INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIFLUCAN® (DIFLUCAN®)

Composition:

Active substance: fluconazole;

1 capsule contains 150 mg of fluconazole;

Excipients: lactose monohydrate; corn starch; sodium lauryl sulfate; magnesium stearate; colloidal anhydrous silicon dioxide.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard, opaque gelatin capsules (size No. 1), containing a white powder, with a light turquoise-blue cap and body, marked with the Pfizer logo and the inscription "FLU-150" in black ink.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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

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

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against 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.

Relationship between pharmacokinetic and pharmacodynamic properties.

According to animal studies, there is a correlation between minimal inhibitory concentration 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 satisfactory.

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 affects its in vivo and clinical efficacy.

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 Candida spp. other than C. albicans, which often show reduced susceptibility (C. glabrata) or are resistant (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant (C. krusei) or emerging (C. auris) Candida species.

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 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 have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and independent of species-specific minimal inhibitory concentration distributions, and species-specific breakpoints, commonly 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

0.001*/16

2/4

S = sensitive;
R = resistant;
a – breakpoints not associated with a specific species, primarily determined based on pharmacokinetic/pharmacodynamic information and not dependent on species-specific distribution according to minimal inhibitory concentration. These were studied only in microorganisms lacking a species-specific breakpoint;
-- susceptibility testing not recommended, as this species is not a target for antimicrobial therapy;

* All C. glabrata isolates fall within category I. 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: a microorganism is categorized as "susceptible with increased exposure" when there is a high probability of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or increasing 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. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of repeated once-daily dosing. Steady-state 90% concentration is reached by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution.
Volume of distribution approximates 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 levels in cerebrospinal fluid reach 80% of plasma concentrations.
High fluconazole concentrations in skin exceeding serum levels are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. Following a 50 mg once-daily dose, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment cessation, concentration remained at 5.8 µg/g. With a 150 mg once-weekly dose, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, concentration remained at 7.1 µg/g.
Fluconazole concentration in nails after 4 months of 150 mg once weekly was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after therapy completion.

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

Elimination.
The plasma half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.
The prolonged plasma half-life allows single-dose administration for vaginal candidiasis and once-weekly dosing for other indications.

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

Lactation.
Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours after a single 150 mg dose of Diflucan in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. In breast milk, fluconazole was detected at an average concentration approximately 98% of that in maternal plasma. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean peak milk concentration, was 0.39 mg/kg/day, representing approximately 40% of the dose recommended for neonates (< 2 weeks of age) 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 ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This parameter is comparable to the plasma elimination half-life of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. Volume of distribution in this age group was approximately 950 mL/kg.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. Mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole 6 mg/kg were administered every 72 hours. Mean 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. AUC (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. Volume of distribution (mL/kg) was 1183 (range 1070–1470) on day 1, increased to 1184 (range 510–2130) on day 7 and 1328 (range 1040–1680) on day 13.

Elderly patients.
A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) receiving 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after 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 compared to those in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of fluconazole excreted unchanged in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this patient group were lower than in younger volunteers. Therefore, pharmacokinetic changes in elderly patients are evidently dependent on renal function parameters.

Clinical characteristics.

Indications.

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

Acute vaginal candidiasis, when local therapy is not appropriate.
Candidal balanitis, when local therapy is not appropriate.

Treatment with Diflucan® may be initiated prior to obtaining results of culture and other laboratory tests; however, antifungal therapy should be adjusted accordingly once test results become available.

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

Contraindications.

Hypersensitivity to fluconazole, other azole compounds, or any of the excipients listed in the section "Composition".
Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on multiple-dose interaction study results).
Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole with 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 resulted in a significant increase in plasma levels of cisapride and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. In one study, administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. Another study using fluconazole doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increases plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

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

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

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

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

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

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

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

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

Effect of other medicinal products on fluconazole.

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

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

Effect of fluconazole on other medicinal products.

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

Alfentanil: during concomitant administration of alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in 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. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

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

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

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam 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 AUC and elimination half-life of midazolam, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use with fluconazole. If benzodiazepines need to be prescribed concomitantly to a patient undergoing fluconazole treatment, their dose should be reduced and appropriate patient monitoring established.

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

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

Celecoxib: during concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. 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 levels.

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

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

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

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

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

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

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

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

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

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

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

Lurasidone: moderate CYP3A4 inhibitors, such as fluconazole, may increase lurasidone plasma concentration. If concomitant use cannot be avoided, the dose of lurasidone should be reduced as specified in the lurasidone product information.

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

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

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

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

Prednisone: a case has been reported where a patient after liver transplantation developed acute adrenal insufficiency on a background of prednisone use, occurring 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 development of adrenal insufficiency after fluconazole discontinuation.

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

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

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

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

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

Tolvaptan: exposure to tolvaptan significantly increased (200% AUC, 80% Cmax) when tolvaptan, a CYP3A4 substrate, was administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute kidney injury. If co-administered, the dose of tolvaptan should be reduced according to instructions in the tolvaptan product information, and the patient should be regularly checked for any adverse reactions related to tolvaptan.

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

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

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

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in zidovudine clearance by 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 doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives: two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives were conducted. At a fluconazole dose of 50 mg, no effect on hormone levels was observed, whereas at a fluconazole dose of 200 mg daily, AUC of ethinylestradiol increased by 40% and levonorgestrel by 24%. This indicates that multiple administration of fluconazole at the specified doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to studies on the use of 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, Diflucan® should not be used for the treatment of dermatophytosis.

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

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

Renal system. The drug should be 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 impaired liver function. 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, 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 treatment should be closely monitored for the development of more severe liver damage.

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 rectifier 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 the use of Diflucan®. 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 are at increased risk of life-threatening ventricular arrhythmias and paroxysmal torsades de pointes ventricular tachycardia.

Diflucan® 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 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. In rare cases, anaphylactic reactions have been reported (see section "Contraindications").

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a potent inhibitor of the CYP2C19 enzyme. Patients receiving Diflucan® concomitantly with 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 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 failed treatment. Therefore, physicians prescribing the drug are advised to consider the prevalence of resistance of various Candida species to fluconazole.

Excipients. The drug contains lactose. This drug should not be administered to patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

One capsule of Diflucan® contains less than 1 mmol of sodium (23 mg), and thus the drug can be considered essentially "sodium-free".

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

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

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

Pregnancy

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

Data from several thousand pregnant women who received fluconazole treatment with a cumulative dose ≤ 150 mg during the first trimester show no increased overall risk of fetal malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg, compared to women who received topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg dose of fluconazole and 1.98 (95% CI: 1.23–3.17) for doses of fluconazole > 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed an 1.8- to 2-fold increased risk of cardiac malformations 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 to 800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Congenital malformations observed in these infants include 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 courses should not be used during pregnancy except when absolutely necessary.

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

Breastfeeding

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

Fertility

Fluconazole did not affect fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of Diflucan® 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 with Diflucan®. If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

Capsules should be swallowed whole. The administration of the drug is not affected by food intake.

Adults.

The drug is administered orally at a single dose of 150 mg.

Elderly patients.

In the absence of signs of renal impairment, the standard adult dose is used for treatment of this patient category.

Renal impairment.

Fluconazole is primarily excreted unchanged in the urine. Dose adjustment is not required in this patient category following single-dose administration.

Hepatic impairment.

Fluconazole should be administered with caution to patients with hepatic dysfunction, as there is insufficient data on fluconazole use in this patient population (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Children.

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

Overdose.

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

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

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

Side effects.

Summary of safety profile

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported in association with fluconazole treatment (see section "Special precautions").

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

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

Blood and lymphatic system disorders.

Uncommon: anaemia.

Rare: agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders.

Rare: anaphylaxis.

Metabolism and nutrition disorders.

Uncommon: decreased appetite.

Rare: hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

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 precautions").

Gastrointestinal disorders.

Common: abdominal pain, nausea, diarrhoea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders.

Common: increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels (see section "Special precautions").

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

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

Skin and subcutaneous tissue disorders.

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

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

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

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 studies in children were comparable to those in adults.

Reporting of suspected adverse reactions.

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

Shelf life. 5 years.

Storage conditions. Store below 30 °C in a place inaccessible to children.

Packaging. 1 capsule in a blister; 1 blister in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer. Fareva Amboise / Fareva Amboise.

Manufacturer's location and address of place of business.

Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France /
Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.