Fluconazole-zdorovya forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE-ZDOROVYE FORTE (FLUCONAZOLE-ZDOROVYE FORTE)

Composition:

Active substance: fluconazole;

1 capsule contains fluconazole 200 mg;

Excipients: lactose monohydrate; potato starch; povidone; calcium stearate; capsule shell contains titanium dioxide (E 171), gelatin, black printing ink (if the company trademark is printed – ZT; contains shellac Glaze 45 % solution in ethanol, iron oxide black (E 172), propylene glycol, concentrated ammonia solution).

Pharmaceutical form: Hard capsules.

Main physicochemical properties: hard gelatin capsules of white color. The capsule contents – white to yellowish powder. The presence of powder particle agglomerates is acceptable. The company trademark – ZT may be printed on the capsule.

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 (CYP), an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

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

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

In vitro susceptibility. In vitro, fluconazole demonstrates 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.

In vitro, fluconazole also demonstrates activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic dimorphic fungi 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 AUC and fluconazole dose (approximately 1:1). There is also a direct, but suboptimal, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment outcomes for infections caused by strains with high minimum inhibitory concentrations to fluconazole are less favorable.

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 non-albicans Candida species, often exhibiting reduced 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 infections.

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 against Candida species have been established. These have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on the distribution of minimum inhibitory concentrations across species, and species-specific breakpoints, mainly associated with human infections. These breakpoints are listed below.

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

S = susceptible;

R = resistant;

a – breakpoints not associated with 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 for which no species-specific breakpoint exists;

– susceptibility testing is not recommended, as this organism is not a target for antimicrobial therapy;

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

Pharmacokinetics.

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

Absorption. Fluconazole is well absorbed after oral administration, with plasma concentrations 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 administration on an empty stomach. Plasma concentrations of the drug are proportional to the dose administered. Steady-state 90% concentration is achieved by day 4–5 of treatment with once-daily dosing. A steady-state 90% concentration is achieved by day 2 when a loading dose twice the standard daily dose is administered on the first day.

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

Fluconazole penetrates well into all studied body fluids. Concentrations in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations 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.

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

Excretion. The plasma half-life (T½) of fluconazole is approximately 30 hours. The drug is primarily eliminated 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 of the drug 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 half-life increases from 30 hours to 98 hours. Therefore, this patient population requires dose reduction of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole concentration by approximately 50%.

Lactation. Fluconazole passes into breast milk.

Children. Following administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 μg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer plasma elimination half-life of approximately 24 hours was observed after single-dose administration.

Elderly patients. Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical characteristics.

Indications.

Treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

• cryptococcal meningitis (see section "Special precautions");
• coccidioidomycosis (see section "Special precautions");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic mucocutaneous candidiasis;
• chronic atrophic candidiasis (denture-related candidiasis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is inappropriate;
• candidal balanitis, when topical therapy is inappropriate;
• dermatomycoses, including tinea pedis, tinea of glabrous skin, tinea cruris; pityriasis versicolor and cutaneous candidiasis, when systemic therapy is appropriate;
• dermatophytic onychomycosis, when use of other medicinal products is inappropriate.

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 in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation) (see section "Pharmacological properties. Pharmacodynamics").

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

The drug may be used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prevention of candidiasis in immunocompromised patients. The drug may also 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 any component of the drug or to other azole compounds. Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg daily or higher. 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 torsade 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.

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 have been conducted. When fluconazole was administered at a dose of 200 mg daily, no QTc interval prolongation was observed. Administration of fluconazole at doses of 400 mg daily or higher significantly increases terfenadine plasma levels when these drugs are used 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. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the torsade 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 torsade 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 torsade de pointes type) and, as a consequence, sudden cardiac death. 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 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 torsade de pointes type) and, as a consequence, sudden cardiac death. The combination of these medicinal products should be avoided.

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

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

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

Effect of other medicinal products on fluconazole. There is no clinically significant effect on fluconazole absorption following oral administration when fluconazole is taken concomitantly with food, cimetidine, antacids, or whole-body irradiation (in bone marrow transplantation).

Rifampicin. Concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in fluconazole half-life (T½). Therefore, dose adjustment of fluconazole should be considered for patients receiving rifampicin.

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 fluconazole dosing regimen for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products. Fluconazole is a potent inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4. Fluconazole also inhibits the CYP2C19 isoenzyme. In addition to the documented and described interactions listed below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when used concomitantly with fluconazole. Therefore, such drug combinations should be used with caution, and patients should be closely monitored. Due to the long half-life of fluconazole, its inhibitory effect on enzymes persists for 4–5 days.

Alfentanil. Concomitant administration of 400 mg fluconazole and 20 µg/kg alfentanil results in a twofold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates dose adjustment of alfentanil.

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 one week after initiation. Dose adjustment of amitriptyline or nortriptyline may be required if necessary.

Amphotericin B. Concomitant use of fluconazole and amphotericin B in infected immunocompetent and immunocompromised 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 A. fumigatus infection. The clinical significance of these results is unknown.

Anticoagulants. As with other azole antifungal agents, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported during concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. 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 concomitant coumarin anticoagulants. Warfarin dose adjustment may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam. Administration of fluconazole after oral administration of midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of 200 mg fluconazole and 7.5 mg midazolam orally resulted in a 3.7- and 2.2-fold increase in AUC and T½, respectively. Administration of 200 mg fluconazole daily and 0.25 mg triazolam orally resulted in a 4.4- and 2.3-fold increase in AUC and T½, 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 benzodiazepines concomitantly, the dose of the latter should be reduced and appropriate patient monitoring established.

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

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

Celecoxib. When fluconazole (200 mg daily) and celecoxib (200 mg) were used 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 may be used concomitantly, considering the potential risk of increased serum bilirubin and creatinine concentrations.

Fentanyl. A fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. Fluconazole significantly slows 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 creatine kinase levels are significantly elevated, or if myopathy/rhabdomyolysis is suspected or detected, HMG-CoA reductase inhibitors should be discontinued.

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

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

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. When 200 mg fluconazole daily and 2.7 mg/kg/day cyclosporine were used concomitantly, cyclosporine AUC increased 1.8-fold. These drugs may be used concomitantly provided cyclosporine dose is reduced according to its concentration.

Everolimus. Fluconazole may increase everolimus serum 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 according to its concentration and effects.

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

Losartan. Fluconazole inhibits the conversion of losartan to its active metabolite (E-3174). 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 flurbiprofen alone. Similarly, concomitant use of fluconazole with racemic ibuprofen (400 mg) resulted in a 15 % and 82 % increase in Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer, respectively, compared to racemic ibuprofen 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. NSAID dose adjustment may be required.

Phenytoin. Fluconazole inhibits hepatic phenytoin metabolism. Multiple concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases phenytoin AUC24 by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration is required when these drugs are used concomitantly to avoid phenytoin toxicity.

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

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

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

Sulfonylurea derivatives. Concomitant use of fluconazole with oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) prolonged their half-life. Frequent blood glucose monitoring is recommended, and sulfonylurea derivative dose should be reduced accordingly when used concomitantly with fluconazole.

Theophylline. Administration of 200 mg fluconazole for 14 days resulted in an 18 % decrease in theophylline plasma clearance. 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. Fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A. A case was reported in which a patient receiving concomitant all-trans retinoic acid (the acid form of vitamin A) and fluconazole experienced central nervous system adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of central nervous system 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) resulted in an average increase in voriconazole Cmax and AUCτ 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 administered after fluconazole, monitoring for voriconazole-associated adverse effects is recommended.

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

Azithromycin. No significant pharmacokinetic interactions were observed after single oral concomitant administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.

Oral contraceptives. No effect on hormone levels was observed with fluconazole at a dose of 50 mg, whereas administration of fluconazole at 200 mg daily resulted in a 40 % increase in ethinylestradiol AUC and a 24 % increase in levonorgestrel AUC. 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 ivacaftor exposure threefold and hydroxymethylivacaftor (M1) exposure 1.9-fold. For patients concomitantly receiving moderate CYP3A inhibitors such as fluconazole and erythromycin, ivacaftor dose should be reduced to 150 mg once daily.

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, tofacitinib dose should be reduced to 5 mg once daily when used in combination with these drugs.

Special precautions for use.

Dermatophytosis. It is known that when fluconazole is used to treat dermatophytosis in children, its efficacy does not exceed that of griseofulvin, and the overall efficacy rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

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

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

Candidiasis. Studies have shown an increased prevalence of infections caused by Candida species other than C. albicans. These species are often intrinsically resistant (e.g., C. krusei and C. auris) or demonstrate reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy, especially after failure of prior treatment. Therefore, prescribers 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").

Hepatobiliary system. Fluconazole should be used with caution in 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 conditions. In cases where hepatotoxicity has been associated with fluconazole use, there was no clear dependence on the total daily dose, duration of therapy, patient's sex, or age. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole 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 medicinal products affecting the QT interval.

Fluconazole should be used with caution in patients at risk of arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 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.

Skin reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and Lyell's syndrome have been reported during fluconazole use. Patients with AIDS are more prone to developing 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 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 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 CYP3A4. Fluconazole is also an inhibitor of CYP2C19. Patients receiving fluconazole concomitantly with medicinal products having 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 is used concomitantly with fluconazole at doses below 400 mg per day.

The product contains lactose. If a patient has been diagnosed with an intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

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 elimination half-lives) should be observed before conception (see section "Pharmacokinetics").

For longer 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 of pregnancy compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand women who received a cumulative dose of ≤ 150 mg fluconazole during the first trimester of pregnancy do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, oral use of fluconazole during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women who received a cumulative therapeutic dose ≤ 450 mg compared to women who received topical azoles, and approximately 4 additional cases per 1000 women who received cumulative doses exceeding 450 mg. The relative risk was 1.29 (95% CI 1.05–1.58) for oral fluconazole 150 mg and 1.98 (95% CI 1.23–3.17) for doses exceeding 450 mg.

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, including several thousand pregnant women who received fluconazole during the first trimester, found a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use or use of topical azoles.

Cases of congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for at least 3 months for the treatment of coccidioidomycosis. Congenital abnormalities observed in these children included 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 and short-term courses of fluconazole should not be used during pregnancy except when 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 period.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma. Breastfeeding may be continued after a single standard dose of fluconazole (150 mg or less).

The benefit of breastfeeding for the child's development and health, the mother's clinical need for fluconazole, and any potential adverse effects of fluconazole or the mother's underlying condition on the breastfed child should be carefully evaluated.

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

Fertility.

Fluconazole did not affect fertility in animal studies.

Ability to influence reaction rate while driving or operating machinery.

Studies on the effect of fluconazole on the ability to drive or operate machinery have not 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.

The drug should be administered orally. The administration of the drug is not affected by food intake. If it is necessary to use fluconazole at a dose less than 200 mg, dosage forms allowing appropriate dose adjustment should be used.

The daily dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose is sufficient. If repeated administration is required, treatment of infections should be continued until disappearance of clinical and laboratory signs of fungal infection activity. Inadequate duration of treatment may lead to recurrence of the active infection process.

Adults.

Cryptococcosis.

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

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

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

Candidiasis of mucous membranes.

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

Prevention of relapse of mucosal candidiasis in HIV-infected patients at high risk of its development.

• Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose is 100–200 mg once daily or 200 mg three times weekly. The duration of treatment is indefinite for patients with immunosuppression.

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

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: the recommended dose is 150 mg as a single dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more recurrences per year): the 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 that, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous fungal infections, tinea cruris, cutaneous candidiasis: the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophytic onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued until a healthy nail replaces the infected one. Healthy nail regrowth on fingers and great toes usually takes 3–6 months and 6–12 months, respectively. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-term chronic infections, nail appearance may sometimes remain altered.

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

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

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

Dosage of the drug in children with impaired renal function is given below. The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.

Children aged 12 years. Depending on body weight and pubertal development, the physician should assess which dose (adult or pediatric) is optimal for the patient. Clinical data indicate that clearance of fluconazole in children is higher than in adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg once daily to children results in comparable systemic exposure.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. 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 initial dose may be administered on the first day to achieve steady-state concentration more rapidly.

Invasive candidiasis, cryptococcal meningitis: the dose is 6–12 mg/kg once daily, depending on the severity of the disease.

Maintenance therapy for prevention of relapse of cryptococcal meningitis in children at high risk of its development: the dose is 6 mg/kg once daily, depending on the severity of the disease.

Prophylaxis of candidiasis in patients with immunodeficiency: the dose is 3–12 mg/kg once daily, depending on the severity and duration of induced neutropenia (see adult doses).

Elderly patients. The dose should be adjusted according to renal function (see below).

Patients with renal insufficiency. Fluconazole is predominantly excreted unchanged in urine. Dose adjustment is not required after a single dose. 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 therapeutic indications. Subsequently, the daily dose (depending on the indication) should be calculated according to the table below:

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

Patients undergoing regular hemodialysis should receive 100% of the recommended dose after each hemodialysis session. On days when hemodialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Liver function impairment. Fluconazole should be administered with caution to patients with liver function abnormalities, as there is insufficient data regarding the use of fluconazole in this patient group.

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

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Fluconazole is primarily excreted in the urine; therefore, 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 were: headache, abdominal pain, diarrhea, nausea, vomiting, increased levels of alanine aminotransferase (ALT), increased levels of aspartate aminotransferase (AST), increased blood alkaline phosphatase levels, rash.

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, paraesthesia, taste disturbance, tremor.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: paroxysmal torsades de pointes ventricular tachycardia, QT interval prolongation.

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

Hepatobiliary disorders: increased levels of ALT, AST, alkaline phosphatase, cholestasis, jaundice, increased bilirubin levels, hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury.

Skin and subcutaneous tissue disorders: rash, pruritus, drug rash, urticaria, increased sweating, Lyell's syndrome, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders: myalgia.

General disorders: increased fatigue, malaise, asthenia, fever.

Children. The frequency and nature of adverse reactions and laboratory abnormalities are comparable to those in adults.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging. Capsules No. 1, No. 2, No. 3, No. 4, No. 7, No. 10 in a blister pack in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

22, Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.