Diflucan®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIFLUCAN® (DIFLUCAN®)

Composition:

Active substance: fluconazole;

One capsule contains 50 mg or 100 mg of fluconazole;

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

Pharmaceutical form. Capsules.

Main physicochemical properties:

50 mg – hard, opaque gelatin capsules (capsule size №4) containing a white powder, with a light turquoise-blue cap and a white body, marked with the Pfizer logo and the inscription "FLU-50" in black ink.

100 mg – hard, opaque gelatin capsules (capsule size №2) containing a white powder, with a blue cap and a white body, marked with the Pfizer logo and the inscription "FLU-100" in black ink.

Pharmacotherapeutic group. Systemic antifungal agents. 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 fungal ergosterol biosynthesis. Accumulation of 14-alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg 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 once daily does not exhibit clinically significant effects on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Studies investigating interactions with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole do not affect antipyrine metabolism.

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant 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 minimal inhibitory concentration (MIC) 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 suboptimal, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment outcomes for infections caused by strains exhibiting high minimal inhibitory concentrations to fluconazole are less favorable.

Mechanisms 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 in vivo efficacy and clinical outcomes.

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

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

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (EUCAST accompanying interpretative document for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective 04.02.2020). These breakpoints are categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific minimal inhibitory concentration distributions, and species-specific breakpoints, typically associated with human infections. These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints, S ≤ / R > in mg/L						Non-species-related breakpoints,a S ≤ / R > in mg/L
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

S = susceptible;

R = resistant;

a – breakpoints not associated with a specific species, which were primarily defined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a species-specific breakpoint;

-- susceptibility testing not recommended, as this species 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 strains. I – susceptible with increased exposure: a microorganism is categorized as "susceptible with increased exposure" when there is a high likelihood of therapeutic success due to increased drug exposure achieved by adjusted dosing regimens or 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, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect drug absorption following oral administration. Peak plasma concentrations are reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of once-daily dosing. A 90% steady-state concentration is reached by day 2 when a loading dose twice the standard daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to 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. After a daily dose of 50 mg, fluconazole concentration in the stratum corneum was 73 µg/g after 12 days of treatment and remained at 5.8 µg/g seven days after treatment ended. With a weekly dose of 150 mg, fluconazole concentration on day 7 of treatment was 23.4 µg/g; seven days after the next dose, the concentration was still 7.1 µg/g.

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

Biotransformation.

Fluconazole is 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 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 single-dose treatment for 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, 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 after a single 150 mg dose of Diflucan in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. In breast milk, fluconazole was detected 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 fluconazole dose received by an infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on the mean peak milk concentration, was 0.39 mg/kg/day, amounting 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.

Pediatrics.

Pharmacokinetic data were evaluated in 113 children across five studies: two single-dose studies, two multiple-dose studies, and one study in premature neonates.

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*hr/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours; volume of distribution was 880 mL/kg. A longer plasma half-life 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 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole at 6 mg/kg were administered every 72 hours. The mean elimination half-life 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. The area under the curve (AUC, µg*hr/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

Elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently taking diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*hr/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. 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.

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 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, cutaneous candidiasis, 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;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prophylaxis of candidal infections 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 candidal infections in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section "Special precautions for use").

The use of the drug in capsule form in this patient category is possible only when children are able to swallow the capsule safely, which is generally feasible at the age of 5 years and older.

Treatment with Diflucan® may be initiated before the results of culture and other laboratory tests are available; however, after obtaining the 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 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 by 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 paroxysmal ventricular tachycardia of the "torsades de pointes" type, have been reported in patients who received 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 were conducted. In one study, administration of fluconazole at a dose of 200 mg/day did not result in QTc interval prolongation. Another study using fluconazole at doses of 400 mg and 800 mg/day demonstrated that fluconazole at doses of 400 mg/day 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 used at doses below 400 mg/day concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsades de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (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 "torsades 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 "torsades de pointes" type) and, as a consequence, 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 "torsades de pointes" type) and, as a consequence, sudden cardiac 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 oral administration of fluconazole simultaneously with food, cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

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

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.

• 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 used concomitantly with fluconazole. Therefore, such combinations of drugs should be used with caution; careful monitoring of patients is necessary. 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").

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 product information.

Alfentanil: during concomitant administration of alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg to healthy volunteers, a twofold increase in AUC10 was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

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

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

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

Short-acting benzodiazepines, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life of midazolam, respectively. Administration of fluconazole at a dose of 200 mg/day and 0.25 mg triazolam orally resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life of triazolam, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam. If a patient undergoing fluconazole therapy needs to be prescribed benzodiazepines concomitantly, the dose of the latter should be reduced and appropriate patient monitoring should be established.

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

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

Celecoxib: during concomitant administration of fluconazole (200 mg/day) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. During concomitant use of celecoxib and fluconazole, 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 levels.

Fentanyl: one 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 (reduced hepatic metabolism of the statin)), increases the risk of myopathy and rhabdomyolysis (dose-dependent). If concomitant use of these drugs is necessary, careful monitoring of patients for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels should be performed. If 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 necessary, as indicated in the statin product information.

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

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

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 at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an 1.8-fold increase in cyclosporine AUC was observed. These drugs 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 by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism by the CYP3A4 enzyme 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 up to 5-fold during oral administration due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. During intravenous administration of tacrolimus, no significant changes in pharmacokinetics were observed. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced depending on tacrolimus concentration.

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

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

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

Nonsteroidal anti-inflammatory drugs (NSAIDs): during concomitant use with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to corresponding values when flurbiprofen was used alone. Similarly, during concomitant use 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 used.

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. Dose adjustment of NSAIDs may be required.

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

Prednisone: a case has been reported where a patient after liver transplantation developed acute adrenal insufficiency while receiving prednisone, following discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving fluconazole and prednisone concomitantly over a long period should be carefully monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

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

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

Sulfonylurea derivatives: fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when administered to healthy volunteers. Frequent blood glucose monitoring and appropriate reduction of sulfonylurea derivative dose are recommended during concomitant use 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 used concomitantly with medicinal products 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% AUC, 80% Cmax) when tolvaptan, a CYP3A4 substrate, is used concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute kidney injury. If co-administered, the tolvaptan dose should be reduced according to the instructions in the tolvaptan product information and the patient should be regularly checked for any adverse reactions related to tolvaptan.

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

Vitamin A: a case has been reported where a patient receiving all-trans retinoic acid (acid form of vitamin A) concomitantly with fluconazole experienced central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri; 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 orally (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an average increase in Cmax and AUCτ of voriconazole by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

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

Azithromycin: 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 a dose of 200 mg/day resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. This suggests that multiple administration of fluconazole at the indicated doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use

Dermatophytia. According to studies on the use of 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, dosage recommendations for the treatment of such infections are not available.

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, dosage recommendations for the treatment of such infections are not available.

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

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

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

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of more severe liver injury.

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

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 cytochrome P450 enzyme. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported during Diflucan® use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other medicinal products affecting the QT interval. Patients with hypokalemia and progressive heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Diflucan® should be used with caution in patients at risk of 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. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has also been reported. Patients with AIDS are more prone to develop severe skin reactions when using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. In rare cases, anaphylactic reactions have been reported (see section "Contraindications").

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

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

Candidiasis. Studies have demonstrated an increasing prevalence of infections caused by Candida species other than C. albicans. These are often inherently resistant (e.g., C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after treatment failure. Therefore, prescribers are advised to consider the prevalence of resistance among different Candida species to fluconazole.

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

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

Use during pregnancy or breastfeeding

Women of childbearing potential

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

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

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

Pregnancy

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

Data from several thousand pregnant women who received fluconazole treatment with a cumulative dose ≤ 150 mg during the first trimester show no increased overall risk of fetal malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to 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 > 450 mg. The adjusted relative risk was 1.29 (95% CI: 1.05–1.58) for a fluconazole dose of 150 mg orally and 1.98 (95% CI: 1.23–3.17) for fluconazole doses > 450 mg.

Available epidemiological studies on the risk of congenital heart defects following fluconazole use during pregnancy provide conflicting results. However, a meta-analysis of five observational studies involving several thousand pregnant women who received fluconazole during the first trimester found 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.

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. Congenital malformations observed in these infants include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

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

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

Breastfeeding

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

Fertility

Fluconazole had no effect on fertility in male and female rats.

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

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

Patients should be informed about the possibility of developing dizziness or seizures (see section "Adverse reactions") 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 necessary, 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 the active infectious process.

Diflucan® is administered, depending on the dosage form, 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. 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: 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 treatment of certain forms of infection, especially meningitis, a dose of 800 mg/day may be appropriate.

Invasive candidiasis.

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

Candidiasis of mucous membranes.

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

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

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

Prophylaxis of 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 dose is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After this, a maintenance dose of 150 mg once weekly should be administered for 6 months.

Dermatomycoses.

• Tinea pedis, cutaneous candidiasis, tinea cruris, cutaneous candidiasis: the recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: the recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophytic onychomycosis: the recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced by healthy nail. Healthy nail growth on hands and great toes usually takes 3–6 months and 6–12 months, respectively. However, nail growth rate may vary among patients and depend on age. After successful treatment of chronic long-standing 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 the urine. Dose adjustment of fluconazole is not required after a single dose. For patients (including children) with impaired renal function requiring multiple doses, the initial dose on the first day of treatment should be 50–400 mg depending on the indication. Subsequently, the daily dose (depending on the indication) should be adjusted according to the table below:

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

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

Patients with hepatic impairment.

Fluconazole should be 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 clinical and mycological response. Diflucan® is administered once daily.

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

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

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or pediatric 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. Available information is presented 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 concentration 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 relapse 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.

The drug in capsule form may be administered to this patient population only when children are able to swallow capsules safely, which is generally 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.

In case of overdose, symptomatic 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%.

Adverse reactions.

Summary of safety profile

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

The most commonly reported adverse reactions were: headache, abdominal pain, diarrhoea, nausea, vomiting, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased 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 (≥ 1/10000 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, thrombocytopenia, neutropenia.

Immune system disorders.

Rare: anaphylaxis.

Metabolism and nutrition disorders.

Uncommon: decreased appetite.
Rare: hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Psychiatric disorders.

Uncommon: insomnia, somnolence.

Nervous system disorders.

Common: headache.
Uncommon: convulsions, paraesthesia, dizziness, taste disturbance.
Rare: tremor.

Ear and labyrinth disorders.

Uncommon: vertigo.

Cardiac disorders.

Rare: paroxysmal ventricular tachycardia of torsades de pointes type, QT interval prolongation (see section "Special warnings and precautions for use").

Gastrointestinal disorders.

Common: abdominal pain, nausea, diarrhoea, 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 rash (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 oedema, facial swelling, alopecia (see section "Special warnings and precautions for use").
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, 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.

Reporting of suspected adverse reactions.

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

Shelf life. 5 years.

Storage conditions.
Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.
50 mg capsules: 7 capsules in a blister pack, 1 blister pack in a cardboard box.
100 mg capsules: 10 capsules in a blister pack, 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer.
Fareva Amboise / Fareva Amboise.

Address of manufacturer and location of site of manufacture.
Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.