Diaflu

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT diaFLU

Composition:

Active substance: fluconazole;

1 capsule contains 50 mg or 100 mg of fluconazole;

Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Capsules.

Main physicochemical properties:

50 mg — hard gelatin capsules with a light-blue cap and white body, filled with white or almost white powder;

100 mg — hard gelatin capsules with a red cap and white body, filled with 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 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 once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Studies on interaction with antipyrine demonstrated that single or repeated administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, whereas C. krusei and C. auris are resistant to fluconazole. 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.

Pharmacokinetic/pharmacodynamic relationship.

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 AUC and fluconazole dose (approximately 1:1). There is also a direct, but insufficient, correlation 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 exhibiting high minimal inhibitory concentrations to fluconazole is less effective.

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 its in vivo and clinical effectiveness.

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

Superinfections caused by Candida spp. other than C. albicans have been reported, often involving species with reduced susceptibility (C. glabrata) or resistance to fluconazole (e.g., C. krusei, C. auris). Alternative antifungal agents should be used for the treatment of such infections. Resistance mechanisms are not yet fully understood in some intrinsically resistant (C. krusei) or emerging (C. auris) Candida species.

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

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

S = Susceptible.

R = Resistant.

a — Non-species-related breakpoints, primarily defined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific distribution of minimal inhibitory concentrations. These were evaluated only in microorganisms lacking a specific breakpoint.

-- Susceptibility testing not recommended, as this organism is not a target for drug therapy.

* All C. glabrata isolates fall into category I. 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 – Susceptible-dose dependent: a microorganism is categorized as "susceptible-dose dependent" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or achieving higher drug concentrations 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, with plasma levels and systemic bioavailability exceeding 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption of the drug when administered orally. Peak plasma concentration is reached within 0.5–1.5 hours after fasting administration. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of once-daily dosing. A steady-state concentration of 90% is reached by day 2 when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

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

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

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

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

Biotransformation.

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

The prolonged plasma half-life allows for single-dose treatment in vaginal candidiasis and once-weekly dosing for other indications.

Renal impairment.

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

Lactation.

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

Children.

Pharmacokinetic data were evaluated in 113 children across five studies: two single-dose studies, two multiple-dose studies, and one 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 elimination half-life ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life 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 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 doses of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (range: 44–185) on day 1, decreasing to 53 hours (range: 30–131) on day 7 and 47 hours (range: 27–68) on day 13. The area under the curve (AUC, µg*h/mL) was 271 (range: 173–385) on day 1, increased to 490 (range: 292–734) on day 7, then decreased to 360 (range: 167–566) on day 13. The volume of distribution (mL/kg) was 1183 (range: 1070–1470) on day 1, increased to 1184 (range: 510–2130) on day 7, and to 1328 (range: 1040–1680) on day 13.

Elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten participants 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 elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Thus, pharmacokinetic changes in elderly patients are evidently dependent on renal function parameters.

Clinical characteristics.

Indications.

Diflucan is indicated for the treatment of the following fungal infections in adults (see section “Pharmacodynamics”):

• cryptococcal meningitis (see section “Special precautions for use”);
• coccidioidomycosis (see section “Special precautions for use”);
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic mucocutaneous candidiasis;
• chronic atrophic oral candidiasis (denture-related candidiasis) when oral hygiene or topical therapy is 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 mycosis, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis, when use of other medicinal products is not appropriate.

Diflucan is indicated for prophylaxis of the following conditions in adults:

• prevention of recurrence of cryptococcal meningitis in patients at high risk of developing it;
• prevention of recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it.

For reducing the frequency of recurrent vaginal candidiasis (4 or more episodes per year).

For prophylaxis of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation) (see section “Pharmacological properties. Pharmacodynamics”).

Diflucan is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prophylaxis of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section “Special precautions for use”).

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

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

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients listed in the section “Composition”.
• 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 use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections “Special precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

Interaction with other medicinal products and other forms of interaction.

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

Cisapride: cardiac adverse reactions, including paroxysmal ventricular tachycardia of the torsade 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 cisapride levels 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 between these agents were conducted. In one study, administration of fluconazole 200 mg daily did not result in QTc interval prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased plasma terfenadine levels when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section “Contraindications”). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the torsade de pointes type. Concomitant use of fluconazole and astemizole is contraindicated (see section “Contraindications”).

Pimozide and quinidine: concomitant use 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 paroxysmal ventricular tachycardia of the torsade de pointes type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section “Contraindications”).

Erythromycin: concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the torsade de pointes type) and, consequently, sudden cardiac death. Use of this combination is contraindicated (see section “Contraindications”).

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

Halofantrine: fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these medicinal products may increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the torsade de pointes type) and, consequently, sudden cardiac death. The combination should be avoided (see section “Special precautions for use”).

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

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

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

• Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole concomitantly with food, cimetidine, antacids, or total body irradiation for bone marrow transplantation has no clinically significant effect on fluconazole absorption.

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

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

• 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 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 its administration due to its long elimination half-life (see section “Contraindications”).

Alfentanil: during concomitant administration of alfentanil 20 µg/kg and fluconazole 400 mg to healthy volunteers, a twofold increase in AUC₁₀ 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. Dose adjustment of amitriptyline/nortriptyline may be required if necessary.

Amphotericin B: concomitant administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice yielded 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 midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally increased AUC and elimination half-life of midazolam by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant administration of fluconazole and triazolam. If benzodiazepines need to be prescribed concomitantly to a patient undergoing fluconazole therapy, their dose should be reduced and appropriate patient monitoring established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity manifestations. 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: during concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. When celecoxib and fluconazole are used concomitantly, a halving of the celecoxib dose may be necessary.

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

Fentanyl: a fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, 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.

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

Ibrutinib: moderate CYP3A4 inhibitors, such as fluconazole, increase ibrutinib plasma concentration, increasing the risk of toxicity. If avoiding the drug combination is not possible, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) to continue inhibitor use, with continuous clinical monitoring.

Ivacaftor: concomitant administration of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased ivacaftor exposure threefold and hydroxymethylivacaftor (M1) exposure 1.9-fold. Patients concomitantly taking moderate CYP3A inhibitors, such as fluconazole and erythromycin, are recommended to reduce the ivacaftor dose to 150 mg once daily.

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

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

Cyclosporine: fluconazole significantly increases cyclosporine concentration and AUC. 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 drugs 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 serum concentration due to CYP3A4 inhibition.

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

Tacrolimus: fluconazole may increase tacrolimus serum concentrations nearly fivefold during oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed during intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced depending on tacrolimus concentration.

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

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

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

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 NSAIDs is recommended. NSAID dose adjustment may be required.

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

Prednisone: a case has been reported where a patient after liver transplantation developed acute adrenal insufficiency while receiving prednisone, occurring after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone 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 drug combination.

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

Sulfonylurea derivatives: fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative dose 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% decrease 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 causing moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these drugs.

Vaptans (tolvaptan): exposure to tolvaptan significantly increases (200% AUC, 80% Cmax) when tolvaptan, a CYP3A4 substrate, is administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute renal failure. If co-administered, the tolvaptan dose should be reduced according to instructions in the medical use instructions, and the patient should be regularly checked for any adverse reactions associated with tolvaptan.

Vinca alkaloids: although appropriate studies have not been conducted, fluconazole, likely via CYP3A4 inhibition, may increase 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 receiving all-trans retinoic acid (acid form of vitamin A) and fluconazole concomitantly; this effect disappeared 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 for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 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 adverse effects associated with voriconazole is required.

Zidovudine: fluconazole increases zidovudine Cmax and AUC by 84% and 74%, respectively, due to approximately 45% reduction in zidovudine clearance after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128% after administration of the fluconazole-zidovudine combination. Patients receiving this drug combination should be monitored for zidovudine-related adverse reactions. 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 administration at 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 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 these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytia. According to studies on fluconazole for the treatment of dermatophytia in children, fluconazole does not exceed griseofulvin in efficacy, and the overall efficacy rate is less than 20%. Therefore, Diflucan should not be used for the treatment of dermatophytia.

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

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

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

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

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rare. Adrenal insufficiency associated with concomitant treatment with prednisone 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 medicinal product should be used with caution in patients with impaired liver function. The use of fluconazole has been associated with rare cases of severe hepatotoxicity, including fatal outcomes, primarily in patients with serious underlying conditions. In cases where hepatotoxicity has been associated with fluconazole use, there was no clear dependence on the total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormalities in liver function tests during fluconazole 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 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 rapid potassium rectifier channel (Ikr). QT interval prolongation due to other medicinal products (e.g., amiodarone) may be potentiated by inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and torsades de pointes have been reported with fluconazole use. These reports involved patients with severe illnesses 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.

Diflucan 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 cytochrome P450 enzyme 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").

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. 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 use of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole should be discontinued in case of bullous eruptions or erythema multiforme.

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

Hypersensitivity. Rare cases of 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 Diflucan 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").

Terfenadine. Careful monitoring 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").

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

Use during pregnancy or breastfeeding.

Women of reproductive age

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

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

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

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

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

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use and/or use of topical azoles.

Case reports describe congenital malformations in infants whose mothers received high doses (400 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 and short-term courses of fluconazole should not be used during pregnancy except when absolutely necessary.

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

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

Fertility. Fluconazole did not affect fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of Diflucan 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 Diflucan use. If such symptoms occur, driving or operating machinery is not recommended.

Method of administration and dosage.

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

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

Fluconazole is administered orally (capsules) or intravenously by infusion (infusion solution), depending on the dosage form. 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. Duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis.

• Recommended dose is 200–400 mg once daily. 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 disappearance of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose — 100–200 mg once daily. Duration of treatment is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose — 100–200 mg once daily. Duration of treatment is 14–30 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Candiduria: recommended dose is 200–400 mg once daily for 7–21 days. Duration of treatment may be extended in patients with severe immunodeficiency.
• 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. 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.

• Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg once daily or 200 mg three times per week. Duration of treatment is indefinite in immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia.

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

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: recommended dose is 150 mg as a single dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more episodes per year): recommended dose is 150 mg on days 1, 4, and 7 (three doses total). After that, maintenance dose of 150 mg once weekly for 6 months is recommended.

Dermatomycoses.

• Tinea pedis, tinea of glabrous skin, tinea cruris, cutaneous candidiasis: recommended dose is 150 mg once weekly or 50 mg once daily. Duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Tinea versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophytic onychomycosis: recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced by healthy nail. Regrowth of healthy fingernails usually takes 3–6 months and toenails 6–12 months. 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.

Diflucan is eliminated from the body primarily unchanged in urine. Dose adjustment is not required after a single dose. Patients (including children) with impaired renal function requiring multiple doses should receive an initial dose of 50–400 mg on the first day of treatment, depending on the indication. Subsequently, the daily dose (depending on the indication) should be adjusted according to the table below:

Patients undergoing regular 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 administered with caution to patients with hepatic dysfunction, as there is insufficient information regarding 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 the clinical and mycological response. DIAFLU is administered once daily.

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

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

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should evaluate which dosage (adult or pediatric) is optimal for the patient. Clinical data indicate that children have a higher clearance of fluconazole 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 provided in the section "Adverse reactions." If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose 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 for prevention of 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 patients with immunodeficiency: dosage is 3–12 mg/kg once daily, depending on the severity and duration of induced neutropenia (see adult dosages).

Children.

The drug in capsule form may be administered to this patient population when children are able to safely swallow capsules, which is usually possible from the age of 5 years (see section "Administration and dosage").

Overdose.

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

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

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

Side effects.

Summary of safety profile

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported with fluconazole use (see section "Special warnings and precautions for use").

The most commonly reported adverse reactions (>1/10) are: headache, abdominal pain, diarrhoea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase in blood, and rash.

The following frequency classification is used to assess the incidence of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders.

Uncommon: anaemia.

Rare: agranulocytosis, leucopenia, neutropenia, thrombocytopenia.

Immune system disorders.

Rare: anaphylaxis.

Metabolism and nutrition disorders.

Uncommon: decreased appetite.

Rare: hypertriglyceridaemia, hypercholesterolaemia, hypokalaemia.

Psychiatric disorders.

Uncommon: insomnia, somnolence.

Nervous system disorders.

Common: headache.

Uncommon: convulsions, dizziness, paraesthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders.

Uncommon: vertigo.

Cardiac disorders.

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

Gastrointestinal disorders.

Common: abdominal pain, diarrhoea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders.

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

Uncommon: cholestasis, jaundice, increased bilirubin levels.

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

Skin and subcutaneous tissue disorders.

Common: rash.

Uncommon: drug eruption (including fixed drug eruption), urticaria, pruritus, hyperhidrosis.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, exfoliative dermatitis, angioneurotic oedema, facial swelling, alopecia.

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia.

General disorders and administration site conditions.

Uncommon: fatigue, malaise, asthenia, pyrexia.

Paediatric population.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorisation is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with local regulatory requirements.

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach and sight of children.

Packaging.

10 capsules in a blister made of polyvinyl chloride film and aluminium foil, with labelling in Ukrainian.

1 blister pack with the instruction for medical use in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

STRIDES PHARMA SCIENCE LIMITED

Strides Pharma Science Limited

Manufacturer's address and place of business.

No. 36/7, Suragajakkanahalli, Indlavadi Cross, Anekal Taluk, Bengaluru, Karnataka 562106, India

No. 36/7, Suragajakkanahalli, Indlavadi Cross, Anekal Taluk, Bengaluru, Karnataka 562106, India

Marketing Authorisation Holder. M. Biotech Ltd

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9GH, Surrey, United Kingdom