Flunol®

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

Composition:

Active ingredient: fluconazole;

1 capsule contains fluconazole 150 mg;

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

Hard gelatin capsule: gelatin, titanium dioxide (E 171), azorubine (E 122).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules No. 1 with a pink cap and a 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-methylsterols 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 have a clinically significant effect 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 the most common 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.

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

Pharmacokinetic/pharmacodynamic relationship

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 pharmacokinetic concentration-time curve (AUC) and the dose of fluconazole (approximately 1:1). There is also a direct, but not fully 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 (MICs) 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 (MICs) against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo efficacy and clinical effectiveness. 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 species-specific minimum inhibitory concentration (MIC) distributions, and species-specific breakpoints, associated most frequently with human infections. These breakpoints are listed below.

S = sensitive;

R = resistant;

a – breakpoints not linked to a specific species, which were primarily determined 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, and plasma drug levels and systemic bioavailability exceed 90% of those achieved with intravenous administration. Concomitant food intake does not affect absorption of the drug when administered orally. Maximum plasma concentration (Cmax) is reached within 0.5–1.5 hours after 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 treatment with repeated dosing. A steady-state 90% concentration is reached by day 2 of treatment when a loading dose twice the normal daily dose is administered on the first day.

Distribution

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

Fluconazole penetrates well into all investigated 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 7 days after treatment completion, the concentration 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, and 7 days after the next dose, the 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 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 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 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 fluconazole concentrations were evaluated over 48 hours following a single 150 mg dose of fluconazole in a pharmacokinetic study involving ten lactating women who temporarily or completely discontinued breastfeeding. Fluconazole in breast milk reached an average concentration of approximately 98% of maternal plasma levels. The mean maximum 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 0.39 mg/kg/day, approximately 40% of the dose recommended for neonates (<2 weeks of age) and 13% of the dose recommended 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*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer plasma half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma half-life of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

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

Elderly patients

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) receiving 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher 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, pharmacokinetic changes 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"):

Acute vaginal candidiasis when topical therapy is not appropriate.

Candidal balanitis when topical therapy is not appropriate.

Treatment with the drug may be initiated before the results of cultures and other laboratory tests are available; however, after obtaining test results, antimicrobial therapy should be adjusted accordingly.

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

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

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

Cisapride. Cases of cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients who received fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in plasma cisapride levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated.

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

Astemizole. Concomitant use of fluconazole and astemizole may reduce astemizole clearance. This increase in plasma astemizole 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, lead to the development of 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, as a consequence, sudden cardiac death. The use of this combination of medicinal products is contraindicated.

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 potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, as a consequence, sudden cardiac death. The use of this combination of medicinal products 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 its 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, 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 potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the CYP2C19 isoenzyme. In addition to observed/documentarily confirmed 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 of drugs 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. When alfentanil at a dose of 20 mcg/kg and fluconazole at a dose of 400 mg were administered concomitantly 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. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B. Concomitant administration of fluconazole and amphotericin B to immunocompetent and immunocompromised infected mice resulted in the following outcomes: 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 the results obtained in these studies is unknown.

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

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

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

Carbamazepine. Fluconazole inhibits carbamazepine metabolism and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its concentration and drug effects.

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. When fluconazole (200 mg daily) and celecoxib (200 mg) were administered concomitantly, Cmax and AUC of celecoxib increased by 68% and 134%, respectively. When celecoxib and fluconazole are used concomitantly, a halving of the celecoxib dose may be necessary.

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

Fentanyl. A fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study involving 12 healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, patient status should be closely monitored. Fentanyl dose adjustment may be necessary.

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), 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 a significant increase in creatine kinase levels occurs, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.

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

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

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole at a dose of 200 mg daily and cyclosporine at a dose of 2.7 mg/kg/day were administered concomitantly, cyclosporine AUC increased by 1.8 times. These drugs can be used concomitantly provided cyclosporine dose is reduced depending on its concentration.

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

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

Tacrolimus. Fluconazole may increase tacrolimus serum concentration up to 5 times when administered orally 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 tacrolimus dose should be reduced depending on tacrolimus concentration.

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

Methadone. Fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary when methadone and fluconazole are used concomitantly.

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

Although specific studies have not 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. NSAID dose adjustment may be required.

Phenytoin. Fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin leads to a 75% increase in phenytoin AUC24 and a 128% increase in Cmin. Serum phenytoin concentration should be monitored when these drugs are used concomitantly to avoid phenytoin toxicity.

Prednisone. A case has been reported where a patient after liver transplantation developed acute adrenal insufficiency while on prednisone, following discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients who have been receiving fluconazole and prednisone concomitantly for a prolonged period should be closely monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

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

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

Sulfonylurea derivatives. When used concomitantly, 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 reduction of sulfonylurea derivative dose are recommended when used concomitantly with fluconazole.

Theophylline. Drug interaction studies showed that administration of fluconazole at 200 mg for 14 days led to an 18% reduction in the average plasma theophylline clearance. Patients receiving theophylline at high doses 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 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 the development of neurotoxic effects.

Vitamin A. A case has been reported where a patient receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole experienced central nervous system adverse reactions in the form of pseudotumor cerebri; this effect disappeared after discontinuation of fluconazole. These medicinal products can be used concomitantly, but the risk of central nervous system 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 the first day, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers led to an average increase in voriconazole Cmax and AUC of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

Zidovudine. Fluconazole increases zidovudine Cmax and AUC by 84% and 74%, respectively, due to a reduction in zidovudine clearance of approximately 45% following its 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 of medicinal products should be monitored for adverse reactions associated with zidovudine use. Consideration may be given to reducing the zidovudine dose.

Azithromycin. A 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. No effect on hormone levels was observed with fluconazole at a dose of 50 mg, whereas administration of fluconazole at a dose of 200 mg daily resulted in a 40% increase in ethinylestradiol AUC and a 24% increase in levonorgestrel AUC. This indicates that multiple administration of fluconazole at the specified doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor. Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases ivacaftor exposure by 3 times and hydroxymethylivacaftor (M1) by 1.9 times. For patients concurrently using moderate CYP3A inhibitors such as fluconazole and erythromycin, it is recommended to reduce the ivacaftor dose to 150 mg once daily.

Special precautions for use.

Dermatophytosis. According to studies on fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed 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 these 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 Candida species other than C. albicans. These species are often 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 failure. Therefore, physicians are advised to consider the prevalence of fluconazole resistance among different Candida species.

Renal system. The drug should be used with caution in patients with impaired renal function.

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rarely observed. Adrenal insufficiency associated with concomitant prednisone therapy is described in the section "Interaction with other medicinal products and other types of interactions. Effect of fluconazole on other medicinal products."

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

Patients who develop abnormalities in liver function tests during fluconazole treatment should be closely monitored for the development of more severe liver 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 should be sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of the cytochrome P450 system. Very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the torsades de pointes type have been reported during the use of Flunol®. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other drugs affecting the QT interval.

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 the cytochrome P450 system 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.

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

Hypersensitivity. Rare cases of anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients receiving concomitant treatment with Flunol® and drugs with a narrow therapeutic window metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

Terfenadine. Close monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at a fluconazole dose of less than 400 mg per day.

Excipients. The medicinal product contains lactose. This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The medicinal product contains azorubine (E 122), which may cause allergic reactions.

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 waiting period of approximately 1 week (corresponding to 5–6 half-lives) should be observed before attempting conception (see section "Pharmacokinetics").

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, corresponding to 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 exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI 1.23–3.17) for doses exceeding 450 mg of fluconazole.

Available epidemiological studies on the development of heart defects 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 congenital heart defects compared to no fluconazole use or use of topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400 to 800 mg/day) of fluconazole during pregnancy for at least 3 months for the treatment of coccidioidomycosis. Malformations observed in these children 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 lower concentrations than in plasma. Breastfeeding may be continued after a single standard dose of fluconazole of 150 mg or less.

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

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

Ability to affect reaction speed when 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 developing dizziness or seizures during treatment with Flunol®. If such symptoms occur, driving or operating machinery is not recommended.

Dosage and Administration

Capsules should be swallowed whole. The administration of the drug is independent of food intake.

Adults.

The drug should be administered orally at a dose of 150 mg as a single dose.

Elderly patients.

In the absence of signs of impaired renal function, treat this patient category with the standard adult dose.

Renal impairment.

Fluconazole is primarily excreted unchanged in the urine. When administered as a single dose, dose adjustment is not required in this patient category.

Hepatic impairment.

Fluconazole should be administered with caution to patients with hepatic dysfunction, as there is insufficient data on the use of fluconazole in this patient population.

Children.

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

Overdose.

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

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

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

Adverse Reactions

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

There have been reports of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with fluconazole treatment (see section "Special Warnings and Precautions for Use").

The following classification is used to assess the frequency of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 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: seizures, dizziness, paresthesia, taste disturbance
Rare: tremor

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

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

Gastrointestinal disorders

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

General disorders

Uncommon: increased fatigue, malaise, asthenia, fever

Children

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

Shelf life. 4 years.

Storage conditions.

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

Packaging.

1 or 2 capsules in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Over-the-counter – 150 mg capsule, 1 capsule
By prescription only – 150 mg capsule, 2 capsules

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskı Akcakoca Avenue, No: 299, 81100 Duzce, Turkey.