Fluconazole-kr: detailed information

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 in mammals.

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

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

In vitro susceptibility

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

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

Pharmacokinetic/pharmacodynamic relationship

According to animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and efficacy in experimental models of mycoses caused by Candida species. Clinical studies indicate a linear relationship between AUC and fluconazole dose (approximately 1:1). There is also a direct, although not fully sufficient, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains exhibiting high minimum inhibitory concentrations to fluconazole is less effective.

Mechanism of resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo and clinical efficacy. 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 to fluconazole (e.g., C. krusei, C. auris). Such infections may require alternative antifungal therapy.

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, clinical 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

Species-specific breakpoints

S ≤ / R >

Non-species-related breakpointsα

S ≤ /R >

Candida albicans

Candida glabrata

Candida krusei

Candida parapsilosis

Candida tropicalis

Fluconazole

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 the absorption of the drug when administered orally. Peak plasma concentration is reached within 0.5–1.5 hours after dosing on an empty stomach. Drug plasma concentration is proportional to the dose. Steady-state 90% concentration is achieved by day 4–5 of repeated once-daily dosing. A steady-state concentration of 90% is reached by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

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

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, including 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 was 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a weekly dose of 150 mg, fluconazole concentration on day 7 of treatment was 23.4 µg/g; seven days after the next dose, the concentration remained at 7.1 µg/g.

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

Biotransformation.

Fluconazole is minimally metabolized. After administration of radiolabeled 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 eliminated by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma 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, this patient group requires dose reduction of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Lactation.

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

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, and the volume of distribution was 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life 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 injections of fluconazole at 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–111) 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. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, the observed changes in pharmacokinetics in elderly patients are likely 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 topical therapy is ineffective;
vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
candidal balanitis, when topical therapy is not appropriate;
dermatomycoses, including tinea pedis, tinea of glabrous skin, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

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

prevention of recurrence of cryptococcal meningitis in patients at high risk;
prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk;
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 (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 safely swallow the capsule, which is usually feasible from the age of 5 years.

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

Contraindications.

Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients 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 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 were conducted. In one study, administration of fluconazole 200 mg daily did not result in QTc prolongation. Another study using fluconazole doses of 400 mg and 800 mg daily showed 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. This increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the “torsades de pointes” type. Concomitant use of fluconazole and astemizole is contraindicated (see section “Contraindications”).

Pimozide 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 shown that oral administration of fluconazole with food, co-administration with 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, repeated 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.

Effect of fluconazole on other medicinal products.

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

Alfentanil: during concomitant administration of alfentanil 20 mcg/kg and fluconazole 400 mg to healthy volunteers, a twofold increase in AUC 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. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

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

Anticoagulants: as with other azole antifungal agents, 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 midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole 200 mg and oral midazolam 7.5 mg increased midazolam AUC and elimination half-life by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg increased triazolam AUC and elimination half-life by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam. If benzodiazepines must be administered concomitantly to a patient undergoing fluconazole therapy, the benzodiazepine dose should be reduced and appropriate patient monitoring established.

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

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, 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 celecoxib Cmax and AUC 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 patient monitoring is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), increases the risk of myopathy and rhabdomyolysis. If concomitant use 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 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. Concomitant administration of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in an 1.8-fold increase in cyclosporine AUC. These drugs may be used concomitantly provided cyclosporine dose is reduced according to its concentration.

Everolimus: although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase everolimus serum concentration 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 according to its concentration and effects.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5-fold with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced according to 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 therapy. Continuous monitoring of blood pressure in patients is recommended.

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

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

Although no specific studies have been conducted, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for NSAID-related adverse reactions and toxic effects is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases phenytoin AUC24 by 75 % and Cmin by 128 %. Serum phenytoin concentration should be monitored when these drugs are used concomitantly to avoid phenytoin toxicity.

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

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

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

Sulfonylurea derivatives: fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent blood glucose monitoring is recommended, and sulfonylurea derivative dose should be reduced accordingly when used concomitantly with fluconazole.

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

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

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

Vitamin A: adverse reactions from the central nervous system (CNS), such as pseudotumor cerebri, have been reported in a patient receiving all-trans retinoic acid (the 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 voriconazole Cmax and AUCτ of 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for voriconazole-associated adverse effects is recommended.

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

Azithromycin: in an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effect of azithromycin and fluconazole on each other’s pharmacokinetics was evaluated after single oral 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. No effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily increased AUC of ethinylestradiol by 40 % and levonorgestrel by 24 %. This suggests that repeated 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 ivacaftor exposure by 3 times and hydroxymethylivacaftor (M1) by 1.9 times. For patients receiving moderate CYP3A inhibitors such as fluconazole and erythromycin concomitantly, a reduction in ivacaftor dose to 150 mg once daily is recommended.

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, physicians 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, and the overall efficacy rate is less than 20%. Therefore, Fluconazole-KR should not be used for the treatment of dermatophytosis.
Cryptococcosis.* Evidence of fluconazole efficacy in treating cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, there are no dosage recommendations for treating such conditions.
Deep endemic mycoses.* Evidence of fluconazole efficacy in treating other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, there are no dosage recommendations for treating these conditions.
Renal system.* The drug should be administered with caution in patients with impaired renal function (see section "Method of administration and dosage").
Adrenal insufficiency.* Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rare. 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 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 has been linked to fluconazole, no clear dependence on total daily dose, duration of therapy, sex, or age of the patient has been observed. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for 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 medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported during use of Fluconazole-KR. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte imbalances, 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 developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 cytochrome P450 enzyme is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine.* Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when 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.* Rarely, exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has also been reported. Patients with AIDS are more prone to developing severe skin reactions when taking many drugs. If a patient with a superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with 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 strong inhibitor of the CYP2C19 enzyme. Patients receiving Fluconazole-KR concomitantly with drugs having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").
Terfenadine.* Close monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at doses below 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
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, 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 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 a cumulative fluconazole dose ≤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 above 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 above 450 mg of fluconazole.

Available epidemiological studies on congenital heart defects associated with 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 congenital heart defects 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 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 fluconazole treatment should not be used during pregnancy except when absolutely necessary.

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

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg). Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole. The benefit of breastfeeding for the child's development and health, the mother's clinical need for 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 had no effect on fertility in male and female rats.

Ability to influence reaction speed when driving or operating machinery.

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

Patients should be informed about the possibility of dizziness or seizures (see section "Adverse reactions") during treatment 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 disappeared. 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. The duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: the recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis.

The recommended dose is 200–400 mg once daily. The duration of treatment is 11–24 months or longer depending on the patient's condition. For some 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. The duration of treatment is 7–21 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. The duration of treatment is 14–30 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
Candiduria: the recommended dose is 200–400 mg once daily for 7–21 days. For patients with severe immunodeficiency, the duration of treatment may be extended.
Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
Chronic cutaneous and mucosal candidiasis: the recommended dose is 50–100 mg once daily. The duration of treatment is up to 28 days, but may be extended depending on the severity and type of infection or immunosuppression.

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

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

Prophylaxis of candidiasis in patients with prolonged neutropenia.

The recommended dose is 200–400 mg once daily. Treatment should be initiated several days before 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 dose 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, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

Tinea pedis, cutaneous candidiasis, tinea cruris, candidal skin infections: the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
Dermatophyte onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is completely replaced by healthy nail. Healthy nail regrowth typically takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-standing chronic infections, nail appearance may sometimes 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 the urine. Dose adjustment is not required for single-dose administration. For patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the 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 administered with caution to patients with hepatic dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special precautions" and "Adverse reactions").

Children.

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

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

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

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

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or pediatric dosage regimen is optimal for the patient. Clinical data indicate that fluconazole clearance in children is higher 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 administer the drug to adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose may be administered on 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 for prevention of 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 dosing recommendations).

Children.

The use of the drug in capsule form in this patient population is possible when children are able to swallow the capsule safely, which is usually feasible from the age of 5 years (see section "Administration and dosage").

Overdose.

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

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

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

Side effects.

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

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 levels of alanine aminotransferase (ALT), increased levels of aspartate aminotransferase (AST), increased levels of alkaline phosphatase (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: increased fatigue, malaise, asthenia, fever.

Children.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged 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 category. Prescription only.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and location of its operations.

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