Fluconazole

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE (FLUCONAZOLE)

Composition:

Active substance: fluconazole;

1 ml of solution contains 2 mg of fluconazole;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, colorless solution.

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 have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

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

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against clinically common species of Candida (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and epidemiological cut-off values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those for C. albicans.

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

Pharmacokinetic/pharmacodynamic relationships.

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

Mechanisms 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 efficacy in vivo and in clinical practice.

In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by non-albicans Candida species, which often have reduced susceptibility (e.g., C. glabrata) or are resistant (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for the treatment of such infections.

Resistance mechanisms are not yet fully understood in certain intrinsically resistant species (e.g., C. krusei) or emerging species (e.g., C. auris).

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (EUCAST accompanying explanatory document for fluconazole (2020) — version 3. European Committee on Antimicrobial Susceptibility Testing. Antifungal agents. Breakpoint tables for interpretation of MICs, version 10.0, effective 04.02.2020). These breakpoints are categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic information and independent of species-specific MIC distributions, and species-specific breakpoints, typically associated with human infections.

These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints, S ≤ / R > in mg/l						Non-species-related breakpoints,a S ≤ / R > in mg/l
	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 determined based on pharmacokinetic/pharmacodynamic data and are independent of species-specific distribution of minimal inhibitory concentrations. These were studied only in microorganisms for which no specific breakpoint exists.

-- susceptibility testing is not recommended, as this species is not a target for drug therapy.

* All C. glabrata isolates fall into the I category. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S strains. I — susceptible with increased exposure: the microorganism is categorized as "susceptible with increased exposure" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjustment of the dosing regimen or higher drug concentration at the site of infection.

Pharmacokinetics.

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

Absorption.

Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect drug absorption following oral administration. Peak plasma concentration is reached within 0.5–1.5 hours after dosing on an empty stomach. Drug concentration in plasma is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of treatment with once-daily dosing. A steady-state concentration of 90% is reached by day 2 of treatment 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 administration of a 50 mg dose once daily, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration was still 5.8 µg/g. After administration of a 150 mg dose once weekly, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

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

Biotransformation.

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

Elimination.

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

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

Renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 hours to 98 hours. Therefore, this patient group requires dose reduction. 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 had temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of approximately 98% of that in maternal plasma. The average peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on average 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.

Children.

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

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

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous fluconazole injections at 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (range 44–185) on day 1, decreasing to 53 hours (range 30–131) on day 7 and 47 hours (range 27–68) on day 13. The area under the curve (µg·h/mL) was 271 (range 173–385) on day 1, increased to 490 (range 292–734) on day 7, then decreased to 360 (range 167–566) on day 13. The volume of distribution (mL/kg) was 1183 (range 1070–1470) on day 1, increased to 1184 (range 510–2130) on day 7, and to 1328 (range 1040–1680) on day 13.

Elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached 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, pharmacokinetic changes in elderly patients appear to depend 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.

The drug 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, antimicrobial therapy should be adjusted accordingly once 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 is contraindicated 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: cardiac adverse reactions, including QT interval prolongation and torsades de pointes, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in plasma cisapride levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. In one study, administration of fluconazole 200 mg daily did not result in QTc prolongation. Another study using fluconazole doses of

400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increases plasma terfenadine levels when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to torsades de pointes. 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 appropriate in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to torsades de pointes. 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, torsades de pointes) 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, torsades de pointes) and, consequently, sudden cardiac death. 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 and 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 with food, concomitant use of cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

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

• Effect of fluconazole on other medicinal products.

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

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

Alfentanil: during concomitant administration of alfentanil 20 mcg/kg and fluconazole 400 mg to healthy volunteers, a two-fold increase in AUC was observed, possibly due to CYP3A4 inhibition. Alfentanil dose adjustment may be necessary.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and after 1 week. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

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

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported during concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indanediones concomitantly. Anticoagulant dose adjustment 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 resulted in a 3.7-fold and 2.2-fold increase in midazolam AUC and elimination half-life, respectively. Administration of fluconazole 200 mg daily and oral triazolam 0.25 mg resulted in a 4.4-fold and 2.3-fold increase in triazolam AUC and elimination half-life, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam. If benzodiazepines must be prescribed to a patient undergoing fluconazole therapy, the dose of benzodiazepines 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. Carbamazepine dose adjustment may be necessary depending on its concentration and effect.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by 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 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. Fentanyl dose adjustment may be necessary.

HMG-CoA reductase inhibitors: concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin (reduced hepatic metabolism of statin)), increases the risk of myopathy and rhabdomyolysis (dose-dependent). If concomitant use of these drugs is necessary, careful monitoring for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels should be performed. 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 ibrutinib plasma concentration and may increase the risk of toxicity. If combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) to continue inhibitor use, with continuous clinical monitoring.

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class): concomitant administration of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased ivacaftor exposure by 3-fold and hydroxymethylivacaftor (M1) exposure by 1.9-fold. Dose reduction of ivacaftor (as monotherapy or in combination) is required, as specified in the ivacaftor prescribing information (as monotherapy or in combination).

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase olaparib plasma concentrations, and their concomitant use is not recommended. If such 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 a 1.8-fold increase in cyclosporine AUC. 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 via CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted based on 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 based on tacrolimus concentration.

Losartan: fluconazole inhibits losartan metabolism to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan administration. 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. Methadone dose adjustment may be necessary during concomitant use with fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): during concomitant use with fluconazole, Cmax and AUC of flurbiprofen increased by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, 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 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 NSAID-related adverse reactions and toxic effects is recommended. NSAID dose adjustment may be necessary.

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

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

Rifabutin: fluconazole increases rifabutin serum concentration, leading to 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 saquinavir AUC and Cmax by approximately 50 % and 55 %, respectively, due to inhibition of hepatic saquinavir metabolism by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Saquinavir dose adjustment may be necessary.

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

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

Tofacitinib: the effect of tofacitinib increases 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.

Conivaptan: exposure to conivaptan, a CYP3A4 substrate, significantly increased (200 % AUC, 80 % Cmax) when 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 conivaptan dose should be reduced according to the prescribing information and the patient should be regularly monitored for any adverse reactions associated with conivaptan.

Vinca alkaloids: fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: a single case has been reported of central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri during concomitant use of all-trans retinoic acid (acid form of vitamin A) and fluconazole, which resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, 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 AUC by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is administered after fluconazole, monitoring for voriconazole-associated adverse effects is recommended.

Zidovudine: fluconazole increases zidovudine Cmax and AUC by 84 % and 74 %, respectively, due to a decrease in zidovudine clearance of approximately 45 % after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole-zidovudine combination. 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 effects of azithromycin and fluconazole on each other's pharmacokinetics were evaluated after single oral administration at doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives: two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives were conducted. 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 repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to study results 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, the medicinal product should not be used for the treatment of dermatophytosis.

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

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

Renal system. The drug 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 rare. Adrenal insufficiency associated with concomitant treatment with prednisone is described in the section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products".

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

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of more severe liver 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 treatment should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 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.

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

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

Cutaneous reactions. Rare cases of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has also been reported.

Patients with AIDS are more prone to developing severe skin reactions when using many medicinal products. If a patient with 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 fluconazole treatment 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 concomitant fluconazole and medicinal products with a narrow therapeutic index metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Excipients. This medicinal product contains 88.5 mg of sodium per 25 ml, which corresponds to 4.4% of the WHO recommended maximum daily intake of 2 g of sodium for adults.

The maximum daily dose of this medicinal product is equivalent to 71% of the WHO recommended maximum daily sodium intake.

Fluconazole 2 mg/ml infusion solution belongs to sodium-rich solutions. This should be particularly considered when prescribing the drug to patients on a low-salt diet.

Use during pregnancy or breastfeeding.

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 take fluconazole or used topical azoles during the same period.

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg fluconazole 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 one additional case per 1000 women receiving cumulative doses ≤450 mg compared to women receiving topical azoles, and approximately four additional cases per 1000 women receiving cumulative doses exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI 1.23–3.17) for doses exceeding 450 mg fluconazole.

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

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

Standard doses of fluconazole and short-term 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.

Women of childbearing potential.

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

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

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

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 150 mg fluconazole.

Breastfeeding is not recommended with repeated fluconazole use or with high-dose fluconazole treatment.

The benefit of breastfeeding for the child's development and health, the mother's clinical need for fluconazole, and any potential adverse effects of the drug or the mother's underlying condition on the breastfed child should be carefully evaluated.

Fertility.

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

Ability to influence reaction speed while driving or operating machinery.

Studies on the effect of the drug 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 treatment. 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 should be continued until clinical and laboratory signs of fungal infection have resolved. Inadequate duration of treatment may lead to recurrence of active infection.

Fluconazole is administered either orally (capsules) or intravenously by infusion (infusion solution), 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.

The medicinal product is compatible with:

• 5% and 20% glucose solutions;
• Ringer’s solution;
• Hartmann’s solution;
• potassium chloride in glucose solution;
• 4.2% and 5% sodium bicarbonate solutions;
• 3.5% aminozine solution;
• 0.9% sodium chloride solution;
• diaflex (6.36% solution for intraperitoneal dialysis).

Fluconazole may be administered through the same infusion system together with one of the solutions listed above. 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. The solution is sterile; therefore, dilution must be performed under aseptic conditions. The solution should be inspected visually for presence of particulate matter and discoloration. Do not use if the container seal is compromised or if the contents are cloudy. 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, especially meningitis, a daily dose of 800 mg may be appropriate.

Invasive candidiasis. The loading dose is 800 mg on the first day. The maintenance dose is 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 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. The duration of treatment may be extended in patients with severe immunodeficiency.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic mucocutaneous 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 developing the infection.

• Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100–200 mg once daily or 200 mg three times per week. 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 count rises above 1000/mm³.

Elderly patients.

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

Patients with renal impairment.

Fluconazole is eliminated from the body primarily unchanged in the urine. Dose adjustment is not required after a single dose. For patients (including children) with impaired renal function requiring repeated 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 dialysis session. On days when hemodialysis 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 for use" and "Adverse reactions").

Children.

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

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

Dosing of fluconazole in children with renal impairment is described in the section "Patients with renal insufficiency". The pharmacokinetics of fluconazole have not been studied in children with renal impairment (see below regarding use in newborns, in whom primary renal immaturity is frequently observed).

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should evaluate whether the dose of fluconazole (adult or pediatric) is optimal for the patient. Clinical data indicate that clearance of fluconazole in children is higher than in adults. Administration of doses of 100, 200, and 400 mg in adults and doses of 3, 6, and 12 mg/kg in 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: fluconazole dose 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: fluconazole dose is 6 mg/kg once daily, depending on the severity of the disease.
• Prophylaxis of candidiasis in patients with immunodeficiency: fluconazole dose is 3–12 mg/kg once daily, depending on the severity and duration of induced neutropenia (see adult doses).

Children aged from birth to 27 days.

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

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

Children.

Fluconazole is administered to children from birth; see section "Administration and dosage".

Overdose.

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

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

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

Adverse Reactions

Summary of Safety Profile

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported in association with fluconazole treatment (see section "Special Warnings and Precautions for Use").

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

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), 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: convulsions, paraesthesia, dizziness, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders:

Uncommon: vertigo.

Cardiac disorders:

Rare: paroxysmal ventricular tachycardia of the torsades de pointes type, QT interval prolongation (see section "Special Warnings and Precautions for Use").

Gastrointestinal disorders:

Common: abdominal pain, nausea, diarrhea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders:

Common: increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels (see section "Special Warnings and Precautions for Use").

Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special Warnings and Precautions for Use").

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders:

Common: rash (see section "Special Warnings and Precautions for Use").

Uncommon: drug eruption (including fixed drug eruption), urticaria, pruritus, increased sweating (see section "Special Warnings and Precautions for Use").

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

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

Musculoskeletal and connective tissue disorders:

Uncommon: myalgia.

General disorders and administration site conditions:

Uncommon: increased fatigue, malaise, asthenia, fever.

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

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after first opening of the container.

The product should be used immediately after opening the packaging. Any unused amount of infusion solution should be discarded.

If the product is not used immediately, the user is responsible for storage conditions and duration during use; generally, the product should be stored no longer than 24 hours at a temperature of 2 to 8 °C.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

No incompatibilities with fluconazole have been reported. Fluconazole should not be mixed in the same container with other medicinal products, except as specified in the section "Dosage and Administration."

Packaging. 100 ml in a container, 1 container per cardboard box.

Prescription status. Prescription only.

Manufacturer. Subsidiary enterprise "Farmatreyd".

Manufacturer's address and place of business.

85 Sambirska St., Drohobych, Lviv Oblast, 82111, Ukraine.

Marketing Authorization Holder.

Subsidiary enterprise "Farmatreyd".

Address of Marketing Authorization Holder.

85 Sambirska St., Drohobych, Lviv Oblast, 82111, Ukraine.