Fluconazole-darnitsa: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE-DARNITSA (Fluconazole-DARNITSA)

Composition:

Active substance: fluconazole;

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

Excipients: potato starch, lactose monohydrate, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate, gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules with white body and cap. The capsule contents are white or almost white powder.

Pharmacotherapeutic group.

Antifungal agents for systemic use. Triazole derivatives.

ATC Code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Fluconazole, an antifungal agent of the triazole class, is a potent and selective inhibitor of fungal enzymes essential for ergosterol synthesis. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation mediated by cytochrome P450, 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 of mammals.

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

C. glabrata exhibits a wide range of susceptibility to fluconazole, whereas C. krusei is resistant to it. Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic molds Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetics.

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

Distribution. The volume of distribution is approximately equal to total body water content. 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 drug concentrations. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid reach 80% of plasma concentrations.

High fluconazole concentrations exceeding serum levels are achieved in the stratum corneum, epidermis, dermis, sweat, and skin. Fluconazole accumulates in the stratum corneum.

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

Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent 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 elimination half-life of the drug from plasma allows for single-dose administration in vaginal candidiasis, as well as once-weekly dosing for other indications.

Pharmacokinetics in special patient populations.

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, this patient group requires a reduced dose of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Geriatric patients.

Pharmacokinetic changes in elderly patients appear to depend on renal function parameters.

Clinical characteristics.

Indications.

Adults.

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

Prophylaxis: prevention of recurrence of cryptococcal meningitis in patients at high risk of recurrence; prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of recurrence;

to reduce the frequency of recurrent vaginal candidiasis (4 or more episodes per year); prophylaxis of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy, or patients undergoing hematopoietic stem cell transplantation).

Children.

Treatment: cryptococcal meningitis; mucosal candidiasis; invasive candidiasis.

Prophylaxis: prevention of candidiasis in immunocompromised patients.

The medicinal product may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of recurrence.

Treatment with the medicinal product may be initiated before the results of culture and other laboratory tests are available; antibacterial therapy should be adjusted accordingly once results are obtained.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

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

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies were conducted. In one study, administration of fluconazole at a dose of 200 mg/day did not result in QTc interval prolongation. Another study using fluconazole doses of 400 mg and 800 mg/day showed that administration of fluconazole at doses of 400 mg/day or higher significantly increased plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg/day concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant administration 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 (see section "Contraindications").

Pimozide and quinidine: concomitant administration of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although appropriate in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to the development of paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

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

Concomitant administration 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 lead to cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsades de pointes" type) and, as a consequence, sudden cardiac death. The use of this combination should be avoided (see section "Special warnings and precautions for use").

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

Amiodarone: concomitant administration of fluconazole and amiodarone may lead to QT interval prolongation. Fluconazole should be used with caution concomitantly with amiodarone, especially when high-dose fluconazole (800 mg) is prescribed.

Effect of other medicinal products on fluconazole.

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

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

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

Effect of fluconazole on other medicinal products.

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

Abrocitinib: fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155%. When administered concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to the abrocitinib product information.

Alfentanil: during concomitant administration of alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in AUC was observed, possibly due to CYP3A4 inhibition. 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 administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice showed the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these study results 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 administration of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant administration of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be carefully monitored in patients receiving coumarin anticoagulants or indanediones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Careful patient monitoring and reduction of benzodiazepine dose are recommended when these medicinal products are used concomitantly. Concomitant administration of fluconazole 200 mg and oral midazolam 7.5 mg resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole 200 mg/day and 0.25 mg oral triazolam 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 during concomitant administration of fluconazole and triazolam. If benzodiazepines must be administered concomitantly with fluconazole, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and causes a 30% increase in carbamazepine serum levels. 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. 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. When celecoxib is used concomitantly with fluconazole, a 50% reduction in celecoxib dose may be necessary.

Cyclophosphamide: concomitant administration of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. The combination may be used with increased attention to the risk of elevated serum bilirubin and creatinine levels.

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

Increased plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) lead to neurotoxic effects. Elevated levels of tacrolimus are associated with nephrotoxicity. These combinations should be used with caution, with careful patient monitoring. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long elimination half-life. Interactions between fluconazole and the combination of saquinavir/ritonavir have not been studied and may be more pronounced.

HMG-CoA reductase inhibitors: concomitant administration of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin (reduced hepatic metabolism of statin)), increases the risk of myopathy and rhabdomyolysis (dose-dependent). If concomitant administration of these agents is necessary, careful monitoring for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels are required. If significant elevation of creatine kinase levels occurs, or if myopathy/rhabdomyolysis is diagnosed or suspected, administration of HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be necessary as specified in the statin product information.

Ibrutinib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of ibrutinib and may increase the risk of toxicity. If combination cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily (2 capsules) to allow continued use of the inhibitor with continuous clinical monitoring.

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class): concomitant administration of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased exposure to ivacaftor by 3-fold and exposure to hydroxymethylivacaftor (M1) by 1.9-fold. Dose reduction of ivacaftor (as monotherapy or in combination) is required as specified in the ivacaftor product information (as monotherapy or in combination); a reduction of ivacaftor dose to 150 mg once daily is recommended.

Olaparib: moderate CYP3A4 inhibitors such as fluconazole increase plasma concentrations of olaparib; their concomitant use is not recommended. If such 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. During concomitant administration of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These agents may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus: although in vitro and in vivo studies have not been conducted, it is known that 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 agents may be used concomitantly provided sirolimus dose is adjusted based 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 CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced based on tacrolimus concentration.

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

Lurasidone: moderate CYP3A4 inhibitors such as fluconazole may increase lurasidone plasma concentration. If concomitant administration cannot be avoided, the lurasidone dose should be reduced as specified in the lurasidone product information.

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

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

Although specific studies have not been conducted, fluconazole may 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 NSAID use 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 phenytoin AUC24 by 75% and Cmin by 128%. Monitoring of phenytoin serum concentration is required during concomitant use to avoid phenytoin toxicity.

Prednisone: a case has been reported in which a patient after liver transplantation developed acute adrenal insufficiency while receiving prednisone, following discontinuation of a 3-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 for prolonged periods should be carefully monitored to prevent adrenal insufficiency after fluconazole discontinuation.

Rifabutin: fluconazole increases rifabutin serum concentration, leading to up to an 80% increase in rifabutin AUC. Uveitis has been reported during concomitant administration 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 saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose levels and appropriate dose reduction of sulfonylurea derivatives are recommended during concomitant administration with fluconazole.

Theophylline: in a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days resulted in an 18% reduction in the average plasma clearance of theophylline. 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 when administered concomitantly with medicinal products that cause moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the dose of tofacitinib to 5 mg once daily when used in combination with these agents.

Tolvaptan: exposure to tolvaptan significantly increased (200% AUC, 80% Cmax) when tolvaptan, a CYP3A4 substrate, was administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor. This significantly increased the risk of adverse reactions, including marked diuresis, dehydration, and acute renal failure. If co-administered, the dose of

tolvaptan should be reduced according to instructions in the tolvaptan product information, and the patient should be regularly checked for any adverse reactions related to tolvaptan.

Vinca alkaloids: although appropriate studies have not been conducted, fluconazole, likely through inhibition of CYP3A4, may cause increased plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: adverse reactions from the central nervous system (CNS), in the form of pseudotumor cerebri, have been reported in a patient who concurrently received all-trans retinoic acid (acid form of vitamin A) and fluconazole, which resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be kept in mind.

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

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a reduction in zidovudine clearance of approximately 45% with 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 adverse reactions associated with zidovudine. Consideration may be given to reducing the zidovudine dose.

Azithromycin: in an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effect of azithromycin and fluconazole on each other's pharmacokinetics was evaluated after single oral doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives: two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives were conducted. 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/day 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.

Special precautions for use.

Insufficient duration of treatment may lead to recurrence of the active infectious process.

Dermatophytosis. * According to the results of studies on fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, and the overall efficacy rate is less than 20%. Therefore, the medicinal product Fluconazole-Darnitsia should not be used for the treatment of dermatophytosis.
Cryptococcosis. * Evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, there are no recommendations regarding dosage regimens for the treatment of such conditions.
Deep endemic mycoses. * Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, there are no recommendations regarding dosage regimens for the treatment of such conditions.
Urinary system. * The drug 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 apply to fluconazole, although it is rarely observed. 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. * The drug 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 associated with fluconazole use, no clear dependence on the 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 in whom abnormal liver function test results occur during fluconazole treatment should be closely monitored for the development of more severe liver damage.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole treatment should be discontinued immediately, and medical advice should be 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 due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported during the use of Fluconazole-Darnitsia. These reports involved patients with severe underlying diseases and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and progressive heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

The medicinal product Fluconazole-Darnitsia 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 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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 (see section "Interaction with other medicinal products and other forms of interaction").
Dermatological reactions. * Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has also been reported. Patients with AIDS are more prone to developing severe skin reactions when using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.
Hypersensitivity. * In rare cases, anaphylactic reactions have been reported (see section "Contraindications").
Cytochrome P450. * Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a potent inhibitor of the CYP2C19 enzyme. Patients receiving Fluconazole-Darnitsia concomitantly with medicinal products having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").
Terfenadine. * Close monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at doses less than 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Candidiasis. * Studies have demonstrated an increased prevalence of infections caused by Candida species other than C. albicans. These are often intrinsically resistant (e.g., C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after failed treatment. Therefore, prescribers are advised to consider the prevalence of resistance of various Candida species to fluconazole.
Excipients. * The drug contains lactose. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

One capsule of Fluconazole contains less than 1 mmol of sodium (23 mg); therefore, the drug can be considered sodium-free.

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, the elimination period of fluconazole, which is approximately 1 week (corresponding to 5–6 half-lives), should be observed before conception (see section "Pharmacokinetics").

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

Pregnancy. *

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

Data from several thousand pregnant women who received fluconazole treatment with a cumulative dose ≤ 150 mg in the first trimester show no increase in the overall risk of fetal malformations. In one large observational cohort study, oral use of fluconazole in the first trimester was associated with a slight increase in the risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women who received cumulative doses ≤ 450 mg, compared to women who received topical azoles, and approximately 4 additional cases per 1000 women who received cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a 150 mg dose of fluconazole orally and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the development of heart defects 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 revealed an 1.8–2-fold increased risk of congenital heart defects in infants compared to infants of mothers who did not use fluconazole and/or used topical azoles.

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

Standard doses of fluconazole and short-term fluconazole treatment courses should not be used during pregnancy except in cases of extreme necessity.

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

Breastfeeding. *

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of fluconazole (150 mg). Breastfeeding is not recommended with repeated administration of fluconazole or with high-dose fluconazole. The benefit of breastfeeding for the child's development and health, the mother's clinical need for Fluconazole-Darnitsia, and any potential adverse effects of Fluconazole-Darnitsia or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Fertility. *

Fluconazole did not affect 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 with the medicinal product. If such symptoms occur, driving or operating machinery is not recommended.

Administration and Dosage.

The dosage of the medicinal product depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose is sufficient.

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

Fluconazole-Darnitsya is administered depending on the dosage form either orally (capsules) or intravenously by infusion (infusion solution). The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching from oral to intravenous administration or vice versa.

Capsules 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 once daily. The duration of treatment is usually at least 6–8 weeks. In life-threatening infections, the daily dose may be increased up to 800 mg.
Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: the recommended dose is 200 mg once daily for an indefinite period.

Coccidioidomycosis

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

Invasive Candidiasis

Loading dose is 800 mg on the first day. Maintenance dose – 400 mg once daily. 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 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: recommended dose is 200–400 mg once daily for 7–21 days. For patients with severe immunodeficiency, the duration of treatment may be extended.
Chronic atrophic candidiasis: recommended dose is 50 mg once daily for 14 days.
Chronic cutaneous and mucosal candidiasis: 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 immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV-infected patients at high risk of developing it

Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg once daily or 200 mg three times weekly. The duration of treatment is indefinite in immunocompromised patients.

Prophylaxis of Candida infections in patients with prolonged neutropenia

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: recommended dose is 150 mg as a single 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, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses

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

Elderly patients.

Dosage should be adjusted according to renal function (see "Patients with Renal Impairment" below).

Patients with Renal Impairment.

Fluconazole is predominantly excreted unchanged in urine. Dose adjustment is not required for single-dose administration. For patients (including children) with impaired renal function requiring multiple dosing, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the indication.

Afterwards, the daily dose (depending on the indication) should be calculated according to the recommendations in the table below:

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

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

Patients with hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction, as there is insufficient data on the use of fluconazole in this patient population (see sections "Special precautions for use" and "Adverse reactions").

Children.

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

As with similar infections in adults, the duration of treatment depends on clinical and mycological response. Fluconazole-Darnytsia is administered once daily.

Dosage recommendations for children with renal impairment are provided in the subsection "Patients with renal impairment".

The pharmacokinetics of fluconazole have not been studied in children with renal impairment.

Children aged 12 years and older.

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

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established. Available information is presented in the section "Adverse reactions." If there is a compelling need to use the drug in children 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 is 3 mg/kg/day. The initial dose may be administered on the first day to achieve steady-state concentrations more rapidly.

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

Prophylaxis of candidiasis in immunocompromised patients: dosage is 3–12 mg/kg once daily, depending on the severity and duration of induced neutropenia (see adult dosing recommendations).

Children.

The capsule formulation may be used in this patient population only when children are able to safely swallow capsules, which is generally possible at the age of 5 years and older.

Overdose.

Cases of fluconazole overdose have been reported, resulting in hallucinations and paranoid behavior.

Treatment: symptomatic and supportive therapy; gastric lavage may be performed if necessary. Fluconazole is predominantly excreted in urine, so forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Side effects

The most commonly reported (> 1/10) adverse reactions were: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in blood, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with fluconazole treatment (see section "Special precautions").

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

From the ear and vestibular system side:

Uncommon: vertigo.

From the gastrointestinal tract side:

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

From the liver and biliary system side:

Common: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase.

Uncommon: cholestasis, jaundice, increased plasma bilirubin levels.

Rare: liver failure, hepatocellular necrosis, hepatitis, hepatocellular injury.

From the metabolism and nutritional disorders side:

Uncommon: decreased appetite.

Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

From the nervous system side:

Common: headache.

Uncommon: seizures, dizziness, paresthesia, taste disturbances.

Rare: tremor.

From the psychiatric side:

Uncommon: insomnia, somnolence.

From the cardiac side:

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

From the blood and lymphatic system side:

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

From the immune system side:

Rare: anaphylaxis, bronchospasm.

From the skin and subcutaneous tissue side:

hypersensitivity reactions, including:

Common: rash.

Uncommon: pruritus, hyperemia, drug dermatitis, urticaria, increased sweating.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, anaphylactic shock, alopecia.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

From the musculoskeletal and connective tissue side:

Uncommon: myalgia.

General disorders:

Uncommon: increased fatigue, malaise, asthenia, fever.

Children.

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Capsules 50 mg or 100 mg: 10 capsules in a blister pack; 1 blister pack in a carton.

Capsules 150 mg: 1 capsule in a blister pack; 2 or 3 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity.

13 Borispilska Street, Kyiv, 02093, Ukraine.