INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE (FLUCONAZOLE)

Composition:

Active substance: fluconazole;

1 capsule contains 150 mg of fluconazole;

Excipients: lactose monohydrate; potato starch; magnesium stearate; colloidal anhydrous silicon dioxide;

Capsule shell composition: gelatin, titanium dioxide (E 171), indigocarmine-blue (E 132).

Dosage form. Capsules.

Main physicochemical properties: hard gelatin capsules size №1, cylindrical in shape with hemispherical ends; body – white, cap – blue or dark blue; contents of the capsule – white or almost white odourless powder.

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, which is 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 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 produce clinically significant effects on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

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

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows low 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 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 efficacy and clinical effectiveness. Cases of superinfection with Candida spp., caused by species other than C. albicans, which often show low susceptibility (C. glabrata) or resistance to fluconazole (e.g., C. krusei, C. auris), have been reported. Alternative antifungal agents should be used for the 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, with plasma levels and systemic bioavailability exceeding 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 drug intake. Plasma drug concentration is proportional to the dose. Steady-state concentration reaches 90% of the target level by the second day of treatment when a loading dose, twice the usual 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. Levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid reach 80% of plasma concentrations.

High 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. After administration of 50 mg once daily, fluconazole concentration in the stratum corneum was 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a dose of 150 mg once weekly, the concentration on day 7 of treatment was 23.4 µg/g; seven days after the next dose, the concentration remained at 7.1 µg/g.

Fluconazole concentration in nails after 4 months of 150 mg once weekly dosing was 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 fluconazole, only 11% of the dose 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.

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 less than 20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, dose reduction 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%.

Geriatric patients.

Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical Characteristics.

Indications.

Acute vaginal candidiasis when topical therapy is not appropriate.

Candidal balanitis when topical therapy is not appropriate.

Contraindications.

Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the medicinal product.
Concomitant use of fluconazole and terfenadine in patients receiving repeated doses of fluconazole 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 CYP2A4 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. Cases of cardiac adverse reactions, including QT interval prolongation and torsades de pointes, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily significantly increased plasma levels of cisapride and prolonged the QT interval. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine. Due to cases of severe cardiac arrhythmias associated with QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies were conducted. In one study, administration of fluconazole 200 mg daily did not result in QTc prolongation. Another study using fluconazole 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 (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. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to torsades de pointes. Concomitant use of fluconazole and astemizole is contraindicated.

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, torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.

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

Amiodarone. Concomitant use of fluconazole with amiodarone may lead to inhibition of amiodarone metabolism. There is an association between amiodarone use and QT interval prolongation. 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 increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes) and, consequently, sudden cardiac death. The combination should be avoided.

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

Effect of other medicinal products on fluconazole.

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

Rifampicin. Concomitant administration 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 fluconazole dose.

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

Effect of fluconazole on other medicinal products.

Fluconazole is a 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 administration due to its long elimination half-life.

Alfentanil. During concomitant administration of alfentanil 20 mcg/kg and fluconazole 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 required if necessary.

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

Anticoagulants. As with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported during concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant administration 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 indanediones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam. Administration of fluconazole after oral administration of midazolam resulted in significantly increased midazolam concentrations and enhanced psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally increased AUC and elimination half-life by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If benzodiazepines must be administered concomitantly to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

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

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

Celecoxib. Concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. When celecoxib is used concomitantly with fluconazole, a 50% reduction in celecoxib dose may be necessary.

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

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

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), increases the risk of myopathy and rhabdomyolysis. If concomitant use is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If creatine kinase levels are significantly elevated, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.

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

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. Concomitant administration of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in a 1.8-fold increase in cyclosporine AUC. 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, it is known that fluconazole may increase serum everolimus concentration by inhibiting CYP3A4.

Sirolimus: Fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted based on concentration and clinical effect.

Tacrolimus. Fluconazole may increase serum tacrolimus concentrations up to fivefold after oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the gut. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. 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 therapy. Continuous monitoring of blood pressure in patients is recommended.

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

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

Although no specific studies have been conducted, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for NSAID-related adverse reactions and toxic effects is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin. Fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases AUC24 of phenytoin by 75% and Cmin by 128%. When these medicinal products are used concomitantly, serum phenytoin concentration should be monitored to avoid phenytoin toxicity.

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

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

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

Sulfonylurea derivatives. Fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent blood glucose monitoring is recommended, and sulfonylurea derivative dose should be reduced accordingly 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.

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

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

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4). Concomitant oral administration of voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an average increase in Cmax and AUC 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, patients should be monitored for voriconazole-related adverse effects.

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

Azithromycin. Studies 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. No hormonal effects were observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. This suggests that 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 moderate CYP3A inhibitors such as fluconazole and erythromycin concomitantly, a reduced dose of ivacaftor to 150 mg once daily is recommended.

Special precautions for use.

Dermatophytosis. According to clinical studies of fluconazole in the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, and the overall effectiveness rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. There is insufficient evidence of fluconazole efficacy in treating cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, dosage recommendations for treatment of such infections are not available.

Deep endemic mycoses. There is insufficient evidence of fluconazole efficacy in treating other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, dosage recommendations for treatment of such infections are not available.

Candidiasis.

Clinical studies have shown an increasing prevalence of infections caused by Candida species other than C. albicans. Some Candida species are inherently resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Alternative antifungal therapy may be required for such infections. Therefore, physicians prescribing fluconazole are advised to consider the prevalence of resistance among different Candida species to fluconazole.

Renal system. Fluconazole should be used with caution in patients with impaired renal function (see section "Dosage and administration").

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

Hepatobiliary system. Fluconazole should be used 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 was linked to fluconazole, no clear dependence on the total daily dose, duration of therapy, gender, or patient age was 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 progression to more severe liver injury.

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

Cardiovascular system. Some azoles, including fluconazole, have been 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 fluconazole use. These reports involved patients with severe underlying diseases and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs affecting the QT interval.

Fluconazole should be used cautiously 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 flucon azole is not recommended.

Cutaneous reactions. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported. 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 developing severe skin reactions when using 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 skin rash, careful monitoring is required, and fluconazole should be discontinued in case of bullous eruptions or development of erythema multiforme.

Hypersensitivity. Anaphylactic reactions have been reported rarely.

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 fluconazole and medicinal products with a narrow therapeutic index metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

Terfenadine. Careful monitoring of the patient is required when terfenadine is used concomitantly with fluconazole at doses less than 400 mg per day.

Excipients. The medicinal product contains lactose. This product 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.

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 the use of fluconazole at doses ≤ 150 mg in several thousand pregnant women during the first trimester do not indicate an increased overall risk of fetal malformations.

In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving a cumulative therapeutic dose ≤ 450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving a cumulative therapeutic dose exceeding 450 mg. The relative risk was 1.29 (95% CI 1.05–1.58) with a 150 mg dose 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 provide conflicting results. However, a meta-analysis of five 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 and/or use of topical azoles.

Case reports have described congenital malformations in infants whose mothers received high doses (400 to 800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Congenital malformations observed in these infants include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

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

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

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

Breastfeeding is not recommended during repeated or high-dose fluconazole use.

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

No studies on the effect of the medicinal product 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. If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

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

Adults

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

Elderly Patients

In the absence of signs of impaired renal function, the usual adult dose should be used for treatment in this patient category.

Renal Impairment

Fluconazole is primarily excreted unchanged in urine. When administered as a single dose, dosage 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 the drug in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the usual adult dosage should be used.

Overdose

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

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

Fluconazole is significantly excreted in urine; forced diuresis may accelerate 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, increased blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

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, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10 000, < 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 torsades de pointes ventricular tachycardia, 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, ALP;
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 swelling, 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.

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

Reporting of suspected adverse reactions.

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

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

1 capsule in a blister; 1, 2, 3 or 4 blisters per carton.

Prescription status.

150 mg № 1 – over-the-counter.

150 mg № 2; № 3; № 4 – prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and place of business.

6 Kyivska Street, city of Vyshneve, Kyiv-Sviatoshyn district, 08132, Ukraine.