Diflazon®

INSTRUCTIONS for medical use of the medicinal product Diflazon® (Diflazon®)

Composition:

active substance: fluconazole;

1 ml of infusion solution contains 2 mg of fluconazole;

excipients: sodium chloride, water for injections.

Medicinal form. Infusion solution.

Main physicochemical properties: clear, colorless solution free from visible mechanical inclusions.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Fluconazole, an antifungal agent of the triazole class, is a potent and selective inhibitor of fungal enzymes essential for ergosterol synthesis. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, an essential step in fungal ergosterol biosynthesis. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss 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.

It has been reported that administration of fluconazole at a dose of 50 mg 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 clinically significant effects on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

An interaction study with antipyrine demonstrated that administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro susceptibility

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

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

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

Pharmacokinetic/pharmacodynamic relationship

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

Mechanism of resistance

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

In susceptible Candida species, the most commonly observed 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 with Candida species other than Candida albicans, which often have reduced susceptibility (e.g., Candida glabrata) or resistance to fluconazole (e.g., Candida krusei, Candida auris), have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms have not been fully elucidated for some Candida species with intrinsic resistance (e.g., Candida krusei) or newly emerging species (e.g., Candida auris).

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

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

S = susceptible;

R = resistant;

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

• susceptibility testing is not recommended, as this organism is not a target for antimicrobial therapy;

* All Candida glabrata isolates belong to category I. MICs against Candida glabrata should be interpreted as resistant if they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) helps avoid misclassification of "I" strains as "S" strains. I – Susceptible-dose dependent: a microorganism is categorized as "susceptible-dose dependent" when there is a high likelihood of therapeutic success due to increased exposure of the agent, achieved by adjusting the dosing regimen or increasing its 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 drug administration. Plasma drug concentration is proportional to dose. Steady-state concentration reaches 90% by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution

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

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

High fluconazole concentrations exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. With a 50 mg once-daily dose, fluconazole concentration in the stratum corneum was 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a 150 mg once-weekly dose, fluconazole concentration on day 7 of treatment was 23.4 µg/g, and seven 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 dosing was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disorders; fluconazole was detectable in nail samples up to 6 months after completion of therapy.

Biotransformation

Fluconazole is only minimally metabolized. After administration of a 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 (see section "Interaction with other medicinal products and other forms of interaction").

Elimination

The plasma half-life (T½) 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 T½ 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), T½ increases from 30 to 98 hours. Therefore, this patient group requires dose reduction of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Lactation period

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

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, mean plasma T½ of fluconazole ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer T½ of approximately 24 hours was observed after single-dose administration of fluconazole. This is comparable to the plasma T½ of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole at 6 mg/kg were administered every 72 hours. Mean T½ was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and to 47 hours (27–68) on day 13. AUC (µg•h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. Volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7 and to 1328 (1040–1680) on day 13.

Elderly patients

A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) who received 50 mg fluconazole orally. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4 ± 20.3 µg•h/mL. Mean T½ was 46.2 hours. These pharmacokinetic parameters are higher 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 are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

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

• cryptococcal meningitis (see section "Special precautions");
• coccidioidomycosis (see section "Special precautions");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic candidal skin and mucosal infections;
• chronic atrophic oral candidiasis (denture-related candidiasis) when oral hygiene or local therapy is ineffective.

Prevention of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• prevention of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation) (see section "Pharmacodynamics").

Diflazon® may be used in children from birth for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for the prevention of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section "Special precautions").

Treatment with Diflazon® may be initiated before the results of culture and other laboratory tests are available. After obtaining test results, antimicrobial therapy should be adjusted accordingly.

Contraindications.

Hypersensitivity to fluconazole, other azole compounds, or to any excipients of the drug.

Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg daily (based on multiple-dose interaction study results).

Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via cytochrome P450 (CYP) 3A4 (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions").

Interaction with other medicinal products and other types of interactions.

Concomitant use of fluconazole and the following medicinal products is contraindicated

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

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

Pimozide and quinidine. Concomitant use of fluconazole 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, paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

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

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

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

Concomitant use of fluconazole and the following medicinal products requires caution

Amiodarone. Concomitant use of fluconazole and amiodarone may lead to QT interval prolongation. Caution should be exercised if concomitant use of fluconazole and amiodarone is necessary, especially when high doses of fluconazole (800 mg) are used.

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 concomitant food intake, administration of cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption after oral administration.

Rifampicin. Concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the half-life (T½) of fluconazole. Therefore, dose escalation of fluconazole should be considered for patients receiving rifampicin.

Hydrochlorothiazide. Repeated concomitant use of hydrochlorothiazide resulted in a 40% increase in fluconazole plasma concentration. This effect does not necessitate dose adjustment in patients receiving diuretics concomitantly, but physicians should be aware of the potential interaction.

Effect of fluconazole on other medicinal products

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

Abrocitinib. Fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure of 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), a twofold increase in AUC was observed, possibly due to CYP3A4 inhibition. Dose adjustment of alfentanil may be necessary.

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

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

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

Short-acting benzodiazepines, e.g., midazolam, triazolam. Administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in AUC and T½, respectively. Concomitant use of fluconazole 200 mg daily and oral triazolam 0.25 mg resulted in a 4.4-fold and 2.3-fold increase in AUC and T½, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use with fluconazole.

If benzodiazepines must be administered concomitantly to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring should be established.

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

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

Celecoxib. Concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. When used concomitantly with fluconazole, the dose of celecoxib may need to be reduced by half.

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. Fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful patient monitoring is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4, such as atorvastatin and simvastatin, or HMG-CoA reductase inhibitors metabolized by CYP2C9, such as fluvastatin (which reduces hepatic statin metabolism), increases the risk (dose-dependent) of myopathy and rhabdomyolysis. If concomitant use is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If significant elevation of creatine kinase levels occurs or myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be necessary according to statin prescribing information.

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

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

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

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

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. During concomitant use of fluconazole 200 mg daily and cyclosporine 2.7 mg/kg/day, cyclosporine AUC increased by 1.8-fold. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus. Although in vitro and in vivo studies have not been conducted, fluconazole may increase 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 concentration and drug effects.

Tacrolimus. Fluconazole may increase tacrolimus serum concentration up to 5-fold with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral 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 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 lurasidone prescribing information.

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

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

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be necessary.

Phenytoin. Fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases phenytoin AUC24 by 75% and minimum concentration (Cmin) by 128%. Serum phenytoin concentration should be monitored during concomitant use of these drugs to avoid phenytoin toxicity.

Prednisone. A case was reported in which a liver transplant patient developed acute adrenal insufficiency after discontinuation of a three-month fluconazole therapy course while on prednisone. Discontinuation of fluconazole likely enhanced CYP3A4 activity, leading to accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after fluconazole discontinuation.

Rifabutin. Fluconazole increases rifabutin serum concentration, leading to up to an 80% increase in rifabutin AUC. 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 saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. The interaction between fluconazole and saquinavir/ritonavir has not been studied, so it may be more pronounced. Dose adjustment of saquinavir may be necessary.

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

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

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

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

Vinca alkaloids. Although no studies are available, there is a possibility that fluconazole, via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A. 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 resolved after discontinuation of fluconazole. These drugs 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) 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 used after fluconazole, patients should be monitored for adverse effects associated with voriconazole.

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 half-life (T½) of zidovudine was also prolonged by approximately 128% after administration of the fluconazole-zidovudine combination. Patients receiving this drug combination should be monitored for zidovudine-related adverse reactions. Consideration may be given to reducing the zidovudine dose.

Azithromycin. No significant pharmacokinetic interactions were observed after single oral administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.

Oral contraceptives. No hormonal effects were observed when fluconazole 50 mg was administered with a combined oral contraceptive, whereas administration of fluconazole 200 mg daily resulted in a 40% increase in ethinylestradiol AUC and a 24% increase in levonorgestrel AUC. This indicates that repeated administration of fluconazole at these doses does not affect the efficacy of combined oral contraceptives.

Special precautions for use.

Attention should be paid to the official guidelines for the appropriate use of antifungal agents.

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 Diflazon® should not be used for the treatment of dermatophytosis.

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

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

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

Adrenal insufficiency. It is known that ketoconazole can cause adrenal insufficiency; this may also rarely occur with fluconazole. Adrenal insufficiency has been associated with concomitant therapy with prednisolone (see section "Interaction with other medicinal products and other forms of interaction").

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

Patients who develop abnormalities in liver function tests during fluconazole therapy 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 should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole causes QT interval prolongation 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 paroxysmal torsades de pointes ventricular tachycardia have been reported during treatment with Diflazon®. 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 established heart failure have an increased risk of developing ventricular arrhythmias and life-threatening torsades de pointes ventricular tachycardia (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

The medicinal product Diflazon® should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated.

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

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

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

Cytochrome P450. Fluconazole is a moderate inhibitor of the cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of the CYP2C19 enzyme. Patients receiving concomitant therapy with Diflazon® and medicinal products with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

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

Candidiasis. Studies have shown increased prevalence of infections caused by Candida species other than Candida albicans. These are often inherently resistant (e.g., Candida krusei and Candida auris) or exhibit reduced susceptibility to fluconazole (Candida glabrata). Such infections may require alternative antifungal therapy due to treatment failure. Therefore, it is recommended to consider the prevalence of resistance among different Candida species to fluconazole.

Excipients. 100 mL of the medicinal product (1 vial) contains 353.8 mg (equivalent to 15.38 mmol) of sodium. 1 mL of the medicinal product contains 3.538 mg (equivalent to 0.1538 mmol) of sodium. This should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Women of reproductive potential

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

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

Pregnancy

According to observational study data, there is an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester of pregnancy compared to women who did not receive fluconazole or used topical azoles during the same period.

Data from several thousand pregnant women who received a cumulative dose of ≤ 150 mg fluconazole in the first trimester do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, exposure to oral fluconazole in the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women who received cumulative doses ≤ 450 mg, compared to women who received topical azoles, and approximately 4 additional cases per 1000 women who received cumulative doses exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI: 1.23–3.17) for doses exceeding 450 mg of fluconazole.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed a 1.8–2-fold increased risk of congenital heart defects in infants compared to infants whose mothers did not receive fluconazole and/or used topical azoles.

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

Standard doses of fluconazole and short-term 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 life-threatening infections.

Lactation

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 therapy. The benefits of breastfeeding for the child's development and health, the mother's clinical need for fluconazole, and any potential adverse effects of fluconazole on the breastfed infant or the mother's underlying condition should be considered.

Fertility

Fluconazole does not affect fertility in male and female rats.

Ability to influence the speed of reactions when 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 during fluconazole therapy. 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 disappeared. Inadequate duration of treatment may lead to recurrence of active infection.

Administration method

The medicinal product Diflazon® is administered depending on the dosage form either orally or intravenously by infusion. 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 physician should select the most appropriate dosage form and dose based on age, body weight, and indication. Capsule formulations are not intended for use in children under 6 years of age who cannot swallow capsules. Oral liquid formulations of fluconazole are available and are more suitable for pediatric patients.

Compatibility of the medicinal product

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

Diflazon® is compatible with the following solutions:

• 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;
• dialaflex (6.36% solution for intraperitoneal dialysis).

The medicinal product Diflazon® may be administered through the same infusion system together with one of the above-mentioned solutions. Although cases of nonspecific incompatibility with other medicinal products have not been reported, mixing Diflazon® with other drugs prior to infusion is not recommended.

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 product must be discarded.

Adults

Cryptococcosis

• Treatment of cryptococcal meningitis: the recommended loading dose is 400 mg on the first day, followed by a maintenance dose of 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 high-risk patients: 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

The loading dose is 800 mg on the first day, followed by a maintenance dose of 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 candidiasis

• Oropharyngeal candidiasis: the loading dose is 200–400 mg on the first day, followed by a maintenance dose of 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: the loading dose is 200–400 mg on the first day, followed by a maintenance dose of 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. For patients with severe immunodeficiency, the duration of treatment may be extended.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic cutaneous and mucosal candidiasis: the recommended dose is 50–100 mg once daily. The duration of treatment is up to 28 days, but may be extended depending on the severity and type of infection or degree of immunosuppression.

Prevention of recurrent oropharyngeal candidiasis in HIV 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 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 cells/mm³.

Special patient groups

Geriatric patients

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

Patients with renal impairment

Fluconazole is primarily excreted unchanged in the urine. No dose adjustment is required after a single dose. For patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day depending on the indication. Subsequent daily doses (depending on the indication) should be adjusted according to the table below:

Patients undergoing haemodialysis should receive 100 % of the recommended dose after each haemodialysis session. On days when dialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Patients with hepatic impairment

Fluconazole should be used with caution in patients with hepatic dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children

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

As with similar infections in adults, the duration of treatment depends on clinical and mycological response. The medicinal product Diflazon® should be administered once daily.

Dosage recommendations for children with renal impairment are provided in the section "Patients with renal impairment". The pharmacokinetics of fluconazole have not been studied in children with renal impairment (see below information regarding use in neonates, 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 adult or pediatric dose is optimal for the patient. Clinical data indicate that the clearance of fluconazole in children is higher than in adults. Administration of doses of 100 mg, 200 mg, and 400 mg in adults and doses of 3 mg/kg, 6 mg/kg, and 12 mg/kg in children results in comparable systemic exposure.

Children aged 28 days to 11 years

Oropharyngeal 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.

Suppression therapy to prevent relapse of cryptococcal meningitis in children at high risk of recurrence: dosage is 6 mg/kg/day depending on the severity of the disease.

Prophylaxis of candidiasis in patients with immunodeficiency

Dosage is 3–12 mg/kg once daily depending on the severity and duration of induced neutropenia (see doses for adults).

Children from birth to 27 days of age

In neonates, fluconazole is eliminated slowly. Pharmacokinetic data support the following dosing regimens in term neonates (see 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.

The product is indicated for use in children from birth (see section "Dosage and administration").

Overdose.

There have been reports of fluconazole overdose causing hallucinations and paranoid behaviour.

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

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

Adverse Reactions

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

The most commonly reported adverse reactions (>1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in blood.

The following classification was 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, neutropenia, thrombocytopenia

Immune system disorders

Rare: anaphylaxis

Metabolism and nutrition disorders

Uncommon: decreased appetite
Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia

Psychiatric disorders

Uncommon: insomnia, somnolence

Nervous system disorders

Common: headache
Uncommon: convulsions, dizziness, paraesthesia, 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

Gastrointestinal disorders

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

*Hepatobiliary disorders

Common: increased levels of ALT, AST, alkaline phosphatase
Uncommon: cholestasis, jaundice, increased bilirubin levels
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury

*Skin and subcutaneous tissue disorders

Common: rash
Uncommon: pruritus, drug-induced dermatitis (including persistent drug erythema), urticaria, increased sweating
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia
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

*See section "Special Warnings and Precautions for Use".

Children

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 5 years.

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

Incompatibilities.
Fluconazole infusion solutions should not be mixed with other medicinal products in the same container, except as specified in the section "Dosage and Administration".

Packaging. 100 ml in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.