Fluzamed

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

Composition:

active substance: fluconazole;

1 capsule contains fluconazole 150 mg;

excipients: microcrystalline cellulose; lactose monohydrate; magnesium stearate; sodium lauryl sulfate; gelatin capsule: iron oxide black (E 172), iron oxide yellow (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Basic physicochemical properties: hard gelatin capsules, size № 1, cap and body of dull light-green color, containing powder from white to almost white.

Pharmacotherapeutic group

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation mediated by cytochrome P450, 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 daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not produce clinically significant effects on endogenous steroid levels or on the response to adrenocorticotropic hormone stimulation in healthy male volunteers.

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

In vitro susceptibility

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant. Minimal inhibitory concentrations and epidemiological cut-off values (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those for C. albicans.

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

Relationship between pharmacokinetic and pharmacodynamic properties

According to animal studies, there is a correlation between the minimal inhibitory concentration and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between the area under the concentration–time curve (AUC) and the dose of fluconazole (approximately 1:1). There is also a direct, but suboptimal, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains with high minimal inhibitory concentrations to fluconazole is less satisfactory.

Mechanism of resistance

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimal inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts efficacy in vivo and in clinical practice.

In normally susceptible Candida species, the most common resistance mechanism involves the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Cases of superinfection with non-albicans Candida species, often showing reduced susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole, have been reported. Alternative antifungal agents should be used for the treatment of such cases. Resistance mechanisms are not yet fully understood in some intrinsically resistant species (e.g., C. krusei) or emerging species (e.g., C. auris).

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (Supporting Information Document for Fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective 04.02.2020).

These breakpoints have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific minimal inhibitory concentration distributions, and species-related breakpoints, associated with species most commonly causing human infections. These breakpoints are listed below.

S = sensitive;

R = resistant;

a – breakpoints not linked to a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic data and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms for which no species-specific breakpoint exists;

-- susceptibility testing is not recommended, as this species is not a target for antimicrobial therapy;

* All C. glabrata isolates fall within the I category. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S. I – intermediate: a microorganism is categorized as "intermediate" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or increasing drug concentration at the site of infection.

Pharmacokinetics

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

Absorption

Fluconazole is well absorbed after oral administration, and plasma fluconazole levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect the absorption of fluconazole when administered orally. Peak plasma concentration (Cmax) is reached within 0.5–1.5 hours after oral administration of fluconazole on an empty stomach. Plasma fluconazole concentration is proportional to the dose. Steady-state 90% concentration is achieved by day 4–5 of treatment with fluconazole when administered repeatedly once daily. A 90% steady-state concentration is reached by day 2 when a loading dose twice the standard daily dose is administered on the first day.

Distribution

The volume of distribution approximates 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 concentrations in cerebrospinal fluid reach 80% of plasma levels.

High fluconazole concentrations exceeding plasma levels are achieved in the skin, particularly 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 after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration remained at 5.8 µg/g. After administration of a 150 mg dose once weekly, 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 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 completion of therapy.

Metabolism

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

Elimination

The plasma elimination half-life (t1/2) is approximately 30 hours. The majority of fluconazole 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 detected.

The prolonged t1/2 allows for single-dose administration of fluconazole in vaginal candidiasis and once-weekly dosing for other indications.

Use in patients with renal impairment

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), t1/2 increases from 30 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%.

Use during breastfeeding

Plasma and breast milk fluconazole concentrations were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving 10 lactating women who temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at a mean concentration of approximately 98% of maternal plasma levels. The mean Cmax in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily fluconazole dose received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on the mean Cmax in milk of 0.39 mg/kg/day, amounts to approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Use in children

Pharmacokinetic data were evaluated in 113 children across 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 study in preterm neonates.

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma t1/2 of fluconazole ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer t1/2 of approximately 24 hours was observed after single-dose administration. This parameter is comparable to the t1/2 of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 preterm infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole at a dose of 6 mg/kg were administered every 72 hours. The mean t1/2 was 74 hours (44–185) on day 1, then decreased to 53 hours (30–131) on day 7 and to 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7 and to 1328 (1040–1680) on day 13.

Use in elderly patients

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean t1/2 was 46.2 hours. These pharmacokinetic parameters are higher compared to those in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Creatinine clearance (74 mL/min), percentage of fluconazole excreted unchanged in urine (22% over 0–24 hours), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were also lower than in younger volunteers. Therefore, the observed changes in pharmacokinetics in elderly patients are likely dependent on renal function parameters.

Clinical characteristics

Indications

FluzaMed is indicated for the treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

• Acute vaginal candidiasis, when topical therapy is not appropriate;
• Candidal balanitis, when topical therapy is not appropriate.

Treatment with the medicinal product may be initiated before obtaining results of culture and other laboratory investigations; however, after laboratory results are available, antifungal therapy should be adjusted accordingly.

Official recommendations regarding appropriate use of antifungal agents should be taken into account.

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 per 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 (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction

Concomitant administration of fluconazole and the following medicinal products is contraindicated

Cisapride

Cases of cardiac adverse reactions, including torsade de pointes ventricular tachycardia, have been reported in patients receiving fluconazole and cisapride concomitantly. 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 cisapride levels and QT interval prolongation. Concomitant use of these agents is contraindicated (see section "Contraindications").

Terfenadine

Due to cases of severe cardiac arrhythmia caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies were conducted. One study using fluconazole 200 mg daily showed no QTc prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that co-administration of fluconazole at doses of 400 mg daily or higher significantly increases plasma terfenadine levels. Concomitant administration 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 administration with fluconazole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to torsade de pointes ventricular tachycardia. Concomitant use of these agents is contraindicated (see section "Contraindications").

Pimozide and quinidine

Concomitant administration with fluconazole 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 torsade de pointes ventricular tachycardia. Concomitant use of these agents is contraindicated (see section "Contraindications").

Erythromycin

Concomitant administration of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia) and, consequently, sudden cardiac death. Concomitant use of these agents is contraindicated (see section "Contraindications").

Concomitant administration of fluconazole and the following medicinal products is not recommended

Halofantrine

Concomitant administration of fluconazole and halofantrine may lead to increased halofantrine plasma concentrations due to inhibition of CYP3A4. The resulting increase in halofantrine plasma concentration may increase the risk of cardiotoxicity (QT interval prolongation, torsade de pointes ventricular tachycardia) and, consequently, sudden cardiac death. Concomitant use of these agents should be avoided (see section "Special 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. Concomitant use of these agents requires caution, especially when high-dose fluconazole (800 mg) is administered.

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

Effect of other medicinal products on fluconazole

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

Rifampicin

Concomitant administration with rifampicin resulted in a 25% decrease in AUC and a 20% reduction in t1/2 of fluconazole. When these agents are used concomitantly, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide

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

Effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to observed/documentarily confirmed 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 agents should be used concomitantly with fluconazole with caution, and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long t1/2 (see section "Contraindications").

Alfentanil

Concomitant administration of alfentanil (20 mcg/kg) to healthy volunteers resulted in a doubling of AUC10 of fluconazole (400 mg), possibly due to CYP3A4 inhibition. Dose adjustment of alfentanil may be necessary when these agents are used concomitantly.

Abrocitinib

Concomitant administration with fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increases exposure to the active moiety of abrocitinib by 155%. When these agents are used concomitantly, the dose of abrocitinib should be reduced according to the instructions for medical use.

Amitriptyline, nortriptyline

Concomitant administration with fluconazole resulted in enhanced effects of amitriptyline or nortriptyline. When these agents are used concomitantly, 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 of these agents 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 with concomitant administration of fluconazole and warfarin. A twofold increase in prothrombin time was observed with concomitant administration of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. When fluconazole is used concomitantly with coumarin anticoagulants or indanedione, prothrombin time should be closely monitored. Dose adjustment of anticoagulants may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam

Concomitant administration with fluconazole resulted in significantly increased plasma concentrations of oral midazolam and enhanced psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in 3.7- and 2.2-fold increases in AUC and t1/2 of midazolam, respectively. Concomitant administration of fluconazole 200 mg daily and triazolam 0.25 mg orally resulted in 4.4- and 2.3-fold increases in AUC and t1/2 of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant administration of fluconazole and triazolam. When fluconazole is used concomitantly with benzodiazepines, the benzodiazepine dose should be reduced and appropriate patient monitoring established.

Carbamazepine

Concomitant administration with fluconazole inhibits carbamazepine metabolism and increases plasma carbamazepine levels by 30%. There is a risk of carbamazepine toxicity. When these agents are used concomitantly, dose adjustment of carbamazepine may be necessary depending on its concentration and effects.

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 when these agents are used concomitantly.

Celecoxib

Concomitant administration with fluconazole (200 mg daily) increased Cmax and AUC of celecoxib (200 mg) by 68% and 134%, respectively. When these agents are used concomitantly, a two-fold reduction in celecoxib dose may be necessary.

Cyclophosphamide

Concomitant administration of cyclophosphamide and fluconazole leads to increased plasma bilirubin and creatinine levels. These agents may be used concomitantly, considering the risk of increased plasma 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, a study in healthy volunteers demonstrated that concomitant administration with fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression. Close monitoring of the patient is required when these agents are used concomitantly. Dose adjustment of fentanyl may be necessary.

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). When concomitant use of these agents is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels in plasma should be monitored. If significant creatine kinase elevation occurs, or myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be necessary, as indicated in the instructions for medical use of statins.

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class):

Concomitant administration with fluconazole increases exposure to ivacaftor (cystic fibrosis transmembrane conductance regulator potentiator) by 3 times and to hydroxymethylivacaftor (M1) by 1.9 times. Dose reduction of ivacaftor (as monotherapy or in combination) is required, as specified in the instructions for medical use of ivacaftor (as monotherapy or in combination).

Ibrutinib

Concomitant administration with moderate CYP3A4 inhibitors, such as fluconazole, increases ibrutinib plasma concentration and may increase the risk of toxicity. If such combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily to continue inhibitor use, and continuous clinical monitoring should be ensured.

Olaparib

Concomitant administration with moderate CYP3A4 inhibitors, such as fluconazole, increases olaparib plasma concentrations. Concomitant use of these agents 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

Concomitant administration with fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole 200 mg daily and cyclosporine 2.7 mg/kg/day are taken concomitantly, an 1.8-fold increase in cyclosporine AUC was observed. These agents may be used concomitantly provided cyclosporine dose is reduced depending on its concentration.

Everolimus

Although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase everolimus plasma concentration through CYP3A4 inhibition.

Sirolimus

Concomitant administration with fluconazole increases sirolimus plasma concentration, likely through inhibition of sirolimus metabolism by CYP3A4 and P-glycoprotein. These agents may be used concomitantly provided sirolimus dose is adjusted depending on concentration and its effects.

Tacrolimus

Concomitant administration with fluconazole may increase tacrolimus plasma concentration up to 5 times 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. When these agents are used concomitantly, the oral tacrolimus dose should be reduced depending on its concentration.

Losartan

Concomitant administration with fluconazole inhibits losartan metabolism to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan use. When these agents are used concomitantly, continuous monitoring of blood pressure in patients is recommended.

Lurasidone

Concomitant administration with fluconazole (moderate CYP3A4 inhibitor) may increase lurasidone plasma concentration. If use of such combination cannot be avoided, the lurasidone dose should be reduced according to the instructions for medical use.

Methadone

Concomitant administration with fluconazole may increase methadone plasma concentration. Dose adjustment of methadone may be necessary when these agents are used concomitantly.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Concomitant administration with fluconazole increased Cmax and AUC of flurbiprofen 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 isomer S-(+)-ibuprofen 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). When these agents are used concomitantly, periodic monitoring for NSAID-related adverse reactions should be conducted. Dose adjustment of NSAIDs may be required.

Phenytoin

Fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant administration of fluconazole 200 mg and intravenous phenytoin 250 mg results in a 75% increase in phenytoin AUC24 and a 128% increase in Cmin. When these agents are used concomitantly, plasma phenytoin concentration should be monitored to avoid toxic effects.

Prednisone

A case was reported in which a liver transplant patient developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole therapy while receiving prednisone. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. When these agents are used concomitantly for prolonged periods, careful patient monitoring is required to prevent adrenal insufficiency after discontinuation of fluconazole.

Rifabutin

Concomitant administration with fluconazole increases rifabutin plasma concentration, leading to up to an 80% increase in rifabutin AUC. Cases of uveitis have been reported with concomitant administration of fluconazole and rifabutin. When these agents are used concomitantly, symptoms of rifabutin toxicity should be considered.

Saquinavir

Concomitant administration with fluconazole increases saquinavir AUC and Cmax by approximately 50% and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary when these agents are used concomitantly.

Sulfonylurea derivatives

Concomitant administration with fluconazole prolongs t1/2 of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. When these agents are used concomitantly, frequent blood glucose monitoring is recommended, and sulfonylurea derivative dose should be reduced accordingly.

Theophylline

In a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in theophylline plasma clearance. When these agents are used concomitantly, patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity appear.

Tofacitinib

The effect of tofacitinib increases with concomitant administration of medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). When used concomitantly with such agents, it is recommended to reduce the tofacitinib dose to 5 mg once daily.

Tolvaptan

Concomitant administration with fluconazole (moderate CYP3A4 inhibitor) significantly increases (200% AUC; 80% Cmax) exposure to tolvaptan (CYP3A4 substrate), thereby increasing the risk of adverse reactions such as enhanced diuresis, dehydration, and acute renal failure. When these agents are used concomitantly, the tolvaptan dose should be reduced according to its instructions for medical use, and the patient should be monitored for tolvaptan-related adverse reactions.

Vinca alkaloids

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

Vitamin A

Cases of central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri have been reported in a patient receiving all-trans retinoic acid (vitamin A acid form) and fluconazole concomitantly; this effect resolved after discontinuation of fluconazole. These agents may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4)

Oral concomitant administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole orally (400 mg on day 1, then 200 mg every 24 hours for 4 days) in 8 healthy male volunteers resulted in an average increase in voriconazole Cmax and AUCτ by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is administered after fluconazole, monitoring for voriconazole-associated adverse reactions should be conducted.

Zidovudine

Concomitant administration with fluconazole increases zidovudine Cmax and AUC by 84% and 74%, respectively, due to approximately 45% reduction in zidovudine clearance after oral administration. The t1/2 of zidovudine was also prolonged by approximately 128% after administration of the fluconazole and zidovudine combination. When these agents are used concomitantly, monitoring for zidovudine-related adverse reactions should be conducted. Dose reduction of zidovudine may be considered.

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. Administration of fluconazole 50 mg had no effect on hormone levels, whereas administration of fluconazole 200 mg daily resulted in a 40% increase in ethinylestradiol AUC and a 24% increase in levonorgestrel AUC. This indicates that repeated administration of fluconazole at the specified doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use

Use in infections caused by Candida species

Studies have shown an increased prevalence of infections caused by Candida species other than C. albicans. These are often resistant (e.g., C. krusei, C. auris) or have reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy following treatment failure. When prescribing fluconazole, the prevalence of resistance among different Candida species to fluconazole should be taken into account.

Use in dermatophytosis

According to study results on fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, with an overall efficacy rate of less than 20%. Therefore, the drug should not be used for the treatment of dermatophytosis.

Use in cryptococcosis

There is insufficient evidence of fluconazole efficacy in treating cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, there are no dosage recommendations for the drug in treating such conditions.

Use in deep endemic mycoses

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

Renal effects

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

Adrenal insufficiency risk

Ketoconazole causes adrenal insufficiency, and this may also apply to fluconazole, although it is rarely observed. Adrenal insufficiency associated with concomitant treatment with prednisone is described in the section "Interaction with other medicinal products and other forms of interaction".

Hepatic effects

The drug should be used with caution in patients with impaired liver function. 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 was associated with fluconazole use, there was no clear dependence on total daily dose, duration of therapy, sex, or patient 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 damage.

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

Cardiovascular effects

Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying 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 paroxysmal torsades de pointes ventricular tachycardia have been reported with fluconazole use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs affecting the QT interval.

Patients with hypokalemia and progressive heart failure have an increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

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 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Interaction with 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").

Risk of dermatological reactions

Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported during fluconazole use. Patients with AIDS are more prone to developing severe skin reactions when using many drugs. If a patient with a superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and if bullous eruptions or erythema multiforme develop, the drug should be discontinued.

Risk of hypersensitivity

Anaphylactic reactions have been reported rarely during fluconazole use (see section "Contraindications").

Interaction with cytochrome P450 enzymes

Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with drugs 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").

Interaction with terfenadine

Careful monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at fluconazole doses below 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Special warnings regarding excipients

The drug contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not use this medicinal product.

The drug contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically 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, a washout period of approximately 1 week (corresponding to 5–6 half-lives) should be observed before attempting pregnancy (see section "Pharmacokinetics").

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

Pregnancy

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

Data from several hundred pregnant women who received a cumulative dose of fluconazole ≤ 150 mg during the first trimester do not indicate an increased risk of fetal malformations. An observational cohort study showed a slight increase in the risk of musculoskeletal malformations (approximately 1 additional case per 1,000 women) with a cumulative fluconazole dose ≤ 450 mg during the first trimester compared to women who received topical azole preparations, and approximately 4 additional cases per 1,000 women with a cumulative dose > 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI 1.23–3.17) for fluconazole doses exceeding 450 mg.

Available epidemiological studies on the risk of heart defects following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of five observational studies involving several thousand pregnant women who received fluconazole during the first trimester revealed a 1.8–2-fold increased risk of congenital heart defects in infants compared to infants whose mothers 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 three months for the treatment of coccidioidomycosis. Malformations observed in these children included brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

The drug should not be used during pregnancy at standard doses or for short-term treatment unless absolutely necessary. The drug should also not be used at high doses and/or for prolonged treatment courses unless for the treatment of life-threatening infections.

Lactation

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard 150 mg dose of the drug. Breastfeeding is not recommended with repeated administration of the drug or when high doses are used. The benefit of breastfeeding for the infant's development and health, the mother's clinical need for the drug, and any potential adverse effects of fluconazole 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 affect driving and use of machines

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 (see section "Adverse reactions") during treatment with the drug. If such symptoms occur, driving or operating machinery is not recommended.

Dosage and Administration

The medicinal product is intended for oral use. Capsules should be swallowed whole. Administration of the medicinal product is not affected by food intake.

Adults

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

Elderly patients

In the absence of signs of renal impairment, elderly patients should receive the standard adult dose.

Patients with renal impairment

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

Patients with hepatic impairment

The medicinal product should be used with caution in patients with hepatic impairment, as data on the use of fluconazole in this patient population are limited (see sections "Special warnings and precautions for use" and "Undesirable effects").

Children

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Available information is provided in the section "Undesirable effects". If there is an urgent need to administer the medicinal product to adolescents (aged 12 to 17 years), standard adult doses should be used.

Overdose

Cases of fluconazole overdose have been reported, with concurrent reports of hallucinations and paranoid behavior.

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

Fluconazole is largely excreted in the urine; forced diuresis may accelerate its elimination. A 3-hour hemodialysis session reduces the plasma concentration of fluconazole by approximately 50%.

Side effects

The most frequently reported side effects (> 1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels in blood, rash.

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

Blood and lymphatic system disorders:

Uncommon – anemia; rare – agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders:

Rare – anaphylaxis.

Metabolism and nutrition disorders:

Uncommon – decreased appetite; rare – hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Psychiatric disorders:

Uncommon – insomnia, somnolence.

Nervous system disorders:

Common – headache; uncommon – seizures, paresthesia, dizziness, taste disturbance; rare – tremor.

Ear and labyrinth disorders:

Uncommon – vertigo.

Cardiac disorders:

Rare – paroxysmal ventricular tachycardia of torsades de pointes type, QT interval prolongation (see section "Special precautions").

Gastrointestinal disorders:

Common – abdominal pain, nausea, diarrhea, vomiting; uncommon – constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders:

Common – increased ALT levels, increased AST levels, increased alkaline phosphatase levels (see section "Special precautions"); uncommon – cholestasis, jaundice, increased bilirubin levels (see section "Special precautions"); rare – hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special precautions").

Skin and subcutaneous tissue disorders:

Common – rash (see section "Special precautions"); uncommon – drug eruption (including fixed drug eruption), urticaria, pruritus, increased sweating (see section "Special precautions"); rare – toxic epidermal necrolysis, Stevens–Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special precautions"); frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders:

Uncommon – myalgia.

General disorders and administration site conditions:

Uncommon – fatigue, malaise, asthenia, fever.

Children.

The frequency and nature of adverse reactions and laboratory test abnormalities observed during clinical trials in children were comparable to those in adults.

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with fluconazole treatment have been reported (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

5 years.

Storage conditions

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging

1 capsule in a blister pack, 1 blister pack in a cardboard box.

Supply classification

Over-the-counter (without prescription).

Manufacturer

UORLDMEDICINE ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.