white to almost white;

150 mg capsules: capsules with light blue body and cap, filled with powder ranging from white to almost white.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, which is an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl sterols correlates with subsequent depletion of ergosterol in the fungal cell membrane and is considered 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 did not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily showed no 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 the most commonly encountered Candida species (including Candida albicans, Candida parapsilosis, and Candida tropicalis). Candida glabrata shows reduced susceptibility to fluconazole, whereas Candida krusei and Candida auris are resistant to fluconazole.

The minimal inhibitory concentration (MIC) and epidemiological cutoff value (ECOFF) of fluconazole for Candida guilliermondii are higher than those for Candida albicans.

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

Pharmacokinetic/pharmacodynamic relationships

According to animal studies, there is a correlation between minimal inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between area under the curve (AUC) and fluconazole dose (approximately 1:1). There is also a direct, although 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 exhibiting high minimal inhibitory concentrations (MICs) to fluconazole is generally less effective.

Mechanisms of resistance

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

In generally susceptible Candida species, the most commonly observed resistance mechanism involves alterations in the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from gene mutations, overexpression of the enzyme, drug efflux mechanisms, or development of compensatory metabolic pathways.

Superinfections with non-albicans Candida species, which often display reduced susceptibility (e.g., Candida glabrata) or resistance (e.g., Candida krusei, Candida auris) to fluconazole, have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms have not been fully elucidated for some Candida species with intrinsic resistance (e.g., Candida krusei) or newly emerging species (e.g., Candida auris).

Breakpoints (according to recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST))

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (EUCAST document on fluconazole rationale (2020) - version 2; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, tables of breakpoints for interpretation of MICs, version 10.0, effective from 04.02.2020). These breakpoints are categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic information and not dependent on species-specific MIC distributions, and species-related breakpoints, typically associated with human infections. These breakpoints are listed below.

S = susceptible;

R = resistant;

α – breakpoints not specific to a given species, which were largely determined based on pharmacokinetic/pharmacodynamic information and do not depend on the distribution of minimal inhibitory concentration for species for which no specific breakpoint exists;

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

* = All Candida glabrata isolates belong to category I. MIC against Candida glabrata should be interpreted as resistant if it exceeds 16 mg/L. The susceptible category (≤ 0.001 mg/L) allows avoiding misclassification of "I" strains as "S" strains. I – Intermediate: isolates are categorized as "intermediate" when there is a high likelihood of therapeutic success due to increased exposure of the agent through adjustment of dosing regimen or increased 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 drug absorption following oral administration. Peak plasma concentration is reached within 0.5–1.5 hours after drug intake. Drug concentration in plasma is proportional to dose. Steady-state concentration reaching 90% is achieved by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution

Volume of distribution approximates 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 in 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 remained at 5.8 µg/g. With a dose of 150 mg once weekly, the concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

Fluconazole concentration in nails after 4 months of 150 mg once weekly 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 radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes (see section "Interaction with other medicinal products and other forms of interaction"). Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme.

Elimination

The plasma half-life (T½) of fluconazole is approximately 30 hours. The majority of the drug is eliminated 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 T½ allows single-dose administration for vaginal candidiasis and once-weekly dosing for other indications.

Renal impairment

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), T½ increases from 30 hours 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%.

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. Fluconazole was detected in breast milk at an average concentration of approximately 98% of maternal plasma levels. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily 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, equals 0.39 mg/kg/day, which is approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended 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 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, mean plasma T½ of fluconazole ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer T½ 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. 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 preterm infants with a gestational age of approximately 28 weeks. 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 injections of fluconazole at 6 mg/kg were administered every 72 hours. Mean T½ 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 receiving diuretics. Cmax was 1.54 µg/mL, reached 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean T½ 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. 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.

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

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

Prevention of the following conditions in adults:

• prevention of recurrent cryptococcal meningitis in patients at high risk of developing it;
• prevention of recurrent 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").

Diflazon® is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prevention 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 capsule formulation of Diflazon® may be used in this patient population only when children are able to swallow the capsule safely, which is usually possible from the age of 5 years.

Treatment with Diflazon® 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 drug.
• 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: cases of cardiac adverse reactions, including torsade de pointes ventricular tachycardia, 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 significantly increased plasma levels of cisapride and prolonged the QT interval. 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 200 mg daily did not result in QTc prolongation. Another study using fluconazole doses of 400 mg and 800 mg daily demonstrated that fluconazole doses of 400 mg daily or higher significantly increased plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

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

Erythromycin: concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia) and, consequently, sudden death. The use of this combination is contraindicated (see section "Contraindications").

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

Halofantrine: fluconazole may increase halofantrine plasma concentrations by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia) and, consequently, sudden 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 co-administration of food, cimetidine, antacids, or total body irradiation for bone marrow transplantation has no clinically significant effect on the absorption of fluconazole following oral administration.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in the half-life (T½) 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 to healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40 %. Such interaction parameters do not require changes in the dosing regimen of fluconazole for patients receiving diuretics concomitantly.

• Effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and CYP3A4. Fluconazole is also a potent inhibitor of CYP2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when used concomitantly with fluconazole. Therefore, such 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.

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 prescribing information.

Alfentanil: during concomitant administration of alfentanil 20 mcg/kg and fluconazole 400 mg to healthy volunteers, a two-fold increase in AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil 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 start of combination therapy and after 1 week. Dose adjustment of amitriptyline/nortriptyline may be required if necessary.

Amphotericin B: concomitant administration of fluconazole and amphotericin B in immunocompetent and immunocompromised mice infected with C. albicans resulted in a slight additive antifungal effect in systemic infection, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism between the two drugs in systemic infection with Aspergillus fumigatus. The clinical significance of these findings 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 during concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants concomitantly. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines with 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 administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and 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 half-life, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If benzodiazepines need to be prescribed concomitantly to a patient undergoing fluconazole treatment, the dose of the latter 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, and felodipine) are metabolized by CYP3A4. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib: during concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), 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 drugs may be used concomitantly, considering the 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. In addition, a study involving 12 healthy volunteers demonstrated that fluconazole significantly slowed 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, such as atorvastatin and simvastatin, or HMG-CoA reductase inhibitors metabolized by CYP2C9, such as fluvastatin (which reduces hepatic statin metabolism), increases the risk (dose-dependent) of myopathy and rhabdomyolysis. 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, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. A dose reduction 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 such a combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) during the period of inhibitor use, and close clinical monitoring should be ensured.

Ivacaftor (alone or in combination with drugs of the same therapeutic class). Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases 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 ivacaftor prescribing information (alone or in combination).

Olaparib: moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of olaparib; 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. During 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 based on its concentration.

Everolimus: although in vitro and in vivo studies have not been conducted, fluconazole may increase serum concentrations of everolimus by inhibiting CYP3A4.

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

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

Losartan: fluconazole inhibits the metabolism 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 lurasidone prescribing information.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs): during concomitant use with fluconazole, Cmax and AUC of flurbiprofen increased by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, during concomitant use of fluconazole 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.

Although specific studies have not been conducted, fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse and toxic reactions 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 intravenous phenytoin increases phenytoin AUC24 by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration is required during concomitant use of these drugs to avoid phenytoin toxicity.

Prednisone: a case has been reported in which a patient after liver transplantation developed acute adrenal insufficiency while 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 prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after fluconazole discontinuation.

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

Saquinavir: fluconazole increases AUC and Cmax of saquinavir by approximately 50 % and 55 %, respectively, by inhibiting saquinavir metabolism in the liver via CYP3A4 and inhibiting 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: fluconazole prolongs the half-life (T½) of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent blood glucose monitoring and appropriate dose reduction of sulfonylurea derivatives are recommended during concomitant use with fluconazole.

Theophylline: in a placebo-controlled interaction study, 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 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 tofacitinib dose to 5 mg once daily when used in combination with these drugs.

• Tolvaptan.* Exposure to tolvaptan significantly increases (200 % in AUC; 80 % in Cmax) when tolvaptan, a CYP3A4 substrate, is used concomitantly with fluconazole, a moderate CYP3A4 inhibitor, with a risk of significantly increased adverse reactions, particularly diuresis, dehydration, and acute kidney injury. When used concomitantly, the tolvaptan dose should be reduced according to tolvaptan prescribing information, and patients should be closely monitored for any adverse reactions related to tolvaptan.

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

Vitamin A: cases have been reported in which patients receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole experienced central nervous system 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 central nervous system adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9 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) to 8 healthy male volunteers 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 related to voriconazole is recommended.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a reduction in zidovudine clearance by approximately 45 % following oral administration. The half-life (T½) of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole and zidovudine combination. Patients receiving this combination should be monitored for adverse reactions related to zidovudine use. 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 following single oral 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. 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 suggests that repeated use of fluconazole at the indicated doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to studies evaluating fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, and the overall effectiveness rate is less than 20%. Therefore, Diflazon® should not be used for the treatment of dermatophytosis.

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

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

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

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

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 has been linked to fluconazole use, there was no clear dependence on the total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of more severe liver damage.

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, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the "torsades de pointes" type have been reported during Diflazon® 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 QT-prolonging drugs. Patients with hypokalemia and progressive heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Diflazon® 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 using many medicinal products. If a patient with a 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 an invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. Anaphylactic reactions have been reported in rare cases (see section "Contraindications").

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

Terfenadine. Close monitoring of patients 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 shown an increased prevalence of infections caused by Candida species other than Candida albicans. These are often inherently resistant (e.g., Candida krusei and Candida auris) or exhibit reduced susceptibility to fluconazole (Candida glabrata). Such infections may require alternative antifungal therapy due to lack of response to fluconazole. Therefore, the prevalence of resistance among different Candida species to fluconazole should be considered.

Excipients. The drug contains lactose. This drug should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

For longer treatment courses, contraception should be considered for women of reproductive potential throughout the entire treatment period and for 1 week after the last dose.

Pregnancy

Observational study data 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 receive fluconazole or used topical azoles during the same period.

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg of fluconazole during the first trimester do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, the effect of oral fluconazole during the first trimester was associated with a slight increase in the risk of musculoskeletal disorders—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 exceeding 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 exceeding 450 mg of fluconazole.

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

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole for more than 3 months during pregnancy for the treatment of coccidioidomycosis. Congenital abnormalities in newborns include auricular dysplasia, enlarged anterior fontanelle, femoral bowing, and radiohumeral synostosis.

A causal relationship between fluconazole use and these cases 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 potentially life-threatening infections.

Breastfeeding period

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

Fertility

Fluconazole does not affect fertility in male or female rats.

Ability to influence reaction rate while driving or operating machinery.

Studies on the effect of Diflazon® 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 treatment with Diflazon® (see section "Adverse reactions"). If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage

The daily dose of fluconazole depends on the nature and severity of the fungal infection. Treatment of infections requiring multiple doses should continue until clinical and laboratory signs of fungal activity have resolved. Inadequate duration of treatment may lead to recurrence of active infection.

The drug can be administered orally (capsules) or intravenously by infusion (infusion solution). The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching from oral to intravenous administration or vice versa.

Capsules should be swallowed whole. The drug may be taken regardless of food intake.

Adults

Cryptococcosis

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg once daily. Duration of treatment is usually at least 6–8 weeks. 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: recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis

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

Invasive Candidiasis

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

Oropharyngeal and Mucosal Candidiasis

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

Prevention of Recurrent Mucosal Candidiasis in HIV-Infected Patients at High Risk

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

Prophylaxis of Candidiasis in Patients with Prolonged Neutropenia

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

Genital Candidiasis

• Acute vulvovaginal candidiasis, candidal balanitis: recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vulvovaginal candidiasis (4 or more episodes per year): recommended regimen is 150 mg every 3 days for a total of 3 doses (on day 1, day 4, and day 7), followed by maintenance therapy with 150 mg once weekly for 6 months.

Dermatomycoses

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

Prophylaxis of Candidiasis in Patients with Prolonged Neutropenia

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

Special Patient Groups

Elderly Patients

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

Patients with Renal Impairment

Dose adjustment is not required for single-dose administration. For patients (including children) with renal impairment requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day depending on the indication. Thereafter, the daily dose (depending on the indication) should be adjusted according to the table below:

Patients undergoing hemodialysis should receive 100% of the recommended dose after each hemodialysis session. On days when dialysis 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 "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 the clinical and mycological response. Diflazon® should be administered once daily.

Dosage recommendations for children with renal impairment are provided in the section "Patients with renal insufficiency."

The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 5 to 11 years

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

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

Maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg 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 intensity and duration of induced neutropenia (see adult dosing recommendations).

Children aged 12 years

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

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

Children

The capsule formulation of the drug may be used in this patient population when children are able to safely swallow capsules, which is generally possible from the age of 5 years (see section "Administration and dosage").

Overdose

There have been reports of fluconazole overdose leading to hallucinations and paranoid behavior.

In case of overdose, symptomatic and supportive therapy should be administered, and gastric lavage should be performed if necessary.

Fluconazole is predominantly excreted in the urine; forced diuresis may enhance drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in association with fluconazole treatment (see section "Special Warnings and Precautions for Use").

The most frequently reported adverse reactions (>1/10) are: headache, abdominal pain, diarrhea, 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), not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia.
Rare: agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.
Rare: hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.
Uncommon: convulsions, paresthesia, dizziness, 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, nausea, diarrhea, vomiting.
Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased alkaline phosphatase (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: drug eruption (including fixed drug eruption), urticaria, pruritus, 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").
Not known: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section "Special Warnings and Precautions for Use").

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever.

Paediatric population

The frequency and nature of adverse reactions and laboratory abnormalities observed in clinical trials involving children are comparable to those in adults.

If severe adverse effects occur, treatment should be discontinued.

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, pharmacists, as well as 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. 5 years.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of reach of children.

Packaging.

50 mg capsules: 7 capsules per blister; 1 blister per carton.

100 mg capsules: 7 capsules per blister; 4 blisters per carton.

150 mg capsules: 2 or 4 capsules per blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.