Fluconazole-cr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOL-KR (FLUCONAZOL-KR)

Composition:

Active substance: fluconazole;

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

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

Capsule shell:

50 mg capsules — gelatin, titanium dioxide (E 171), quinoline yellow (E 104), erythrosine (E 127);

100 mg capsules — gelatin, titanium dioxide (E 171), quinoline yellow (E 104), erythrosine (E 127);

150 mg capsules — gelatin, titanium dioxide (E 171), quinoline yellow (E 104), erythrosine (E 127).

Pharmaceutical form. Capsules.

Main physicochemical properties:

50 mg capsules: hard gelatin capsules with white body and yellow cap;

100 mg capsules: hard gelatin capsules with white body and yellow cap;

150 mg capsules: hard gelatin capsules of yellow color.

The contents of the capsules — white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

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

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

In vitro susceptibility

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, and C. tropicalis). C. glabrata exhibits reduced susceptibility to fluconazole, whereas C. krusei and C. auris are resistant to fluconazole.

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

Pharmacokinetic/pharmacodynamic relationship

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

Mechanisms of resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole demonstrates high MICs against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo efficacy and clinical effectiveness. There have been reports of superinfections with Candida species other than C. albicans, which often have inherently reduced susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole. Such infections may require alternative antifungal therapy.

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species. These have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific MIC distributions, and species-specific breakpoints associated with infections commonly occurring in humans. These breakpoints are listed below.

Antifungal agent	Organism-specific breakpoints S ≤ / R >					Non-organism-specific breakpointsα S ≤ /R >
	Candida albicans	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	IE	--	2/4	2/4	2/4

S = susceptible;
R = resistant;
α – breakpoints not associated with a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a species-specific breakpoint;
-- susceptibility testing not recommended, as this organism is not a target for antimicrobial therapy;
IE – insufficient evidence to determine whether this organism is a target for antimicrobial therapy.

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 dosing on an empty stomach. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of once-daily treatment. A steady-state concentration of 90% is reached by day 2 when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

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

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. With a 50 mg once-daily dose, fluconazole concentration after 12 days of treatment was 73 µg/g, and remained at 5.8 µg/g seven days after treatment ended. With a 150 mg once-weekly dose, fluconazole concentration on day 7 of treatment was 23.4 µg/g; seven days after the next dose, the concentration remained at 7.1 µg/g.

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

Biotransformation.

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

Elimination.

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

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

Renal impairment.

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

Lactation.

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

Pediatric population.

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, the mean plasma elimination half-life ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma half-life of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

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

Geriatric patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg fluconazole orally. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4 ± 20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. 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 also lower than in younger volunteers. Therefore, pharmacokinetic changes in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

Fluconazole-KR 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 mucocutaneous candidiasis;
• chronic atrophic oral candidiasis (denture stomatitis) 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 candidiasis, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

Fluconazole-KR is indicated for prophylaxis of the following conditions in adults:

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

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

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

Treatment with Fluconazole-KR may be initiated before obtaining results of culture and other laboratory tests; however, antimicrobial therapy should be adjusted appropriately once test results are available.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients listed in the section "Composition".
• 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 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 were conducted. In one study, administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased plasma 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 and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although relevant in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

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

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

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. Fluconazole should be used with caution together with amiodarone, especially when high-dose fluconazole (800 mg) is prescribed.

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

• Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole together with food, administration of cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

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

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

• Effect of fluconazole on other medicinal products.

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

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 CYP3A4 inhibition. 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 beginning of combination therapy and after 1 week. Dose adjustment of amitriptyline/nortriptyline may be necessary if required.

Amphotericin B: concomitant administration of fluconazole and amphotericin B to 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 with concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indanediones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, 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 administration of fluconazole 200 mg and oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life of midazolam, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam. If benzodiazepines need to be prescribed concomitantly to a patient undergoing fluconazole treatment, the dose of benzodiazepines should be reduced and appropriate monitoring of the patient 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: concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68 % and 134 %, respectively. When celecoxib is used concomitantly with fluconazole, a 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 concentrations.

Fentanyl: one fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study in healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful monitoring of the patient is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), increases the risk of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, careful monitoring of the patient for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels are required. If a significant increase in creatine kinase levels is observed, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase olaparib plasma concentrations; their concomitant use is not recommended. If such a combination cannot be avoided, olaparib intake should be limited to 200 mg twice daily.

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

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

Everolimus: although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamin A: adverse reactions from the central nervous system (CNS) in the form of pseudotumor cerebri have been reported in a patient receiving all-trans retinoic acid (acid form of vitamin A) and fluconazole concomitantly; this effect resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be kept in mind.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours 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 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 administered after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

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

Azithromycin: 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 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 indicates that multiple-dose administration of fluconazole at the specified doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor: 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. For patients receiving concomitant moderate CYP3A inhibitors such as fluconazole and erythromycin, it is recommended to reduce the ivacaftor dose to 150 mg once daily.

Special precautions for use.

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

• Dermatophytosis.* According to clinical trial results of fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, with an overall efficacy rate of less than 20%. Therefore, Fluconazole-KR should not be used for the treatment of dermatophytosis.

• Cryptococcosis.* Evidence of fluconazole efficacy for treating cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, no dosage recommendations exist for treating these conditions.

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

• 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" under "Effect of fluconazole on other medicinal products."

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

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

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole 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 caused by other drugs (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported with Fluconazole-KR. These reports involved patients with severe illnesses and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs affecting the QT interval. Patients with hypokalemia and progressive heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Fluconazole-KR should be used with caution in patients at risk of arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized via 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").

• Dermatological 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 syndrome) has also been reported. Patients with AIDS are more prone to develop severe skin reactions when using many drugs. If a patient with a superficial fungal infection develops a rash possibly related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

• Hypersensitivity.* Anaphylactic reactions have been reported rarely (see section "Contraindications").

• Cytochrome P450.* Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of CYP2C19. Patients receiving Fluconazole-KR concomitantly with drugs having a narrow therapeutic window that are metabolized via CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

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

• Excipients.* The product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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

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

• Pregnancy*

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

Data from several thousand pregnant women who received a cumulative dose of fluconazole ≤150 mg in the first trimester do not indicate an increased overall risk of fetal malformations.

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

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

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

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

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

• Breastfeeding.*

Fluconazole passes into breast milk and reaches concentrations similar to plasma levels (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 use. The benefit of breastfeeding for the child's development and health, the mother's clinical need for Fluconazole-KR, and any potential adverse effects of Fluconazole-KR or the mother's underlying condition on the breastfed child should be carefully evaluated.

• Fertility.*

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

• Ability to drive and use machines.*

No studies on the effect of Fluconazole-KR on the ability to drive or operate machinery have been conducted.

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

Administration and Dosage.

The dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose of the drug is sufficient.

If repeated administration is required, treatment of infections should be continued until clinical and laboratory signs of fungal infection activity have resolved. Inadequate duration of treatment may lead to recurrence of active infection.

Fluconazole-KR should be administered, depending on the dosage form, 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. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: the recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis.

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

Invasive candidiasis.

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

Candidiasis of mucous membranes.

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

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

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

Prophylaxis of candidiasis in patients with prolonged neutropenia.

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

Genital candidiasis.

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

Dermatomycoses.

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

Elderly patients.

Dosage should be adjusted according to renal function (see "Patients with renal impairment" below).

Patients with renal impairment.

Fluconazole-KR is primarily excreted unchanged in urine. Dose adjustment is not required for single-dose administration. In patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the indication. Thereafter, the daily dose (depending on the indication) should be adjusted according to the table below:

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

Patients undergoing regular hemodialysis should receive 100% of the recommended dose after each hemodialysis session. On days when 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 dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children.

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

As with similar infections in adults, the duration of treatment depends on clinical and mycological response. Fluconazole-KR 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 12 years and older.

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

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

Children aged 5 to 11 years.

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

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg 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 severity and duration of induced neutropenia (see adult dosages).

Children.

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

Overdose.

Cases of fluconazole overdose have been reported; hallucinations and paranoid behavior have also been reported.

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

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

Adverse reactions.

The most commonly 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 in blood, rash.

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

Blood and lymphatic system disorders.

Uncommon: 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.

Auricular and vestibular disorders.

Uncommon: vertigo.

Cardiac disorders.

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

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").

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

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

Skin and subcutaneous tissue disorders.

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

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

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

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

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia.

General disorders and administration site conditions.

Uncommon: increased fatigue, malaise, asthenia, fever.

Paediatric population.

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

Reporting suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

50 mg capsules: 7 or 10 capsules in a blister, 1 blister in a cardboard box.

100 mg capsules: 7 or 10 capsules in a blister, 1 blister in a cardboard box.

150 mg capsules: 1 capsule in a blister, 2 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

PJSC “CHEMICAL PHARMACEUTICAL PLANT “CHERVONA ZIRKA”.

Manufacturer's address and place of business.

1, Hordiienkivska Street, Kharkiv, Kharkiv region, 61010, Ukraine.

INSTRUCTION

for medical use of the medicinal product

FLUCONAZOLE-KR

(FLUCONAZOL-KR)

Composition:

Active ingredient: fluconazole;

1 capsule contains fluconazole 150 mg;

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

Capsule shell: gelatin, titanium dioxide (E 171), quinoline yellow (E 104), erythrosine (E 127).

Dosage form. Capsules.

Main physicochemical properties: hard gelatin capsules of yellow color.

The capsule contents – white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

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

Administration of fluconazole at a dose of 50 mg once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily has no clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Interaction studies with antipyrine demonstrated that single or repeated administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro Susceptibility

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, and C. tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, whereas C. krusei is resistant. C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are intrinsically resistant to fluconazole.

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

Pharmacokinetic/Pharmacodynamic Relationships

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

Mechanism of Resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations (MICs) against fungal strains possessing one or more resistance mechanisms, which negatively impacts in vivo efficacy and clinical outcomes. Cases of superinfection with Candida spp. other than C. albicans, which are often intrinsically less susceptible to fluconazole (e.g., Candida krusei), have been reported. Alternative antifungal agents should be used for the treatment of such infections. Cases of superinfection with Candida species other than C. albicans—which often have inherently reduced susceptibility (e.g., C. glabrata) or intrinsic resistance to fluconazole (e.g., C. krusei, C. auris)—have also been reported. Such infections may require alternative antifungal therapy.

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole against Candida species have been established. These are categorized into non-species-specific breakpoints, primarily determined by pharmacokinetic/pharmacodynamic data and independent of species-specific MIC distributions, and species-specific breakpoints associated with infections commonly occurring in humans. These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints, S ≤ / R > S ≤ / R >					Non-species-specific breakpointsα S ≤ / R >
	Candida albicans	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	IE	--	2/4	2/4	2/4

S = susceptible;
R = resistant;
α – breakpoints not associated with a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a specific breakpoint;
-- susceptibility testing not recommended, as this species is not a target for antimicrobial therapy;
IE – insufficient evidence to determine whether this species is a target for antimicrobial therapy.

Pharmacokinetics

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

Absorption.

Fluconazole is well absorbed after oral administration, and plasma concentrations 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 fasting administration. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of repeated once-daily dosing. A 90% steady-state concentration is achieved 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 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 exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. After a daily dose of 50 mg, fluconazole concentration in the stratum corneum reaches 73 µg/g after 12 days of treatment and remains at 5.8 µg/g seven days after treatment ends. With a weekly dose of 150 mg, the concentration on day 7 of treatment is 23.4 µg/g; seven days after the next dose, the concentration remains at 7.1 µg/g.

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

Biotransformation.

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

Elimination.

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

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

Renal impairment.

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

Lactation.

Plasma and breast milk fluconazole concentrations were evaluated over 48 hours following a single 150 mg dose of Fluconazole-KR in a pharmacokinetic study involving ten lactating women who had 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 ingested by the infant via breast milk (assuming average milk intake of 150 ml/kg/day), calculated based on mean peak milk concentration, was 0.39 mg/kg/day, representing approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Pediatric population.

Pharmacokinetic data were evaluated in 113 children across five studies: two single-dose studies, two multiple-dose studies, and one study in premature neonates.

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

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range: 9–36 hours); mean birth weight was 900 g (range: 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and to 47 hours (27–68) on day 13. 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) receiving 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after administration. Mean AUC was 76.4 ± 20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours: 22%), and renal clearance of fluconazole (0.124 mL/min/kg) were lower in this age group compared to younger volunteers. Therefore, pharmacokinetic changes in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

Fluconazole-KR 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 Fluconazole-KR may be initiated before the results of cultures and other laboratory tests are available; however, after obtaining test results, antimicrobial therapy should be adjusted accordingly.

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

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients listed in the section "Composition".

• 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 by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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

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

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these agents were conducted. In one study, administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased plasma terfenadine levels when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is 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 plasma astemizole concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide and quinidine: concomitant use of fluconazole 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 "torsade de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

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

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

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

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

Amiodarone: concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. Fluconazole should be used with caution together with amiodarone, especially when high-dose fluconazole (800 mg) is prescribed.

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

• Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole concomitantly with food, cimetidine, antacids, or total body irradiation prior to bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

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

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

• Effect of fluconazole on other medicinal products.

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

Alfentanil: during concomitant administration of alfentanil at a dose of 20 mcg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in AUC10 was observed, possibly due to CYP3A4 inhibition. 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 beginning 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 infected mice showed the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these 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 twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants or indanediones. 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 administration of fluconazole 200 mg and midazolam 7.5 mg orally increased the AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally increased the AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam. If benzodiazepines 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: when fluconazole (200 mg daily) and celecoxib (200 mg) were used concomitantly, Cmax and AUC of celecoxib increased by 68 % and 134 %, respectively. When celecoxib is used concomitantly with fluconazole, a halving of the celecoxib dose may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs 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 in healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, patient status should be closely monitored. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), increases the risk 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.

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, cyclosporine AUC increased by 1.8 times. These drugs may be used concomitantly provided cyclosporine dose is reduced depending on its concentration.

Everolimus: although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase everolimus serum concentration due to inhibition of 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 depending on concentration and drug effects.

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

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

Methadone: fluconazole may increase methadone serum concentration. 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 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 only racemic ibuprofen was used.

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

Phenytoin: fluconazole inhibits hepatic metabolism of phenytoin. Concomitant multiple administration of 200 mg fluconazole and 250 mg phenytoin intravenously increases phenytoin AUC24 by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration should be performed during concomitant use of these drugs to avoid phenytoin toxicity.

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

Rifabutin: fluconazole increases rifabutin serum concentration, 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, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied, so they may be more pronounced. Dose adjustment of saquinavir may be necessary.

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

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

Tofacitinib: the effect of tofacitinib increases 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 agents.

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: adverse reactions from the central nervous system (CNS), such as pseudotumor cerebri, have been reported in a patient receiving all-trans retinoic acid (acid form of vitamin A) and fluconazole concomitantly; this effect resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be kept in mind.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an average increase in Cmax and AUCτ of voriconazole by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a decrease in zidovudine clearance by approximately 45 % with oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole and zidovudine combination. Patients receiving this combination of medicinal products should be monitored for adverse reactions associated with 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 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 multiple-dose administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor: 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. For patients receiving concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, it is recommended to reduce the ivacaftor dose to 150 mg once daily.

Special precautions for use.

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

• Dermatophytosis.* According to clinical trial data on fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, with an overall efficacy rate of less than 20%. Therefore, Fluconazole-KR should not be used for the treatment of dermatophytosis.

• Cryptococcosis.* There is insufficient evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be made for the treatment of such infections.

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

• Renal system.* The drug should be administered with caution in patients with impaired renal function (see section "Dosage and administration").

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

• Hepatobiliary system.* The drug should be administered with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was linked to fluconazole, 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 progression to more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole 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 rectifier potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported during treatment with Fluconazole-KR. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and progressive heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

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

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

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

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

• Cytochrome P450.* Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of CYP2C19. Patients receiving Fluconazole-KR concomitantly with medicinal products having a narrow therapeutic index that are metabolized via CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

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

• Excipients.* The drug contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

• Use during pregnancy or breastfeeding.*

• Women of reproductive potential*

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

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

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

• Pregnancy *

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

Data from several thousand pregnant women who received cumulative fluconazole doses ≤ 150 mg during the first trimester do not indicate an increased overall risk of fetal malformations.

In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1,000 women receiving cumulative doses ≤ 450 mg, compared to women receiving topical azoles, and approximately 4 additional cases per 1,000 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.

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

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

Standard doses of fluconazole and short-term treatment courses should not be used during pregnancy except in cases of extreme necessity.

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

• Breastfeeding.*

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

• Fertility.*

Fluconazole did not affect fertility in male and female rats.

• Ability to drive and use machines.*

No studies on the effect of Fluconazole-KR on the ability to drive or operate machinery have been conducted.

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during treatment with Fluconazole-KR. 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 not dependent on 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, this patient category should be treated with the standard adult dose.

Renal impairment.

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

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction due to insufficient data on fluconazole use in this patient group (see sections "Special Warnings and Precautions for Use" and "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), standard adult doses should be used.

Overdose.

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

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

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

Side effects.

The most frequently reported side effects (> 1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels in blood, rash.

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

Blood and lymphatic system disorders.

Uncommon: 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, paraesthesia, 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 precautions").

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").

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

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

Skin and subcutaneous tissue disorders.

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

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

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

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

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia.

General disorders and administration site conditions.

Uncommon: fatigue, malaise, asthenia, fever.

Children.

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

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 are asked to report any suspected adverse reactions in accordance with local regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

150 mg capsules: 1 capsule per blister; 1 blister per cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

PJSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and place of business.

1 Gordiienkivska Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine.