Fluconazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE

Composition:

Active substance: fluconazole;

100 ml of solution contain fluconazole (calculated as 100% dry substance) 0.2 g;

Excipients: sodium chloride, disodium edetate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless liquid;

theoretical osmolarity 315 mosmol/L; pH 4.0–7.0.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

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

Studies 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 commonly encountered Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and epidemiological cutoff values (ECOFF) for fluconazole against C. guilliermondii according to EUCAST are higher than those for C. albicans. Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationship

According to animal studies, there is a correlation between minimal inhibitory concentration (MIC) and efficacy in experimental models of Candida-induced mycoses. Clinical studies have shown a linear relationship between the area under the concentration-time curve (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 outcomes for infections caused by strains with high minimal inhibitory concentrations to fluconazole are less favorable.

Mechanism of resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimal inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo and clinical efficacy. In normally susceptible Candida species, the most common resistance mechanism involves the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways. Cases of superinfection caused by Candida species other than C. albicans, which often display reduced susceptibility (e.g., C. glabrata) or resistance to fluconazole (e.g., C. krusei, C. auris), have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms are not yet fully understood in some intrinsically resistant species (e.g., C. krusei) or emerging species (e.g., C. auris).

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (Supporting Information Document EUCAST for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective date 04.02.2020). These have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific distribution of minimal inhibitory concentrations, and species-specific breakpoints, predominantly associated with human infections. These breakpoints are listed below.

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

S — susceptible; R — resistant;

a — breakpoints not associated with a specific species, which were primarily defined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific minimal inhibitory concentration distributions; these were studied only in microorganisms lacking a specific breakpoint;

-- susceptibility testing not recommended, as this species is not a target for antimicrobial therapy;

* — All C. glabrata isolates fall into the I category. C. glabrata isolates with MICs exceeding 16 mg/L should be considered resistant. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S. I – intermediate: microorganisms categorized as "intermediate" indicate a high likelihood of therapeutic success when drug exposure is increased through adjustment of dosing regimen or increased drug concentration at the site of infection.

Pharmacokinetics.

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

Absorption

Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption of the drug when administered orally. Maximum plasma concentration (Cmax) 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 once-daily therapy. A steady-state concentration of 90% is reached by day 2 when a loading dose twice the normal daily dose is administered on the first day.

Distribution

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

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

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

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

Biotransformation

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

Elimination

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

The prolonged plasma 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 must be reduced 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 plasma and breast milk were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. In breast milk, fluconazole concentration averaged approximately 98% of that in maternal plasma. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole ingested by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean 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.

Children

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

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, with a volume of distribution of 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 doses of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

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) in this age group were lower than in younger volunteers. Thus, the observed changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

Fluconazole 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.

Fluconazole 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;
• 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 is indicated in children from birth 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").

Treatment with the drug may be initiated before the results of culture and other laboratory tests are available; however, after obtaining the results, antimicrobial therapy should be adjusted accordingly.

Contraindications.

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

Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg per 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, such as cisapride, astemizole, pimozide, quinidine, and erythromycin (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated

Cisapride

Cardiac adverse reactions, including torsade de pointes ventricular tachycardia, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in cisapride plasma 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 terfenadine plasma levels when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole

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

Pimozide and quinidine

Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although relevant in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to torsade de pointes ventricular tachycardia. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

Erythromycin

Concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia) 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, torsade de pointes ventricular tachycardia) and, consequently, sudden cardiac death. The use of this combination should be avoided (see section "Special precautions for use").

Concomitant use of fluconazole and the following medicinal products requires caution

Amiodarone

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

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

Effect of other medicinal products on fluconazole

Interaction studies have demonstrated that oral administration of fluconazole simultaneously with food, 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 fluconazole elimination half-life. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide

In a pharmacokinetic interaction study, multiple concomitant administration of hydrochlorothiazide to healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40%. Such interaction parameters do not require changes in fluconazole dosing regimen in 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 the CYP2C19 isoenzyme. In addition to observed/documentarily confirmed interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution, and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long elimination half-life (see section "Contraindications").

Abrocitinib

Fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155%. When used concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to the abrocitinib prescribing information.

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 AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline

Fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and after 1 week. Dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B

Concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice yielded the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these study results is unknown.

Anticoagulants

As with other azole antifungal agents, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported during concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indandione derivatives concomitantly. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines with 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 at a dose of 200 mg and midazolam at a dose of 7.5 mg orally increased AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole at a dose of 200 mg daily and 0.25 mg triazolam orally increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If a patient undergoing fluconazole treatment needs to be prescribed benzodiazepines concomitantly, the dose of the latter should be reduced and appropriate patient monitoring established.

Carbamazepine

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

Calcium channel blockers

Some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib

During concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. During concomitant use of celecoxib and fluconazole, a halving of the celecoxib dose may be necessary.

Cyclophosphamide

Concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs may be used concomitantly, considering the risk of increased serum bilirubin and creatinine levels.

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, close patient monitoring is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors

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

Ibrutinib

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

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class)

Concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased exposure to ivacaftor by 3 times and exposure to hydroxymethylivacaftor (M1) by 1.9 times. Dose reduction of ivacaftor (as monotherapy or in combination) is necessary, as specified in the ivacaftor prescribing information.

Olaparib

Moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentrations; therefore, 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 at a dose of 200 mg daily and cyclosporine at a dose of 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus

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

Sirolimus

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

Tacrolimus

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

Lurasidone

Moderate CYP3A4 inhibitors, such as fluconazole, may increase lurasidone plasma concentration. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in the lurasidone prescribing information.

Methadone

Fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary during concomitant use of methadone and 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 with flurbiprofen 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 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 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 minimum plasma concentration (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 in which a patient after liver transplantation developed acute adrenal insufficiency while on prednisone, following discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely caused increased CYP3A4 activity, leading to 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 an up to 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 the CYP3A4 enzyme and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives

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

Theophylline

In a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days 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 causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these drugs.

Vonoprevir

Exposure to vonoprevir significantly increased (200% AUC, 80% Cmax) when vonoprevir, a CYP3A4 substrate, was administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute renal failure. If co-administered, the vonoprevir dose should be reduced according to the medical instructions and the patient's condition should be regularly checked for any adverse reactions related to vonoprevir.

Vinca alkaloids

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

Vitamin A

A case has been reported in which a patient receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole experienced central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri; this effect disappeared after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be 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 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 of 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 should be monitored for adverse reactions associated with zidovudine use. Dose reduction of zidovudine may be considered.

Azithromycin

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

Oral contraceptives

Two pharmacokinetic studies of multiple-dose 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 administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to clinical studies of fluconazole for the treatment of dermatophytosis in children, fluconazole is not superior to griseofulvin in efficacy, with an overall efficacy rate of less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. Evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, dosage recommendations for treatment of these infections are not available.

Deep endemic mycoses. Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, dosage recommendations for treatment of these infections are not available.

Candidiasis. Clinical studies have shown an increasing prevalence of Candida infections caused by species other than C. albicans. These species are often resistant (e.g., C. krusei and C. auris) or have reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after inadequate response to treatment. Therefore, it is recommended to consider the prevalence of resistance among different Candida species to fluconazole.

Renal system. Fluconazole should be used with caution in patients with impaired renal function (see section "Dosage and administration").

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

Hepatobiliary system. Fluconazole should be used with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity 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 therapy 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 therapy should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole 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 by inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported during fluconazole use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and progressive heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

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

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when 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").

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

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

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of CYP2C19. Patients receiving concomitant fluconazole and medicinal products with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, or 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 is used concomitantly with fluconazole at doses less than 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Excipients. 1 ml of the medicinal product contains 9 mg of sodium chloride and 0.05 mg of edetate disodium (equivalent to 0.1543 mmol of sodium). This should be taken into account when prescribing the drug to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Before initiating treatment, the patient should be informed about the potential risk to the fetus. After a single dose, a washout period of 1 week (corresponding to 5–6 half-lives) is recommended before attempting pregnancy (see section "Pharmacokinetics"). For longer treatment courses in women of childbearing potential, contraception should be considered throughout the treatment period and for 1 week after the last dose.

Pregnancy.

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

Data from treatment of several thousand women during the first trimester of pregnancy with a cumulative fluconazole dose ≤150 mg show that overall risk of fetal malformations is not increased. In one large observational cohort study, oral use of fluconazole during the first trimester of pregnancy was associated with a small increase in the risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤450 mg compared to women using topical azoles, or approximately 4 additional cases per 1000 women receiving cumulative doses >450 mg. Adjusted relative risk was 1.29 (95% CI 1.05–1.58) for oral use of 150 mg fluconazole and 1.98 (95% CI 1.23–3.17) for fluconazole doses >450 mg.

Existing epidemiological studies on 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.

Congenital malformations have been reported in infants whose mothers received high-dose fluconazole (400–800 mg/day) for three months or longer during pregnancy for the treatment of coccidioidomycosis. Congenital defects observed in these infants include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radiohumeral synostosis. A causal relationship between fluconazole use and these congenital defects has not been established.

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

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

Breastfeeding period.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg). Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole. The benefit of breastfeeding for the child's development and health, the mother's clinical need for the drug, and any potential adverse effects of the drug 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 rate while driving or operating machinery.

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

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during fluconazole use. 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.

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 is administered orally or intravenously by infusion, depending on the pharmaceutical form. 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.

The infusion solution should be administered at a rate not exceeding 10 ml/min.

Compatibility of the drug

Fluconazole is compatible with the following solutions:

• 5% and 20% glucose solutions;
• Ringer's solution;
• Hartmann's solution (sodium lactate);
• potassium chloride in glucose solution;
• 4.2% and 5% sodium bicarbonate solutions;
• 3.5% chlorpromazine solution;
• 0.9% sodium chloride solution;
• Dialaflex (6.36% solution for intraperitoneal dialysis).

Fluconazole may be administered through the same infusion system as any of the above-listed solutions. Although cases of nonspecific incompatibility with other drugs have not been reported, fluconazole should not be mixed with other medicinal products prior to infusion.

The intravenous infusion solution is intended for single use only. Dilution must be performed under aseptic conditions. The solution should be inspected visually for the presence of foreign particles and discoloration. The solution should be used only if it is clear and free of particulate matter. Any unused portion of the solution must be discarded.

Adults

Cryptococcosis

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose is 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 certain forms of infection, particularly meningitis, a dose of 800 mg daily may be appropriate.

Invasive Candidiasis

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

Oropharyngeal and Mucosal Candidiasis

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose is 100–200 mg once daily. The duration of treatment is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose is 100–200 mg once daily. The duration of treatment is 14–30 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Candiduria: the recommended dose is 200–400 mg once daily for 7–21 days. Duration may be extended in patients with severe immunodeficiency.
• 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 degree of immunosuppression.

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

• 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 the expected onset of neutropenia and continued for 7 days after neutrophil counts rise above 1000/mm³.

Elderly Patients

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

Patients with Renal Impairment

Fluconazole is primarily eliminated unchanged in urine. Dose adjustment is not required after a single dose. In patients (including children) with impaired renal function who require 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 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" and "Adverse reactions").

Children

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

As with similar infections in adults, the duration of treatment depends on the clinical and mycological response. Fluconazole is 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 (see below information regarding use in neonates, in whom primary immaturity of the kidneys is frequently observed).

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 more appropriate for the individual patient. Clinical data indicate that fluconazole clearance is higher in children than in adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg to children results in comparable systemic exposure.

Children aged 28 days to 11 years

• Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg once daily. The initial dose may be administered on the first day to achieve steady-state concentration more rapidly.
• Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg once daily, depending on the severity of the disease.
• Maintenance therapy 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).

Neonates from birth to 27 days of age

In neonates, fluconazole is eliminated slowly from the body. Pharmacokinetic data supporting dosing recommendations for term neonates, described below, are provided in the "Pharmacokinetics" section.

• Term neonates aged 0 to 14 days: doses equivalent to those recommended above for children aged 28 days to 11 years should be administered every 72 hours. The maximum dose should not exceed 12 mg/kg every 72 hours.
• Term neonates aged 15 to 27 days: doses equivalent to those recommended above for children aged 28 days to 11 years should be administered every 48 hours. The maximum dose should not exceed 12 mg/kg every 48 hours.

Children

The drug can be administered to children from birth; see section "Administration and dosage".

Overdose

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

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

Fluconazole is 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 commonly reported (> 1/10) adverse reactions are: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase blood levels, rash. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during fluconazole treatment (see section "Special precautions").

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 (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), 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: seizures, paresthesia, dizziness, taste disturbances. Rare: tremor.

Ear and labyrinth disorders. Uncommon: vertigo.

Cardiac disorders. Rare: torsades de pointes, QT interval prolongation (see section "Special precautions").

Gastrointestinal disorders. Common: abdominal pain, nausea, diarrhea, vomiting. Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders. Common: increased ALT, increased AST, increased 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 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.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous 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. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

No incompatibility issues with the medicinal product have been reported. The medicinal product should not be mixed with other medicinal products in the same container, except as specified in the section "Method of administration and dosage".

Packaging. 100 ml in a bottle; 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of its operations.

84A Nemirivske Highway, Vinnytski Khotory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.