Fluconazole-zdorovya

INSTRUCTIONS FOR MEDICAL USE|CONSUMPTION| OF THE MEDICINAL PRODUCT FLUCONAZOLE-ZDOROV'YA (FLUCONAZOLE-ZDOROVYE)

Composition:

Active substance: fluconazole;

1 capsule contains fluconazole 50 mg or 100 mg or 150 mg;

Excipients: lactose monohydrate; potato starch; povidone; calcium stearate; capsule shell contains 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) (all strengths), titanium dioxide (E 171), gelatin (50 mg strength) or titanium dioxide (E 171), erythrosine (E 127), quinoline yellow (E 104), gelatin (100 mg strength) or brilliant blue (E 133), quinoline yellow (E 104), sunset yellow FCF (E 110), titanium dioxide (E 171), gelatin (150 mg strength).

Medicinal form. Hard capsules.

Main physicochemical properties: hard gelatin capsules with opaque white-colored body and cap (50 mg strength) or yellow-colored (100 mg strength) or green-colored (150 mg strength). The company trademark – ZT – may be printed on the capsule. Contents of the capsules – white powder with yellowish tinge. Presence of powder particle agglomerates is acceptable.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02AC01.

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 in 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 of mammals.

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

A study of interaction 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). C. glabrata shows reduced susceptibility to fluconazole, whereas C. krusei and C. auris are resistant to it.

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

Pharmacokinetic/pharmacodynamic relationships. Based on animal studies, there is a correlation between 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 not fully sufficient, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis, and to a lesser extent, candidemia. Similarly, treatment of infections caused by strains with high minimum inhibitory concentrations to fluconazole is less effective.

Mechanism of resistance. Candida species possess 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 affects its efficacy in vivo and in clinical practice. Cases of superinfection with Candida spp. other than C. albicans have been reported, often involving species with reduced susceptibility (C. glabrata) or resistance to fluconazole (e.g., C. krusei, C. auris). Alternative antifungal agents should be used for the treatment of such infections.

Breakpoints (according to the recommendations of the European Committee on Antimicrobial Susceptibility Testing).

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole against Candida species have been established. These have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic information and not dependent on species-specific minimum inhibitory concentration distributions, and species-specific breakpoints, most commonly associated with human infections. These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints S ≤ / R >					Non-species-related breakpoints a 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 established based on pharmacokinetic/pharmacodynamic data and do not depend on the species-specific distribution of minimum inhibitory concentrations. These were studied only in microorganisms lacking a species-specific breakpoint;

-- 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, and plasma concentrations 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 dosing on an empty stomach. Drug plasma concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of treatment with once-daily dosing. A steady-state concentration of 90% is reached 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. 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 fluconazole concentrations exceeding serum levels are achieved in the skin, specifically in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum.

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

Excretion. The plasma half-life (T½) 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, as well as 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, dose reduction is required in this patient population. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Lactation. Fluconazole passes into breast milk.

Children. After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer 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 for use");
• coccidioidomycosis (see section "Special precautions for use");
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic mucocutaneous candidiasis;
• chronic atrophic candidiasis (denture-related stomatitis) when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is inappropriate;
• candidal balanitis, when topical therapy is inappropriate;
• dermatomycoses, including tinea pedis, 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 safely swallow capsules, which is generally possible from the age of 5 years.

The drug is indicated for use 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 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 obtaining results of culture and other laboratory tests. After results are available, 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/day or higher. Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin).

Interaction with other medicinal products and other types of interactions.

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

Cisapride: cases of cardiac adverse reactions, including torsade de pointes ventricular tachycardia, 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 plasma terfenadine levels when 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. This increase in plasma astemizole concentration may lead to QT interval prolongation and, rarely, to torsade de pointes ventricular tachycardia. 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, torsade de pointes ventricular tachycardia. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin: concomitant use of erythromycin and fluconazole increases the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia), potentially resulting in sudden cardiac death. Concomitant use of these 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 increases the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia), potentially resulting in 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. No clinically significant effect on fluconazole absorption after oral administration has been observed with concomitant food intake, 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 the half-life (T½) of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide: repeated concomitant administration of hydrochlorothiazide to healthy volunteers receiving fluconazole increased fluconazole plasma concentration by 40 %. These 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 moderate inhibitor of CYP2C9 and CYP3A4. Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme. In addition to documented and described interactions listed below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution; close monitoring of patients is required. Due to the long half-life of fluconazole, its inhibitory effect on enzymes persists for 4–5 days.

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

Amitriptyline, nortriptyline: fluconazole enhances the effects of amitriptyline and nortriptyline. Measurement of plasma concentrations of 5-nortriptyline and/or S-amitriptyline 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 immunocompetent and immunocompromised infected mice showed: 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 findings is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported with concomitant use of fluconazole and warfarin, associated with prolonged prothrombin time. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely 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 midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in AUC and T½, respectively. Administration of fluconazole 200 mg/day and oral triazolam 0.25 mg resulted in a 4.4-fold and 2.3-fold increase in AUC and T½, respectively. Potentiation and prolongation of triazolam effects were observed with 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 effects.

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

Celecoxib: concomitant use 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 increases serum bilirubin and creatinine levels. These drugs may be used concomitantly, but the risk of increased serum bilirubin and creatinine levels should be considered.

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, close monitoring of the patient is required. Dose adjustment of fentanyl may be necessary.

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

Olaparib: moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentrations; 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. Concomitant use 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 reduced based 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 CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted based on concentration and clinical 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 based on tacrolimus concentration.

Losartan: fluconazole inhibits the conversion of losartan to its active metabolite (E-31 74). 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): concomitant use with fluconazole increased Cmax and AUC of flurbiprofen by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, concomitant use 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.

Fluconazole potentially increases 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 phenytoin metabolism. Repeated 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 has been reported in a liver transplant patient receiving prednisone, which developed after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely enhanced CYP3A4 activity, leading to 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, increasing rifabutin AUC by up to 80 %. Uveitis has been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this drug combination.

Saquinavir: fluconazole increases saquinavir AUC and Cmax by approximately 50 % and 55 %, respectively, due to inhibition of hepatic saquinavir metabolism 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: 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 dose should be reduced accordingly when used concomitantly with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days reduced the average plasma theophylline clearance by 18 %. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity appear.

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

Vinca alkaloids: 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 of central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri was reported in a patient receiving all-trans retinoic acid (vitamin A acid form) and fluconazole concomitantly, which resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in voriconazole Cmax and AUCτ 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 used 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 by approximately 45 % after oral administration. Zidovudine half-life was also prolonged by approximately 128 % after concomitant administration of fluconazole and zidovudine. Patients receiving this drug combination should be monitored for zidovudine-related adverse reactions. Consideration may be given to reducing the zidovudine dose.

Azithromycin: no significant pharmacokinetic interactions were observed after single oral doses of azithromycin 1200 mg and fluconazole 800 mg.

Oral contraceptives: no effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily increased AUC of ethinylestradiol by 40 % and levonorgestrel by 24 %. 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 by 3-fold and hydroxymethylivacaftor (M1) by 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.

Special precautions for use.

Dermatophytosis. It is known that when fluconazole is used to treat dermatophytosis in children, it 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 for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be made for treating these conditions.

Deep endemic mycoses. There is insufficient evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, no dosage recommendations can be made for treating these conditions.

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 prior therapy fails. Therefore, physicians prescribing treatment should consider the prevalence of fluconazole resistance among various Candida species.

Renal system. Fluconazole should be administered 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 occur with fluconazole, although rarely. Adrenal insufficiency associated with concomitant prednisone therapy is described in the section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products."

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

Patients who develop 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 sought.

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

Dermatological reactions. Exfoliative skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) have been rarely reported during fluconazole use. Patients with AIDS are more susceptible to developing severe skin reactions when taking various medicinal products. If a patient with a 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 an invasive/systemic fungal infection develops a skin rash, close 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. Anaphylactic reactions have been reported in rare cases.

CYP enzymes. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of CYP2C19. Patients receiving fluconazole concomitantly with medicinal products that have a narrow therapeutic index and are metabolized by CYP2C9, CYP2C19, or CYP3A4 should be closely monitored.

Terfenadine. Close monitoring of patients is required when terfenadine is used concomitantly with fluconazole at doses below 400 mg per day.

The product contains lactose. If the patient has a known 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 half-lives) should be observed before conception (see section "Pharmacokinetics").

For longer treatment courses, women of childbearing potential should consider using 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 congenital 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 cumulative doses above 450 mg. The relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg dose of oral fluconazole and 1.98 (95% CI 1.23–3.17) for doses above 450 mg.

Available epidemiological studies on cardiac malformations associated with 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, 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 describe congenital malformations 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. Congenital malformations 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 of fluconazole and short-term treatment courses 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 life-threatening infections.

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma. Breastfeeding may continue after a single standard dose of fluconazole (200 mg or less).

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

Fertility.

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

Ability to influence 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.

Dosage and Administration.

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

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 should be continued until clinical and laboratory signs of fungal infection have resolved. Inadequate duration of treatment may lead to recurrence of active infection.

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. 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 once daily for an indefinite duration.

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 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. The maintenance dose is 400 mg once daily. The recommended duration of treatment for candidemia is usually 2 weeks after obtaining negative blood cultures and resolution of signs and symptoms of candidemia.

Oral candidiasis.

• 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 prolonged.
• 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 recurrent mucosal candidiasis in HIV-infected patients at high risk of developing the infection.

• 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 immunocompromised patients.

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

Dermatomycoses.

• Tinea pedis, cutaneous candidiasis, tinea cruris, superficial fungal infections: 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.
• Dermatophyte onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued 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 depends on age. After successful treatment of chronic long-term infections, nail appearance may remain altered.

Children. The drug in capsule form may be administered to children only when they are able to swallow the capsule, usually from 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 recommendations for children with impaired renal function are provided below. Fluconazole pharmacokinetics have not been studied in children with renal insufficiency.

Children aged 12 years and older. Considering the child's body weight and pubertal development, the physician should evaluate which dosage (adult or pediatric) is optimal for the patient. Clinical data indicate that fluconazole clearance is higher in children than in adults. Comparable systemic exposure is achieved with doses of 100, 200, and 400 mg in adults and 3, 6, and 12 mg/kg in children.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. If there is a compelling 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 to prevent recurrence of cryptococcal meningitis in children at high risk: the dose is 6 mg/kg once daily, depending on disease severity.

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 dosing).

Elderly patients. Dose selection should be based on renal function (see below).

Patients with renal impairment. Fluconazole is primarily excreted unchanged in urine. No dose adjustment is 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 therapeutic indications. Subsequently, the daily dose (depending on indication) should be adjusted according to the table below:

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

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

Children.

The drug in capsule form may be administered to children once they are able to swallow capsules, usually from the age of 5 years.

Overdose.

Symptoms: hallucinations and paranoid behavior.

Treatment: symptomatic (including gastric lavage and supportive therapy). Fluconazole is primarily excreted in urine; therefore, forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse reactions

The most frequently reported adverse reactions (>1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels in blood, 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, paresthesia, taste disturbances, tremor.

Ear and labyrinth disorders: vertigo.

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

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

Hepatobiliary disorders: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase levels, 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, hyperhidrosis, 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 observed in adults.

Shelf life. 5 years.

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

Keep out of reach of children.

Packaging. Capsules 50 mg or 100 mg, pack of 7, 10 in a blister pack in a box; or 150 mg, pack of 1×2, 1×3, 3, 7 in a blister pack in a box.

Prescription category. Prescription only.

Manufacturer: LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

LIMITED LIABILITY COMPANY "FARMEKS GROUP".

Manufacturer's address and place of business: Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(LIMITED LIABILITY COMPANY "FARMEKS GROUP")