Flunol®

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

Composition:

Active substance: fluconazole;

1 capsule contains fluconazole 50 mg;

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

Hard gelatin capsule: gelatin, titanium dioxide (E 171), indigo carmine (E 132).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size №3 with blue cap and white body, containing a homogeneous white powder.

Pharmacotherapeutic group.

Antifungal agents for systemic use, triazole derivatives. ATC code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl sterols correlates with subsequent depletion of ergosterol in the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective towards fungal cytochrome P450 enzymes than towards 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 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 the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, whereas C. krusei and C. auris are resistant to fluconazole.

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

Pharmacokinetic/pharmacodynamic relationships

According to animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between the area under the concentration-time curve (AUC) and fluconazole dose (approximately 1:1). There is also a direct, but not sufficient, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains with high minimum inhibitory concentrations to fluconazole is less effective.

Mechanism of resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts in vivo efficacy and clinical outcomes. Cases of superinfection with Candida species other than C. albicans have been reported, which often have inherently reduced susceptibility (C. glabrata) or resistance to fluconazole (e.g., C. krusei, C. auris). Such infections may require alternative antifungal therapy.

Clinical breakpoints (according to recommendations of the European Committee on Antimicrobial Susceptibility Testing)

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, clinical breakpoints for fluconazole have been established for Candida species. These have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on the distribution of minimum inhibitory concentrations across species, and species-specific breakpoints, associated most frequently with human infections. These breakpoints are listed below.

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

S = susceptible;

R = resistant;

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

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

IE – insufficient evidence to determine whether this species is a target for antimicrobial therapy.

Pharmacokinetics.

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

Absorption

Fluconazole is well absorbed after oral administration, with plasma levels and systemic bioavailability exceeding 90% of those achieved after intravenous administration. Co-administration with food does not affect absorption of the drug when administered orally. Maximum plasma concentration (Cmax) is reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of once-daily treatment. A 90% steady-state concentration is reached by the second day of treatment when a loading dose twice the normal daily dose is administered on the first day.

Distribution

The 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 concentrations in cerebrospinal fluid reach 80% of plasma levels.

High fluconazole concentrations exceeding serum levels are achieved in the skin, particularly in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. With a daily dose of 50 mg, fluconazole concentration after 12 days of treatment was 73 µg/g, and remained at 5.8 µg/g seven days after treatment ended. With a weekly dose of 150 mg, fluconazole concentration on day 7 of treatment was 23.4 µg/g, and remained at 7.1 µg/g seven days after the next dose.

Nail concentrations of fluconazole after 4 months of 150 mg once weekly were 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 ended.

Biotransformation

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 the CYP2C19 isoenzyme.

Elimination

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

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

Renal impairment

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

Lactation

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

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*hr/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, and 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 observed 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 doses of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (range 44–185) on day 1, decreasing to 53 hours (range 30–131) on day 7 and to 47 hours (range 27–68) on day 13. AUC (µg*hr/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 to 1328 (range 1040–1680) on day 13.

Elderly patients

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*hr/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. Similarly, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, the observed changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

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

• cryptococcal meningitis;
• coccidioidomycosis;
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic candidal skin and mucosal infections;
• chronic atrophic oral candidiasis (denture stomatitis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is inappropriate;
• candidal balanitis, when topical therapy is inappropriate;
• dermatomycoses, including tinea pedis, cutaneous fungal infections, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is appropriate;
• dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

Prevention 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;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidal infections in patients with prolonged neutropenia (e.g., patients with hematologic malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation).

Children

The use of the capsule formulation in this patient population is appropriate when children are able to swallow capsules safely, which is generally possible from the age of 5 years.

Flunol® may be used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for the prevention of candidal infections 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.

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

Contraindications.

• Hypersensitivity to fluconazole, to other azole compounds, or to any excipients of the drug.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg per day or higher (based on results of multiple-dose interaction studies).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin).

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 paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients receiving fluconazole and cisapride concurrently. 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.

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 at a dose of 200 mg daily did not result in QTc prolongation. Another study using fluconazole doses of 400 mg and 800 mg daily demonstrated that fluconazole 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. When fluconazole is administered at doses below 400 mg daily together 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 "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated.

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

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

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

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

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

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

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

Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that concomitant food intake, cimetidine, antacids, or total body irradiation for bone marrow transplantation do not have a clinically significant effect on the absorption of fluconazole following oral administration.

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

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 inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

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

Amphotericin B. Concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in the following: slight additive antifungal effect in systemic 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) have been reported with concomitant use of fluconazole and warfarin, in combination with prolonged prothrombin time. A twofold 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 carefully monitored in patients receiving concomitant coumarin anticoagulants or indandione. Dose adjustment of warfarin may be necessary.

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

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

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

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

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

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

Fentanyl. A fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study involving 12 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), increases the risk of myopathy and rhabdomyolysis. 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.

Olaparib. Moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentrations; 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. With concomitant administration of fluconazole 200 mg daily 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 adjusted based on its concentration.

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

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

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

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

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

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

Although no specific studies have been conducted, fluconazole may potentially 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 phenytoin AUC24 by 75 % and Cmin by 128 %. With concomitant use of these drugs, serum phenytoin concentration should be monitored to avoid phenytoin toxicity.

Prednisone. A case has been reported of acute adrenal insufficiency developing in a patient after liver transplantation who was receiving prednisone, following discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely caused increased CYP3A4 activity, leading to accelerated metabolism of prednisone. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after stopping fluconazole.

Rifabutin. Fluconazole increases rifabutin serum concentration, leading to an up to 80 % increase in rifabutin AUC. Uveitis has been reported with 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 hepatic saquinavir metabolism by the CYP3A4 enzyme and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives. With concomitant administration, fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) in healthy volunteers. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative dose are recommended when used concomitantly with fluconazole.

Theophylline. In a drug 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 with concomitant use of medicinal products that cause moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these drugs.

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

Vitamin A. It has been reported that a patient receiving all-trans retinoic acid (vitamin A acid form) concomitantly with fluconazole developed central nervous system 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 remembered.

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

Zidovudine. Fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a reduction in zidovudine clearance of approximately 45 % with oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole-zidovudine combination. Patients receiving this combination should be monitored for adverse reactions associated with zidovudine. Dose reduction of zidovudine may be considered.

Azithromycin. An open-label, randomized, three-way crossover study evaluated the effect of azithromycin and fluconazole on each other's pharmacokinetics following single oral doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives. Studies on multiple-dose administration of fluconazole and combined oral contraceptives were conducted. With fluconazole 50 mg, no effect on hormone levels was observed, whereas with fluconazole 200 mg daily, AUC of ethinylestradiol increased by 40 % and levonorgestrel by 24 %. This suggests that multiple-dose administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor. Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3-fold and to hydroxymethylivacaftor (M1) by 1.9-fold. For patients receiving moderate CYP3A inhibitors such as fluconazole and erythromycin concomitantly, the recommended dose of ivacaftor is reduced to 150 mg once daily.

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, with an overall efficacy rate of less than 20%. Therefore, Flunol® 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 these infections.

Candidiasis. Studies have shown an increasing prevalence of infections caused by non-C. albicans Candida species. Some of these species are inherently resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy due to treatment inefficacy. Therefore, clinicians are advised to consider the prevalence of fluconazole resistance among different Candida species.

Urinary system. Fluconazole should be administered with caution in patients with renal impairment.

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. Fluconazole should be administered with caution in patients with hepatic impairment. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying conditions. In cases where hepatotoxicity has been linked to fluconazole, no clear dependence on the total daily dose, duration of therapy, sex, or age of the patient has been observed. 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 treatment should be closely monitored for the development of more severe liver injury.

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

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT prolongation and torsades de pointes ventricular tachycardia have been reported during the use of Flunol®. These reports involved patients with severe underlying diseases 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 torsades de pointes.

Flunol® 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.

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when administered at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.

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 taking various medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further treatment with the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. Rare cases of anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole also inhibits the CYP2C19 enzyme. Patients receiving concomitant Flunol® and medicinal products with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, or CYP3A4 should be closely monitored.

Terfenadine. Careful monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at doses below 400 mg per day.

Excipients. The product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential. Before initiating treatment, patients should be informed about the potential risk to the fetus.

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

For prolonged treatment courses, women of childbearing potential are advised to use 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 received topical azoles during the same period.

Data from several thousand pregnant women who received a cumulative dose of fluconazole ≤150 mg during the first trimester do not show an increased overall risk of fetal malformations.

In one large observational cohort study, exposure to oral fluconazole during the first trimester was associated with a small increased risk of musculoskeletal malformations—approximately 1 additional case per 1000 women receiving cumulative doses ≤450 mg, compared to women receiving 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 150 mg of oral fluconazole and 1.98 (95% CI 1.23–3.17) for doses exceeding 450 mg of fluconazole.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies, including several thousand pregnant women who received fluconazole during the first trimester, found a 1.8–2-fold increased risk of cardiac malformations compared to no fluconazole use and/or use of topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for at least 3 months for the treatment of coccidioidomycosis. 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.

Fluconazole should not be used at standard doses or for short-term treatment during pregnancy unless absolutely necessary.

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

Breastfeeding. Fluconazole passes into breast milk and reaches concentrations lower than those in plasma. Breastfeeding may continue after a single standard dose of fluconazole (150 mg or less).

Breastfeeding is not recommended during repeated administration or high-dose fluconazole therapy. The benefit of breastfeeding for the infant's development and health, the mother's clinical need for fluconazole, and any potential adverse effects of the drug or the mother's underlying condition on the breastfed infant should be carefully evaluated.

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

Ability to influence the speed of reactions while driving or operating machinery.

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

Patients should be informed about the possibility of dizziness or seizures during treatment with Flunol®. If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage.

The daily dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose of the drug is sufficient.

If repeated administration is necessary, treatment of infections should be continued until clinical and laboratory signs of fungal infection activity have disappeared. Inadequate duration of treatment may lead to recurrence of the active infectious process.

The drug is administered orally. 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.

Capsules should be swallowed whole. The drug can be taken regardless of food intake.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg daily. Duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in high-risk patients: recommended dose is 200 mg daily for an indefinite duration.

Coccidioidomycosis. Recommended dose is 200–400 mg daily. 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 daily may be appropriate.

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

Oral mucosal candidiasis.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg daily. Duration of treatment is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg daily. Duration of treatment is 14–30 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Candiduria: recommended dose is 200–400 mg daily for 7–21 days. Duration of treatment may be prolonged in patients with severe immunodeficiency.
• Chronic atrophic candidiasis: recommended dose is 50 mg daily for 14 days.
• Chronic cutaneous and mucosal candidiasis: recommended dose is 50–100 mg daily. Duration of treatment is up to 28 days, but may be extended depending on severity and type of infection or immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV patients at high risk of recurrence.

• Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg daily or 200 mg three times weekly. Duration of treatment is indefinite in immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia. Recommended dose is 200–400 mg. Treatment should be initiated several days before anticipated onset of neutropenia and continued for 7 days after neutrophil count rises above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more episodes per year): recommended regimen is 150 mg once every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After this, maintenance therapy should consist of 150 mg once weekly for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous tinea, tinea cruris, cutaneous candidiasis: recommended dose is 150 mg once weekly or 50 mg once daily. Duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Tinea versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks.
• Dermatophyte onychomycosis: recommended dose is 150 mg once weekly. Treatment should continue until the infected nail is replaced by a healthy one. Healthy nail regrowth typically takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of chronic long-term infections, nail appearance may sometimes remain altered.

Children.

The drug in capsule form may be administered to this patient group only when children are able to swallow capsules safely, which is usually possible from the age of 5 years.

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

As in adults with similar infections, treatment duration depends on clinical and mycological response. Flunol® should be administered once daily.

Dosing recommendations for children with renal impairment are provided below. Fluconazole pharmacokinetics have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should determine whether adult or pediatric dosing is more appropriate. Clinical data indicate that fluconazole clearance is higher in children than in adults. Administration of 100, 200, and 400 mg doses in adults and 3, 6, and 12 mg/kg doses in children results in comparable systemic exposure.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite comprehensive data on the use of Flunol® in pediatric patients. If urgent treatment is required in adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose – 3 mg/kg/day. The initial dose may be administered on the first day to achieve steady-state concentration more rapidly.

Invasive candidiasis, cryptococcal meningitis: drug dose is 6–12 mg/kg/day depending on disease severity.

Maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk: drug dose is 6 mg/kg/day depending on disease severity.

Prophylaxis of candidiasis in immunocompromised patients: drug dose is 3–12 mg/kg/day depending on severity and duration of induced neutropenia (see adult doses).

Elderly patients.

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

Patients with renal impairment.

Dose adjustment of fluconazole is not 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. Subsequently, the daily dose (depending on the indication) should be calculated according to the table below:

Creatinine clearance (mL/min)	Percentage of recommended dose
> 50	100 %
≤ 50 (without dialysis)	50 %
Regular dialysis	100 % after each dialysis

Patients undergoing regular dialysis should receive 100% of the recommended dose after each dialysis 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 impairment, as there is insufficient information regarding the use of fluconazole in this patient population.

Children.

The capsule formulation may be administered to this patient population only when children are able to swallow capsules safely, which is generally possible at the age of 5 years.

Overdose.

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

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

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

Side effects

The most common adverse reactions (>1/10) are headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in blood. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported with fluconazole treatment (see section "Special precautions").

To assess the frequency of adverse reactions, the following classification is used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia
Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia

Immune system disorders

Rare: anaphylaxis

Metabolism and nutrition disorders

Uncommon: decreased appetite
Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia

Psychiatric disorders

Uncommon: insomnia, somnolence

Nervous system disorders

Common: headache
Uncommon: convulsions, dizziness, paraesthesia, taste disturbances
Rare: tremor

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

Rare: paroxysmal ventricular tachycardia of the "torsades de pointes" type, QT interval prolongation

Gastrointestinal disorders

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Common: rash
Uncommon: pruritus, drug rash (including fixed drug eruption), urticaria, increased sweating
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever

Paediatric population

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

Shelf life. 4 years

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.

Packaging

3 or 7 capsules in a blister, 1 blister per cardboard pack.

Prescription category. Prescription only

Manufacturer

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location

Sancaklar Quarter, Eskikarakoca Avenue No: 299, 81100 Duzce, Turkey