Fluconazole

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

Composition:

Active substance: fluconazole;

1 tablet contains fluconazole 150 mg;

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

Pharmaceutical form. Film-coated tablets.

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

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Fluconazole, an antifungal agent of the triazole class, is a potent and selective inhibitor of fungal enzymes essential for ergosterol synthesis. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, which is 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 produce clinically significant effects on endogenous steroid levels or on the response to ACTH stimulation in healthy male volunteers.

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

In vitro susceptibility.

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

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

Mechanism of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo and clinical effectiveness. Cases of superinfection with Candida spp. other than C. albicans have been reported, which often show reduced susceptibility to fluconazole (e.g., C. glabrata) or are resistant to fluconazole (e.g., C. krusei and C. auris). Alternative antifungal agents may be required for the treatment of such cases.

Pharmacokinetics.

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

Absorption.

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

Distribution.

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

Fluconazole penetrates well into all studied body fluids. Fluconazole levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid reach 80% of plasma concentrations.

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

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

Biotransformation.

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

Excretion.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for once-daily dosing 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 elimination half-life increases from 30 hours to 98 hours. Therefore, dose adjustment is required for this patient group. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Elderly patients.

Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical characteristics.

Indications.

Acute vaginal candidiasis when topical therapy is not appropriate.

Candidal balanitis when topical therapy is not appropriate.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

Cisapride: cases of cardiac adverse reactions, including 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 cisapride plasma levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

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

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. This increase in astemizole plasma concentration may lead to QT interval prolongation and, in rare cases, 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 with pimozide or quinidine may result in inhibition of pimozide or quinidine metabolism. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, in rare cases, lead to 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 arrest. The use of this combination of medicinal products is contraindicated.

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

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

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

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

Effect of other medicinal products on fluconazole.

Concomitant intake of food, cimetidine, antacids, or whole-body irradiation prior to bone marrow transplantation does not have a clinically significant effect on the absorption of fluconazole following oral administration.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

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

Effect of fluconazole on other medicinal products.

Fluconazole is a potent inhibitor of the CYP2C9 isoenzyme of cytochrome P450 (CYP) and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of CYP2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when administered concomitantly with fluconazole. Therefore, such combinations should be used with caution; close monitoring of patients is necessary. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long elimination half-life.

Alfentanil: during concomitant administration of alfentanil at a dose of 20 mcg/kg and fluconazole at a dose of 400 mg, a twofold increase in AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and after 1 week. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in: a slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic A. fumigatus infection. The clinical significance of these findings is unknown.

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

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

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 carbamazepine serum 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: 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 halving of the celecoxib dose may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole increases serum bilirubin and creatinine levels. These drugs can be used concomitantly, considering the 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. In addition, fluconazole was shown to significantly slow 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 diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.

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

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. During concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These drugs can be used concomitantly provided the 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 the CYP3A4 enzyme and P-glycoprotein. These drugs can be used concomitantly provided the 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 the CYP3A4 enzyme 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 metabolism of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure in patients is recommended.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary during concomitant use with fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): during concomitant use 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) increased Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen by 15 % and 82 %, 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 for adverse reactions and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

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

Prednisone: a case has been reported in which a patient after liver transplantation developed acute adrenal insufficiency following discontinuation of a three-month course of fluconazole therapy while on prednisone. Discontinuation of fluconazole likely 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 discontinuation of fluconazole.

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

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

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

Theophylline: administration of 200 mg fluconazole for 14 days resulted in an 18 % decrease in the average plasma clearance of theophylline. Patients receiving high doses of 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 inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.

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

Voriconazole (inhibitor of CYP2C9 and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on Day 1, then 200 mg every 24 hours for 4 days) to male volunteers resulted in an average increase in Cmax and AUCτ of voriconazole by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is administered after fluconazole, monitoring for voriconazole-associated adverse effects is recommended.

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

Azithromycin: no significant pharmacokinetic interactions between the two have been identified.

Oral contraceptives: no effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily resulted in a 40 % increase in AUC of ethinylestradiol and a 24 % increase in levonorgestrel. This suggests that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor: concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3-fold and to hydroxymethylivacaftor (M1) by 1.9-fold. For patients receiving concomitant moderate CYP3A inhibitors such as fluconazole and erythromycin, a reduction in the ivacaftor dose to 150 mg once daily is recommended.

Special precautions for use.

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

Cryptococcosis. There is insufficient evidence of efficacy of fluconazole in the treatment of other forms of cryptococcosis (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, there are no recommendations regarding dosage regimens for treatment of these infections.

Deep endemic mycoses. There is insufficient evidence of efficacy of fluconazole in the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, there are no recommendations regarding dosage regimens for treatment of these infections.

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

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

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

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

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

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported during use of the drug. 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.

The drug should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated.

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

Skin reactions. Rarely, exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole therapy. Patients with AIDS are more susceptible 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 skin rash, careful monitoring is required, and fluconazole therapy should be discontinued in case of bullous eruptions or development of erythema multiforme.

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

Hypersensitivity. In rare cases, anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients receiving concomitant fluconazole and medicinal products with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

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

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

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

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

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

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg of fluconazole during the first trimester do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, first-trimester exposure to oral fluconazole was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1,000 women receiving a cumulative dose ≤450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1,000 women receiving cumulative doses exceeding 450 mg. The adjusted 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 exceeding 450 mg of fluconazole.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester found an increased risk of cardiac malformations by 1.8–2 times compared to those who did not receive fluconazole and/or used topical azoles.

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

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

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

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

Breastfeeding is not recommended during repeated administration of fluconazole or when high doses of fluconazole are used.

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

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

Method of administration and dosages.

The tablets should be swallowed whole. The administration of the drug is not dependent on food intake.

Adults.

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

Elderly patients.

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

Renal function impairment.

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

Hepatic function impairment.

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

Children.

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

Overdose.

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

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

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

Adverse reactions.

Blood and lymphatic system disorders: anaemia, agranulocytosis, leucopenia, neutropenia, thrombocytopenia.

Immune system disorders: anaphylaxis.

Metabolism and nutrition disorders: decreased appetite, hypertriglyceridaemia, hypercholesterolaemia, hypokalaemia.

Psychiatric disorders: insomnia, somnolence.

Nervous system disorders: headache, seizures, dizziness, paraesthesia, taste disturbance, tremor.

Ear and labyrinth disorders: vertigo.

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

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

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

Skin and subcutaneous tissue disorders: rash, pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic oedema, facial swelling, alopecia. There have been reports of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with fluconazole treatment (see section "Special precautions").

Musculoskeletal and connective tissue disorders: myalgia.

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

Children.

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

Shelf life. 3 years.

Storage conditions.

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

Packaging.

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

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

JSC "Tekhnolog".

Manufacturer's name and address of the place of business.

8 Staroproryzna Street, Uman, Cherkasy region, 20300, Ukraine.

INSTRUCTION

for medical use of medicinal product

FLUCONAZOLE

(FLUCONAZOLE)

Composition:

Active substance: fluconazole;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, film-coated tablets with convex upper and lower surfaces. When examined under a magnifying glass, the cross-section reveals a core surrounded by a single continuous layer.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Fluconazole, an antifungal agent of the triazole class, is a potent and selective inhibitor of fungal enzymes essential for ergosterol synthesis. Its primary mechanism of action is the inhibition of fungal 14 alpha-lanosterol demethylation mediated by cytochrome P450, an essential step in fungal ergosterol biosynthesis. Accumulation of 14 alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

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

Interaction studies with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole do not affect antipyrine metabolism.

In vitro susceptibility.

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

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

Mechanism of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo and clinical efficacy. Cases of superinfection with Candida spp. other than C. albicans have been reported, including species often exhibiting low susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei and C. auris) to fluconazole. Alternative antifungal agents may be required for treatment of such cases.

Pharmacokinetics.

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

Absorption.

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

Distribution.

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

Fluconazole penetrates well into all studied body fluids. Concentrations in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in cerebrospinal fluid reach 80% of plasma levels.

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

After 4 months of treatment with 150 mg once weekly, fluconazole concentration in nails was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after treatment completion.

Biotransformation.

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

Excretion.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.
The long plasma elimination half-life allows for single-dose administration in vaginal candidiasis and once-weekly dosing for other indications.

Renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 hours to 98 hours. Therefore, dose adjustment of fluconazole is required in these patients. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Elderly patients.

Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical characteristics.

Indications.

Treatment of the following diseases in adults:

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

Prevention of the following conditions in adults:

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

Children.

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

Fluconazole may be used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for the prevention of candidiasis infections in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it.

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

Cisapride: cases of cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients receiving fluconazole and cisapride concomitantly. Concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in cisapride plasma levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: cases of severe cardiac arrhythmias due to QTc interval prolongation have been reported in patients receiving azole antifungal agents concomitantly with terfenadine. When fluconazole was administered at a dose of 200 mg daily, no QTc prolongation was observed. Administration of fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increases terfenadine plasma levels when both drugs are administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated.

Pimozide and quinidine: concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin: concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, as a consequence, sudden cardiac arrest. The use of this combination of medicinal products is contraindicated.

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

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

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

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

Effect of other medicinal products on fluconazole.

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

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% shortening of the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the dose of fluconazole.

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

Effect of fluconazole on other medicinal products.

Fluconazole is a potent inhibitor of the CYP2C9 isoenzyme of cytochrome P450 (CYP) and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of CYP2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when administered concomitantly with fluconazole. Therefore, such combinations of drugs should be used with caution; careful monitoring of patients is required. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long elimination half-life.

Alfentanil: during concomitant administration of alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg, a twofold increase in AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. It is recommended to measure concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy and after 1 week. Dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent infected mice and immunocompromised infected mice resulted in the following: 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 the results obtained in these studies is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. 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 carefully monitored in patients receiving coumarin anticoagulants or indanediones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole at a dose of 200 mg/day and 0.25 mg triazolam orally resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam.

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

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

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

Celecoxib: concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. With concomitant use of celecoxib and fluconazole, a halving of the celecoxib dose may be necessary.

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

Fentanyl: one fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, fluconazole was shown to significantly slow fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful monitoring of the patient is required. Dose adjustment of fentanyl may be necessary.

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

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

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

Everolimus: fluconazole may increase serum everolimus concentration by inhibiting CYP3A4.

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

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

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

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary with concomitant use of methadone and fluconazole.

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

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

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

Prednisone: a case was reported in which a patient after liver transplantation developed acute adrenal insufficiency while receiving prednisone, occurring 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 fluconazole and prednisone concomitantly over a long period should be closely monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

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 using this combination of drugs.

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

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

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

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

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

Voriconazole (an 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 the first day, then 200 mg every 24 hours for 4 days) to male volunteers led to an average increase in Cmax and AUCτ of voriconazole by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

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

Azithromycin: no significant pharmacokinetic interactions between them were observed.

Oral contraceptives: when fluconazole was administered at a dose of 50 mg, no effect on hormone levels was observed, whereas administration of fluconazole at a dose of 200 mg daily resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. This indicates that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor: concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3-fold and to hydroxymethylivacaftor (M1) by 1.9-fold. For patients concomitantly receiving moderate CYP3A inhibitors such as fluconazole and erythromycin, a reduction in the dose of ivacaftor to 150 mg once daily is recommended.

Special precautions for use.

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

Cryptococcosis. There is insufficient evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, there are no recommendations regarding dosage regimens for the treatment of such infections.

Deep endemic mycoses. There is insufficient evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, there are no recommendations regarding dosage regimens for the treatment of such diseases.

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

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

Hepatobiliary system. The drug 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 diseases. In cases where hepatotoxicity developed in association with fluconazole use, there was no clear dependence on the total daily dose of the drug, 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 sought.

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

The drug should be used cautiously in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 cytochrome P450 enzyme is contraindicated.

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

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

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported.

Hypersensitivity. In rare cases, anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with medicinal products that have a narrow therapeutic window and are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

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

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

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

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

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

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

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

Data from several thousand pregnant women who received a cumulative dose of ≤150 mg fluconazole during the first trimester do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, first-trimester oral use of fluconazole was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving a cumulative dose ≤450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05–1.58) for 150 mg oral fluconazole 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 have yielded conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester revealed a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use and/or use of topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Congenital malformations observed in these children include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radiohumeral 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 the treatment of life-threatening infections.

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

Breastfeeding is not recommended during repeated administration of fluconazole or when high doses of fluconazole are used.

Ability to influence reaction speed when 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 daily dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose of the drug is sufficient.

If repeated administration is necessary, treatment of infections should be continued until clinical and laboratory signs of active fungal infection have disappeared. Inadequate duration of treatment may lead to recurrence of the active infection.

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

Tablets should be swallowed whole. The drug may be taken regardless of food intake.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg/day. 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/day for an indefinite duration.

Coccidioidomycosis.

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

Invasive candidiasis.

Loading dose is 800 mg on the first day. Maintenance dose – 400 mg/day. The recommended duration of treatment for candidemia is usually 2 weeks after the first negative blood culture results and resolution of signs and symptoms of candidemia.

Oropharyngeal candidiasis.

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

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

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

Prophylaxis of candidiasis in patients with prolonged neutropenia.

Recommended dose is 200–400 mg. Treatment should be initiated several days before anticipated onset of neutropenia and continued for 7 days after neutrophil count rises above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more episodes per year): recommended dose is 150 mg once 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 should be continued for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous candidiasis, tinea corporis, tinea cruris: recommended dose is 150 mg once weekly or 50 mg once daily. Treatment duration is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophytic onychomycosis: 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 depend on age. After successful treatment of chronic long-standing infections, nail appearance may remain altered.

Children.

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

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

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

Dosing in children with impaired renal function is described below. The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should determine whether the adult or pediatric dose is more appropriate for the patient. Children have higher fluconazole clearance compared to adults. Administration of 100, 200, and 400 mg doses in adults and 3, 6, and 12 mg/kg doses in children results in comparable systemic exposure.

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

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose – 3 mg/kg/day. The initial dose may be administered on the first day to achieve steady-state concentration more rapidly.

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

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

Prophylaxis of candidiasis in immunocompromised patients: drug dose is 3–12 mg/kg/day depending on severity and duration of induced neutropenia (see adult doses).

Elderly patients.

Dosage should be adjusted according to renal function (see below).

Patients with renal impairment.

Dose adjustment of fluconazole is not required for single-dose administration. For patients (including children) with impaired renal function requiring multiple-dose therapy, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the indication. Subsequently, the daily dose (depending on the indication) should be adjusted according to the table below:

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

Patients with hepatic impairment.

Fluconazole should be administered with caution to patients with hepatic impairment, as there is insufficient information regarding the use of fluconazole in this patient population.

Children.

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

Overdose.

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

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

Fluconazole is predominantly excreted in the urine; forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse Reactions.

Blood and lymphatic system disorders: anaemia, agranulocytosis, leucopenia, 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 ventricular tachycardia of the "torsades de pointes" type, QT interval prolongation.

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

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

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

Musculoskeletal and connective tissue disorders: myalgia.

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

Children.

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

Shelf life. 3 years.

Storage conditions.

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

Packaging.

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

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

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

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

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

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

Prescription category.

Prescription only.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and place of business.

8 Stara Prorizhna Street, City of Uman, Cherkasy Region, Ukraine, 20300.