Fluconazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE

Composition:

Active substance: fluconazole;

1 tablet contains fluconazole 50 mg, 100 mg, 150 mg;

Excipients: lactose monohydrate, potato starch, povidone, colloidal anhydrous silicon dioxide, sodium croscarmellose, magnesium stearate, hypromellose (hydroxypropyl-methylcellulose), titanium dioxide (E 171), talc, polyethylene glycol 6000 (macrogol 6000), polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, film-coated tablets, white or almost white, with convex upper and lower surfaces. When broken and examined under a magnifying glass, the core surrounded by a single continuous layer is visible.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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

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

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis).

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.

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 its in vivo and clinical efficacy. Cases of superinfection with Candida spp. other than C. albicans have been reported, which often show reduced susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei and C. auris) to fluconazole. Alternative antifungal agents may be required for treatment of such cases.

Pharmacokinetics.

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

Absorption.

Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption of the drug when administered orally. Peak plasma concentration is reached within 0.5–1.5 hours after administration. Plasma concentration of the drug is proportional to the dose. Steady-state concentration reaching 90% of the final level is achieved by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

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

Fluconazole penetrates well into all studied body fluids. Drug 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 concentrations of fluconazole in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. With a daily dose of 50 mg, the concentration of fluconazole in the stratum corneum after 12 days of treatment was 73 µg/g, and 7 days after completion of treatment, the concentration remained at 5.8 µg/g. With a weekly dose of 150 mg, the concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

After 4 months of weekly 150 mg dosing, fluconazole concentrations in nails were 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disorders; fluconazole was detectable in nail samples up to 6 months after completion of therapy.

Biotransformation.

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

Excretion.

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 hours to 98 hours. Therefore, dose adjustment of fluconazole is required in this patient population. 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%.

Elderly patients.

Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical characteristics.

Indications.

Treatment of the following diseases in adults:

• cryptococcal meningitis;
• coccidioidomycosis;
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic cutaneous and mucosal candidiasis;
• chronic atrophic candidiasis (denture-related candidiasis) when local dental hygiene measures are ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
• candidal balanitis, when topical therapy is not appropriate;
• dermatomycoses, including tinea pedis, tinea of glabrous skin, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

Prevention of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidiasis infections in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation).

Children.

The medicinal product can generally be used from the age of 5 years.

Fluconazole may be used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for the prevention of candidiasis 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 the drug may be initiated before the results of culture and other laboratory tests are available; after obtaining the results, antimicrobial therapy should be adjusted accordingly.

Contraindications.

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

Terfenadine: cases of severe cardiac arrhythmias due to QTc interval prolongation have been reported in patients receiving azole antifungal agents concomitantly with terfenadine. Administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. Administration of fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole doses of 400 mg daily or higher significantly increase plasma terfenadine levels when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. This 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. 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 arrest. Use of this combination of medicinal products is contraindicated.

Amiodarone: concomitant use of fluconazole with amiodarone may lead to inhibition of amiodarone metabolism. An association between amiodarone use and QT interval prolongation has been observed. Concomitant use of fluconazole and amiodarone is contraindicated (see section "Contraindications").

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

Halofantrine: fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, as a consequence, sudden cardiac arrest. 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.

Effect of other medicinal products on fluconazole.

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

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% shortening of 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 CYP2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when administered concomitantly with fluconazole. Therefore, such combinations of drugs should be used with caution; careful monitoring of patients is required. 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, 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. It is recommended to measure concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy and after 1 week. Dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent infected mice and immunocompromised infected mice resulted in: a slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic A. 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) in combination with prolonged prothrombin time have been reported during concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be carefully monitored in patients receiving coumarin anticoagulants or indandione derivatives concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole 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/day and 0.25 mg triazolam orally led to a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use 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 developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its concentration and drug effect.

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

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

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs 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, it has been demonstrated that fluconazole significantly slows 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, careful monitoring of patients for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels should be performed. If a significant increase in creatine kinase levels occurs, or if myopathy/rhabdomyolysis is diagnosed or suspected, use of HMG-CoA reductase inhibitors should be discontinued.

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

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

Everolimus: 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 the sirolimus dose is adjusted depending on concentration and drug effects.

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

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

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

Phenytoin: fluconazole inhibits hepatic metabolism of phenytoin. Multiple concomitant administration of 200 mg fluconazole and 250 mg phenytoin intravenously leads to a 75% increase in AUC24 of phenytoin and a 128% increase in Cmin. Monitoring of phenytoin serum concentration should be performed during concomitant use of these drugs to avoid phenytoin toxicity.

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

Rifabutin: fluconazole increases rifabutin serum concentration, leading to an increase in rifabutin AUC by up to 80%. Cases of uveitis have 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 AUC and Cmax of saquinavir 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, so they may be more pronounced. Dose adjustment of saquinavir may be necessary.

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

Theophylline: administration of fluconazole 200 mg for 14 days led to an 18% decrease in the average plasma clearance of theophylline. Patients receiving theophylline at high doses or those at increased risk of developing theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity appear.

Vinca alkaloids: fluconazole, likely via inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g., vincristine, vinblastine), leading to neurotoxic effects.

Vitamin A: a case was reported in which a patient receiving all-trans retinoic acid (acid form of vitamin A) concomitantly with fluconazole developed CNS adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of CNS adverse reactions should be kept in mind.

Voriconazole (inhibitor of CYP2C9 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 male volunteers led to an average increase in Cmax and AUCτ of voriconazole by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is administered after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

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

Azithromycin: no significant pharmacokinetic interactions between them were observed.

Oral contraceptives: 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 AUC of ethinylestradiol and a 24% increase in levonorgestrel. This indicates that repeated 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 concomitant moderate CYP3A inhibitors such as fluconazole and erythromycin, a reduction in the dose of ivacaftor to 150 mg once daily is recommended.

Special precautions for use.

Dermatophytosis. For the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, and the overall efficacy rate is less than 20%. Therefore, the drug 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, dosage regimen recommendations for the treatment of such infections are not available.

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, dosage regimen recommendations for the treatment of such infections are not available.

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

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

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

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

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

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the torsades de pointes type have been reported during the use of the drug. These reports involved patients with severe diseases and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other medicinal products affecting the QT interval.

The drug 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 cytochrome P450 enzyme is contraindicated.

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

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

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported.

Hypersensitivity. In rare cases, 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 fluconazole and medicinal products with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

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

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

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

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

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

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

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

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg of fluconazole during the first trimester of pregnancy do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, first-trimester exposure to oral fluconazole was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving a cumulative dose of ≤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 risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use 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 more than 3 months for the treatment of coccidioidomycosis. Among the congenital malformations observed in these children were brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

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

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

Fluconazole passes into breast milk and reaches lower concentrations than in plasma. Breastfeeding may continue after a single standard dose of fluconazole of 200 mg or less.

Breastfeeding is not recommended with repeated fluconazole use or when high doses of fluconazole are administered.

Ability to influence the reaction rate when driving vehicles or operating machinery.

Studies on the effect of fluconazole on the ability to drive vehicles or operate machinery have not been conducted. Patients should be informed about the possibility of developing dizziness or seizures during treatment with the drug. If such symptoms occur, driving vehicles or operating machinery is not recommended.

Dosage and Administration

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 required, treatment of infections should be continued until clinical and laboratory signs of fungal activity have disappeared. Inadequate duration of treatment may lead to recurrence of the active infection.

The drug is administered orally or intravenously by infusion. The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching between oral and intravenous administration.

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

Coccidioidomycosis.

The recommended dose is 200–400 mg/day. Treatment duration is 11–24 months or longer, depending on the patient's condition. For certain forms of infection, especially meningitis, a dose of 800 mg/day may be appropriate.

Invasive candidiasis.

The loading dose is 800 mg on the first day. Maintenance dose – 400 mg/day. 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/day. Treatment duration is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg/day. Treatment duration is 14–30 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Candiduria: recommended dose is 200–400 mg/day for 7–21 days. Treatment duration may be extended in patients with severe immunodeficiency.
• Chronic atrophic candidiasis: recommended dose is 50 mg/day for 14 days.
• Chronic cutaneous and mucosal candidiasis: recommended dose is 50–100 mg/day. Treatment duration is up to 28 days, but may be extended depending on the severity and type of infection or degree of immunosuppression.

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

• Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg/day or 200 mg three times weekly. Treatment duration is indefinite in immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia.

Recommended dose is 200–400 mg/day. Treatment should be initiated several days before the expected 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 dose is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After this, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

• Tinea pedis, tinea of glabrous skin, tinea cruris, cutaneous candidiasis: recommended dose is 150 mg once weekly or 50 mg once daily. Treatment duration is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophyte onychomycosis: recommended dose is 150 mg once weekly. Treatment should continue until a healthy nail replaces the infected 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 remain altered.

Children.

The drug can usually be administered to children aged 5 years and older.

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

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

Dosing recommendations for children with impaired renal function are provided below. The pharmacokinetics of fluconazole 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. Children have higher fluconazole clearance compared to adults. Doses of 100, 200, and 400 mg in adults and 3, 6, and 12 mg/kg in children result in comparable systemic exposure.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite extensive data on its use in pediatric patients. If there is an urgent need to administer the drug to 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 loading dose may be administered on the first day to achieve steady-state concentration more rapidly.

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

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

Prophylaxis of candidiasis in immunocompromised patients: dose is 3–12 mg/kg/day depending on the 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. For patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the indication. Subsequent daily doses (depending on the indication) should be calculated according to the table below:

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 dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population.

Children.

The medicinal product may be used in children aged 5 years and older.

Overdose.

There have been reports of fluconazole overdose; hallucinations and paranoid behavior have been reported simultaneously.

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

Fluconazole is predominantly 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

Blood and lymphatic system disorders:
Anemia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders:
Anaphylaxis.

Metabolism and nutrition disorders:
Decreased appetite, hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Psychiatric disorders:
Insomnia, somnolence.

Nervous system disorders:
Headache, convulsions, dizziness, paresthesia, taste disturbance, tremor.

Ear and labyrinth disorders:
Vertigo.

Cardiac disorders:
Paroxysmal ventricular tachycardia of the "torsades de pointes" type, QT interval prolongation.

Gastrointestinal disorders:
Abdominal pain, diarrhea, nausea, vomiting, constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders:
Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, cholestasis, jaundice, increased bilirubin levels, hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury.

Skin and subcutaneous tissue disorders:
Rash, pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported in association with fluconazole treatment (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders:
Myalgia.

General disorders and administration site conditions:
Increased fatigue, malaise, asthenia, fever.

Children.

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

Shelf life. 3 years.

Storage conditions.
In the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.
4 tablets of 50 mg and 100 mg in a blister; 1 blister per cardboard pack.

7 tablets of 50 mg and 100 mg in a blister; 1 blister per cardboard pack.

10 tablets of 50 mg and 100 mg in a blister; 1 blister per cardboard pack.

10 tablets of 50 mg and 100 mg in a blister; 100 blisters per cardboard box.

1 tablet of 150 mg in a blister; 2 blisters per cardboard pack.

2 tablets of 150 mg in a blister; 1 blister per cardboard pack.

Prescription category.
Prescription only.

Manufacturer.
JSC "Tekhnolog".

Manufacturer's address and place of business.
8 Staroprizhna Street, Umans, Cherkasy Region, Ukraine, 20300.