Diflazon®

INSTRUCTION for medical use of the medicinal product Diflazon® (Diflazon®)

Composition:

Active substance: fluconazole;

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

Excipients: lactose monohydrate, maize starch, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate;

Capsule shell: titanium dioxide (E 171), patent blue V dye (E 131), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties:

50 mg capsules: capsules with white body and light blue cap, filled with powder from white to almost white;

100 mg capsules: capsules with white body and blue cap, filled with powder from white to almost white;

150 mg capsules: capsules with light blue body and cap, filled with powder from white to almost white.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole and tetrazole 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 depletion of ergosterol in the fungal cell membrane and is considered responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.

Administration of fluconazole at a dose of 50 mg once daily for 28 days did not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily showed no 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 Candida albicans, Candida parapsilosis, and Candida tropicalis). Candida glabrata shows reduced susceptibility to fluconazole, whereas Candida krusei and Candida auris are resistant to fluconazole.

The minimum inhibitory concentration (MIC) and epidemiological cut-off value (ECOFF) of fluconazole for Candida guilliermondii are higher than those for Candida albicans.

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

Pharmacokinetic/Pharmacodynamic Relationships

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

Mechanisms of Resistance

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

In generally susceptible Candida species, the most commonly observed resistance mechanism involves alterations in the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from gene mutations, overexpression of the target enzyme, drug efflux mechanisms, or development of compensatory metabolic pathways.

Superinfections with non-albicans Candida species, which often display reduced susceptibility (e.g., Candida glabrata) or resistance (e.g., Candida krusei, Candida auris) to fluconazole, have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms have not been fully elucidated for some species with intrinsic resistance (e.g., Candida krusei) or for emerging species (e.g., Candida auris).

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

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole against Candida species have been established (EUCAST document on fluconazole rationale (2020) - version 2; European Committee on Antimicrobial Susceptibility Testing, antifungal agents, tables of interpretive MIC breakpoints, version 10.0, effective from 04.02.2020). These have been categorized into non-species-specific breakpoints, primarily determined from pharmacokinetic/pharmacodynamic data and not dependent on MIC distribution within specific species, and species-specific breakpoints, typically associated with human infections. These breakpoints are listed below.

S = susceptible;
R = resistant;

α – breakpoints not linked to a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic information and do not depend on the distribution of minimal inhibitory concentration among specific species, studied only for microorganisms for which no species-specific breakpoint exists;

• susceptibility testing is not recommended, as this organism is not a target for antimicrobial therapy;

* = All Candida glabrata isolates belong to category I. MIC against Candida glabrata should be interpreted as resistant if it exceeds 16 mg/L. The susceptible category (≤ 0.001 mg/L) allows avoiding misclassification of "I" strains as "S" strains. I – Intermediate: microorganisms categorized as "intermediate" when there is a high likelihood of therapeutic success due to increased exposure, achieved by adjusting the dosing regimen or increasing the agent’s 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 levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption of the drug when administered orally. Peak plasma concentrations are reached within 0.5–1.5 hours after drug intake. Drug plasma concentration is proportional to the dose. Steady-state concentration reaches 90% by the second day of treatment when a loading dose twice the standard daily dose is administered on the first day.

Distribution

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

Fluconazole penetrates well into all investigated 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 in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. After a 50 mg once-daily dose, fluconazole concentration reached 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a 150 mg once-weekly dose, fluconazole concentration was 23.4 µg/g on day 7 of treatment and remained at 7.1 µg/g seven days after the next dose.

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 therapy ended.

Metabolism

Fluconazole is only minimally metabolized. After administration of radiolabeled fluconazole, only 11% of the drug is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes (see section "Interaction with other medicinal products and other forms of interaction"). Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme.

Elimination

The plasma half-life (T½) of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The long plasma T½ allows single-dose administration for vaginal candidiasis and once-weekly dosing for other indications.

Renal impairment

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), T½ increases from 30 to 98 hours. Therefore, this patient group requires dose reduction 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%.

Lactation

Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours following a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of approximately 98% of that in maternal plasma. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily dose of fluconazole received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean peak milk concentration, is 0.39 mg/kg/day, which corresponds 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.

Paediatric population

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, mean plasma T½ of fluconazole ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer T½ of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life 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 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 6 mg/kg were administered every 72 hours. Mean T½ was 74 hours (44–185) on day 1, decreasing 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. 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.

Elderly patients

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg fluconazole orally. 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 T½ 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. 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. Therefore, pharmacokinetic changes in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

Diflazon® 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, esophageal candidiasis, candiduria, chronic cutaneous and mucosal candidiasis;
• chronic atrophic oral candidiasis (denture stomatitis) 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, tinea of glabrous skin, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis when use of other medicinal products is not appropriate.

Prevention of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidiasis 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").

Diflazon® is indicated in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prevention of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (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 capsules safely, which is usually possible from the age of 5 years.

Treatment with Diflazon® may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted appropriately once the results are obtained.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the drug.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on multiple-dose interaction study results).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, 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: cases of cardiac adverse reactions, including torsades 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 significantly increased plasma levels of cisapride and prolonged the QT interval. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

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

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to torsades de pointes ventricular tachycardia. 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, torsades de pointes ventricular tachycardia. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section "Contraindications").

Erythromycin: concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes ventricular tachycardia) and, consequently, sudden death. The 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 concentrations by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes ventricular tachycardia) and, consequently, sudden death. The use of this 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 concomitant intake of food, cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on the absorption of orally administered fluconazole.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the half-life (T½) of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the dose of fluconazole.

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 the cytochrome P450 (CYP) 2C9 isoenzyme and CYP3A4. Additionally, fluconazole is a potent inhibitor of CYP2C19. Besides the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution; close monitoring of patients is necessary. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long half-life.

Abrocitinib

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

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

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

Amphotericin B: concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in: 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 findings is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants concomitantly. Dose adjustment of the anticoagulant may be necessary.

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

If benzodiazepines must be prescribed concomitantly to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

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

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

Celecoxib: concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. When celecoxib is used concomitantly with fluconazole, a 50% reduction in celecoxib dose may be necessary.

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

Fentanyl: a fatal case of fentanyl intoxication possibly due to interaction with fluconazole has been reported. In addition, a study involving 12 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, such as atorvastatin and simvastatin, or HMG-CoA reductase inhibitors metabolized by CYP2C9, such as fluvastatin (which reduces hepatic statin metabolism), increases the risk (dose-dependent) of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If significant elevation of creatine kinase levels occurs, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be required according to statin prescribing information.

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

Ivacaftor (alone or in combination with drugs of the same therapeutic class). Concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3 times and to hydroxymethylivacaftor (M1) by 1.9 times. The dose of ivacaftor (alone or in combination) should be reduced according to ivacaftor (alone or in combination) prescribing information.

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. Concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in an 1.8-fold increase in cyclosporine AUC. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus: although no in vitro or in vivo studies have been conducted, fluconazole may increase serum concentrations of everolimus by inhibiting CYP3A4.

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

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

Losartan: fluconazole inhibits losartan metabolism to its active metabolite (E-31 74), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure in patients is recommended.

Lurasidone. Moderate CYP3A4 inhibitors, such as fluconazole, may increase plasma concentrations of lurasidone. If concomitant use cannot be avoided, the lurasidone dose should be reduced as specified in lurasidone prescribing information.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary when used concomitantly with fluconazole.

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

Although no specific studies have been conducted, fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse and toxic effects related to NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic metabolism of phenytoin. Multiple concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases phenytoin AUC24 by 75% and Cmin by 128%. Monitoring of phenytoin serum concentration is required when these drugs are used concomitantly to avoid phenytoin toxicity.

Prednisone: a case was reported of acute adrenal insufficiency in a liver transplant patient receiving prednisone after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving fluconazole and prednisone concomitantly for prolonged periods should be closely monitored to prevent adrenal insufficiency after fluconazole discontinuation.

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

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

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

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

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

Tolvaptan. Exposure to tolvaptan significantly increases (200% in AUC; 80% in Cmax) when tolvaptan, a CYP3A4 substrate, is used concomitantly with fluconazole, a moderate CYP3A4 inhibitor, with risk of significant increase in adverse reactions, especially diuresis, dehydration, and acute renal failure. When used concomitantly, the tolvaptan dose should be reduced according to tolvaptan prescribing information, and patients should be closely monitored for any adverse reactions related to tolvaptan.

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

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

Voriconazole (inhibitor of CYP2C9 and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on 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 used after fluconazole, monitoring for voriconazole-related adverse effects is recommended.

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

Azithromycin: 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. At a fluconazole dose of 50 mg, no effect on hormone levels was observed, whereas at a fluconazole dose of 200 mg daily, AUC of ethinylestradiol increased by 40% and levonorgestrel by 24%. This indicates that multiple administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to clinical studies evaluating fluconazole for the treatment of dermatophytosis in children, fluconazole does not exceed griseofulvin in efficacy, and the overall effectiveness rate is less than 20%. Therefore, Diflazon® should not be used for the treatment of dermatophytosis.

Cryptococcosis. There is insufficient evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be provided for the treatment of these 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, no dosage recommendations can be provided for the treatment of these infections.

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 prednisone therapy is described in the section "Interaction with other medicinal products and other forms of interaction. Effect of fluconazole on other medicinal products."

Hepatobiliary system. The drug should be used with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying diseases. In cases where hepatotoxicity has been linked to fluconazole, 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 abnormal liver function test results during fluconazole therapy should be closely monitored for signs of more severe liver injury.

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

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by 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 during Diflazon® use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other drugs affecting the QT interval. Patients with hypokalemia and progressive heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Diflazon® should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

Hypersensitivity. Rare cases of anaphylactic reactions have been reported (see section "Contraindications").

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes and a potent inhibitor of CYP2C19. Patients receiving Diflazon® concomitantly with drugs having a narrow therapeutic window that are metabolized by CYP2C19 and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine. Careful monitoring of patients is required when terfenadine is used concomitantly with fluconazole at doses less than 400 mg daily (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Candidiasis. Studies have shown an increased incidence of infections caused by Candida species other than Candida albicans. These species are often inherently resistant (e.g., Candida krusei and Candida auris) or exhibit reduced susceptibility to fluconazole (Candida glabrata). Such infections may require alternative antifungal therapy due to lack of response to fluconazole. Therefore, the prevalence of resistance among different Candida species to fluconazole should be taken into account.

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

Use during pregnancy or breastfeeding.

Women of reproductive potential

Before initiating treatment, patients should be informed about the potential risk to the fetus. After a single dose, a washout period of 1 week (corresponding to 5–6 half-lives) should be observed before attempting pregnancy (see section "Pharmacokinetics").

For longer treatment courses, contraception should be considered for women of reproductive potential throughout the treatment period and for 1 week after the last dose.

Pregnancy

Observational study data 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 receive fluconazole or used 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, the use of oral fluconazole during the first trimester was associated with a small increase in the risk of musculoskeletal malformations—approximately one additional case per 1000 women receiving cumulative doses ≤450 mg, compared to women who received topical azoles, and approximately four additional cases per 1000 women receiving cumulative doses exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for 150 mg oral fluconazole and 1.98 (95% CI: 1.23–3.17) for doses exceeding 450 mg fluconazole.

Available epidemiological studies on the risk of congenital heart defects associated with 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 showed a 1.8- to 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 for more than three months during pregnancy for the treatment of coccidioidomycosis. Congenital abnormalities in newborns include auricular dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis.

A causal relationship between fluconazole use and these cases has not been established.

Standard doses and short-term courses of fluconazole should not be used during pregnancy unless 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 period

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

Fertility

Fluconazole has no effect on fertility in male or female rats.

Ability to influence reaction rate when driving or operating machinery.

No studies on the effect of Diflazon® on the ability to drive or operate machinery have been conducted.

Patients should be informed about the possibility of developing dizziness or seizures during Diflazon® use (see section "Adverse reactions"). If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

The daily dose of fluconazole depends on the nature and severity of the fungal infection. Treatment of infections requiring multiple doses should continue until clinical and laboratory signs of fungal activity have resolved. Inadequate duration of treatment may lead to recurrence of active infection.

The drug may be administered orally (capsules) or intravenously by infusion (infusion solution). The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching from oral to intravenous administration or vice versa.

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

Adults

Cryptococcosis

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg once daily. The duration of treatment is usually at least 6–8 weeks. In life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: the recommended dose is 200 mg once daily for an indefinite duration.

Coccidioidomycosis

The recommended dose is 200–400 mg once daily. The duration of treatment is 11–24 months or longer, depending on the patient's condition. For certain forms of infection, especially meningitis, a dose of 800 mg daily 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 and resolution 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. Treatment duration is 7–21 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg once daily. Treatment duration is 14–30 days (until remission is achieved), but may be extended for patients with severe immunodeficiency.
• Candiduria: the recommended dose is 200–400 mg once daily for 7–21 days. Treatment duration may be extended for patients with severe immunodeficiency.
• Chronic atrophic candidiasis: the recommended dose is 50 mg/day for 14 days.
• Chronic cutaneous and mucosal candidiasis: the recommended dose is 50–100 mg once daily. Treatment duration 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: the recommended dose is 100–200 mg once daily or 200 mg three times weekly. Treatment duration is indefinite in immunocompromised patients.

Prophylaxis of Candidiasis in Patients with Prolonged Neutropenia

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

Genital Candidiasis

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

Dermatomycoses

• Tinea pedis, tinea of glabrous skin, tinea cruris, cutaneous candidiasis: the recommended dose is 150 mg once weekly or 50 mg once daily. Treatment duration is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophyte onychomycosis: the recommended dose is 150 mg once weekly. Treatment should continue until a healthy nail has fully regrown. Healthy nail regrowth typically takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate varies among patients and may depend on age. After successful treatment of chronic long-standing infections, nail appearance may sometimes remain altered.

Prophylaxis of Candidiasis in Patients with Prolonged Neutropenia

The 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 cells/mm³.

Special Patient Groups

Elderly Patients

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

Patients with Renal Impairment

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

Patients undergoing 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" 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. Diflazon® should be administered once daily.

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

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

Children aged 5 to 11 years

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

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg once daily, depending on the severity of the disease.

Maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk: dosage is 6 mg/kg once daily, depending on the severity of the disease.

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

Children aged 12 years

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

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established. If there is a compelling need to use the drug in adolescents (aged 12 to 17 years), standard adult doses should be used.

Children.

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

Overdose.

There have been reports of fluconazole overdose causing hallucinations and paranoid behavior.

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

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

Adverse Reactions

A drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with fluconazole treatment (see section "Special Warnings and Precautions for Use").

The most commonly reported adverse reactions (>1/10) are: headache, abdominal pain, diarrhea, nausea, vomiting, elevated alanine aminotransferase (ALT) levels, elevated aspartate aminotransferase (AST) levels, elevated alkaline phosphatase levels, 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), 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 the torsades de pointes type, QT interval prolongation (see section "Special Warnings and Precautions for Use").

Gastrointestinal disorders

Common: abdominal pain, nausea, diarrhea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels (see section "Special Warnings and Precautions for Use").

Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special Warnings and Precautions for Use").

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders

Common: rash (see section "Special Warnings and Precautions for Use").

Uncommon: drug eruption (including fixed drug eruption), urticaria, pruritus, increased sweating (see section "Special Warnings and Precautions for Use").

Rare: toxic epidermal necrolysis, Stevens–Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special Warnings and Precautions for Use").

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special Warnings and Precautions for Use").

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever.

Children

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

If serious adverse effects occur, treatment should be discontinued.

Reporting of suspected adverse reactions

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

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of reach and sight of children.

Packaging.

50 mg capsules: 7 capsules in a blister; 1 blister in a cardboard box.

100 mg capsules: 7 capsules in a blister; 4 blisters in a cardboard box.

150 mg capsules: 2 or 4 capsules in a blister; 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.