Diflucan®

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

Composition:

Active substance: fluconazole;

1 ml of solution contains 2 mg of fluconazole;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution without visible particles, meeting the requirements for parenteral solutions, in transparent vials made of neutral glass.

Pharmacotherapeutic group. Systemic antifungal agents. Triazole derivatives. ATC code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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

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

Studies investigating interactions with antipyrine have 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 prevalent Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and epidemiological cutoff values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those against C. albicans.

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

Pharmacokinetic/pharmacodynamic relationship.

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

Mechanisms of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimal inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo efficacy and clinical performance.

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

Superinfections caused by Candida spp. other than C. albicans, which often exhibit 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 the 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 accompanying interpretative document for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective from 04.02.2020). These have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific MIC distributions, and species-specific breakpoints, most commonly associated with human infections. These breakpoints are listed below.

S = susceptible;

R = resistant;

a – breakpoints not related to a specific species, which are primarily based on pharmacokinetic/pharmacodynamic data and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a species-specific breakpoint;

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

* All C. glabrata isolates are categorized as I. MICs against C. glabrata should be considered 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 likelihood of therapeutic success due to enhanced 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 concentrations are 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 once-daily therapy. A steady-state 90% concentration is reached by day 2 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 in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. After a daily dose of 50 mg, fluconazole concentration on day 12 of treatment was 73 µg/g, and 7 days after treatment cessation, it remained at 5.8 µg/g. With a weekly dose of 150 mg, 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 weekly 150 mg dosing was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after therapy completion.

Biotransformation.

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

Elimination.

The plasma 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 of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal 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. Fluconazole in breast milk reached an average concentration of approximately 98% of the maternal plasma level. The mean peak concentration in breast milk was 2.61 mg/L at 5.2 hours post-dose. The daily fluconazole dose received by an infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean peak milk concentration, is approximately 0.39 mg/kg/day, which corresponds to about 40% of the recommended dose for neonates (age < 2 weeks) or 13% of the recommended dose for infants for treatment of mucosal candidiasis.

Pediatric patients.

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; the volume of distribution was 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

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

Elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) receiving 50 mg oral fluconazole. Ten patients were concurrently taking diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. 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. Thus, the observed changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

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

• cryptococcal meningitis (see section "Special precautions for use");
• coccidioidomycosis (see section "Special precautions for use");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic mucocutaneous candidiasis;
• chronic atrophic oral candidiasis (denture stomatitis) when oral hygiene or topical therapy is ineffective.

Diflucan® is indicated for prophylaxis of the following conditions in adults:

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

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

Treatment with Diflucan® may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted appropriately once results are obtained.

Contraindications.

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

Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on results of multiple-dose interaction studies).

Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride: cardiac adverse reactions, including QT interval prolongation and torsades de pointes, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily significantly increased plasma levels of cisapride 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 QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies were conducted. In one study, administration of fluconazole 200 mg daily did not result in QTc prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased 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 monitoring of the patient is required.

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

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

Erythromycin: concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes) and, consequently, sudden cardiac death. The use of this combination is contraindicated (see section "Contraindications").

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

Halofantrine: fluconazole may increase halofantrine plasma concentrations by inhibiting CYP3A4. Concomitant use of these medicinal products may increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes) and, consequently, sudden cardiac death. The combination should be avoided (see section "Special precautions for use").

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

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

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

• Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole concomitantly with food, cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the dose of fluconazole.

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 the dosing regimen of fluconazole for patients receiving diuretics concomitantly.

• Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. 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 administration due to its long elimination half-life (see section "Contraindications").

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

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

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

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

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

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of 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 increased AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam. If benzodiazepines must be administered concomitantly to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

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

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

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

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 bilirubin and creatinine levels.

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study in healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful monitoring of the patient 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 significant increases in creatine kinase levels occur, 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 prescribing information.

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

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

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

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

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. Concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in an 1.8-fold increase in cyclosporine AUC. These drugs may be used concomitantly provided cyclosporine dose is reduced based 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 based on concentration and drug effects.

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

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

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

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

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

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

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

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

Rifabutin: fluconazole increases rifabutin serum concentrations, leading to up to 80 % increase in AUC of rifabutin. Uveitis has been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this 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 when used concomitantly with fluconazole.

Theophylline: in a placebo-controlled interaction study, 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 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, resulting in a significantly increased risk of adverse reactions, including marked diuresis, dehydration, and acute renal failure. If co-administered, the dose of tolvaptan should be reduced according to the instructions in the tolvaptan prescribing information, and the patient should be regularly monitored for any adverse reactions related to tolvaptan.

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

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

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours 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 administered after fluconazole, monitoring for voriconazole-associated adverse effects 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 % with oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole and zidovudine combination. Patients receiving this combination should be monitored for zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered.

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

Oral contraceptives: two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives were conducted. No effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily resulted in a 40 % increase in AUC of ethinylestradiol and a 24 % increase in levonorgestrel. This suggests that multiple-dose administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

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

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

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

Renal system. Fluconazole should be administered 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 prednisone therapy is described in the section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products".

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

Patients who develop abnormal liver function test results during fluconazole therapy should be closely monitored for progression to more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifier potassium channel (Ikr). QT interval prolongation due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported with Diflucan® use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and advanced heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

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

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when 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 susceptible to 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 therapy 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 and a potent inhibitor of CYP2C19. Patients receiving Diflucan® concomitantly with medicinal products having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine. Close monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at doses less than 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 species are often intrinsically resistant (e.g., C. krusei, C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after treatment failure. Therefore, physicians prescribing this agent are advised to consider the prevalence of resistance among different Candida species to fluconazole.

Excipients.

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

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

Diflucan, infusion solution 2 mg/ml, is considered a high-sodium-content solution. This should be particularly considered when prescribing the product to patients on a low-salt diet.

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

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

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

Pregnancy

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

Data from several thousand pregnant women who received 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 1,000 women receiving cumulative doses ≤ 450 mg, compared to women using topical azoles, and approximately 4 additional cases per 1,000 women receiving cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a fluconazole dose of 150 mg orally and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the risk of congenital heart defects associated with fluconazole use during pregnancy have yielded 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- to 2-fold increased risk of congenital heart defects in infants compared to infants whose mothers did not receive fluconazole 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 radiohumeral synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

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

High-dose and/or prolonged courses of fluconazole 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 be continued after a single standard dose of fluconazole (150 mg). Breastfeeding is not recommended during repeated or high-dose fluconazole administration. 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 considered.

Fertility

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

Effects on ability to drive and use machines.

No studies on the effect of Diflucan® on the ability to drive or operate machinery have been conducted.

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") during Diflucan® use. If such symptoms occur, driving or operating machinery should be avoided.

Dosage and Administration

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 activity have disappeared. Inadequate duration of treatment may lead to recurrence of active infection.

Diflucan® can be administered orally (capsules) or intravenously by infusion (infusion solution), depending on the pharmaceutical form. The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching from oral to intravenous administration or vice versa.

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

Drug compatibility

Diflucan® 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).

Diflucan® may be administered through the same infusion system as one of the solutions listed above. Although cases of nonspecific incompatibility with other drugs have not been reported, mixing Diflucan® with other medicinal products 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 particulate matter and discoloration. The solution should be used only if it is clear and free of particulate matter. Any unused portion of the drug must be discarded.

Adults.

Cryptococcosis

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose: 200–400 mg once daily. The usual duration of treatment is 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, especially meningitis, a dose of 800 mg/day may be appropriate.

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

Candidiasis of mucous membranes

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose: 100–200 mg once daily. Treatment duration is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose: 100–200 mg once daily. Treatment duration 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. Treatment duration may be extended in patients with severe immunodeficiency.
• Chronic atrophic candidiasis: the recommended dose is 50 mg once daily for 14 days.
• Chronic cutaneous and mucosal candidiasis: the recommended dose is 50–100 mg once daily. Treatment duration is up to 28 days, but may be extended depending on the severity and type of infection or immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV-infected patients at high risk of developing the infection

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

Prophylaxis of candidiasis in patients with prolonged neutropenia. The recommended dose is 200–400 mg once daily. Treatment should be initiated several days before the expected onset of neutropenia and continued for 7 days after neutrophil counts rise above 1000/mm³.

Elderly patients.

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

Patients with renal impairment.

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

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 experience with fluconazole in this patient population is limited (see sections "Special warnings and precautions for use" and "Undesirable effects").

Children.

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

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

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

The pharmacokinetics of fluconazole have not been studied in children with renal impairment (see below information on use in neonates, in whom renal immaturity is frequently observed).

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or paediatric dosage is optimal for the patient. Clinical data indicate that children have a higher fluconazole clearance than adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg to children results in comparable systemic exposure.

Children aged 28 days to 11 years.

• Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg once daily. The initial dose may be administered on the first day to achieve steady-state concentrations more rapidly.
• Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg once daily depending on the severity of the disease.
• Maintenance therapy for prevention of relapse of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg once daily depending on the severity of the disease.
• Prophylaxis of candidiasis in immunocompromised patients: dosage is 3–12 mg/kg once daily depending on the severity and duration of induced neutropenia (see doses for adults).

Children aged from birth to 27 days.

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

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

Children.

The drug can be administered to children from birth; see section "Posology and method of administration".

Overdose.

Cases of fluconazole overdose have been reported; hallucinations and paranoid behaviour have also been reported.

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

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

Adverse reactions.

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, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels, rash.

The following frequency classification is used to assess the occurrence of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders.

Uncommon: anaemia.

Rare: agranulocytosis, leucopenia, 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.

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

No special storage conditions required. Keep out of the reach of children. Do not freeze.

Detailed information on storage.

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

From a microbiological point of view, the diluted product should be used immediately. If not used immediately, the user is responsible for the storage conditions and duration prior to use; generally, storage should not exceed 24 hours at a temperature of 2 to 8 °C, unless reconstitution was performed under controlled and validated aseptic conditions.

Incompatibilities.

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

Packaging. 50 ml or 100 ml of solution in flacons, 1 flacon per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Fareva Amboise / Fareva Amboise.

Manufacturer's address.

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