Fluconazole-teva

APPROVED by Order of the Ministry of Health of Ukraine _____________ No _____________ Registration Certificate No UA/16524/01/03 INSTRUCTION for medical use of the medicinal product FLUCONAZOLE-TEVA (FLUCONAZOLE-TEVA)

Composition:

Active substance: fluconazole;

1 hard capsule contains fluconazole 150 mg;

Excipients:

Capsule contents: lactose monohydrate, corn starch, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate;

Capsule shell: titanium dioxide (E 171), brilliant blue FCF (E 133), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules containing a white or yellowish-white homogeneous powder, with an opaque blue cap and body.

Pharmacotherapeutic group. Antifungal agents for systemic use, triazole derivatives. ATC code J02A C01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-α-lanosterol-demethylation mediated by cytochrome P450, an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-α-methyl-sterols correlates with subsequent loss of ergosterol in 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 50 mg once daily for 28 days had no effect on plasma testosterone concentrations in men or on steroid concentrations in women of reproductive age. Fluconazole at doses of 200–400 mg daily did not show clinically significant effects 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 multiple doses of 50 mg fluconazole do not affect antipyrine metabolism.

In vitro susceptibility

In vitro, fluconazole demonstrates antifungal activity against most clinically prevalent species of Candida (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. The minimum inhibitory concentration (MIC) and epidemiological cut-off value (ECOFF) of fluconazole for C. guilliermondii are higher than those for C. albicans.

Fluconazole also exhibits in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic fungal forms Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationships

Animal studies have shown a correlation between MIC values and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have demonstrated an almost 1:1 linear relationship between AUC and fluconazole dose. 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. Treatment is less effective for infections caused by strains with higher fluconazole MIC values.

Mechanisms of resistance

Candida species possess several mechanisms of resistance to azole antifungal agents. Fungal strains that have developed one or more of these resistance mechanisms are known to exhibit high MIC values to fluconazole, which negatively impacts efficacy in vivo and in clinical settings.

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

Cases of superinfection with Candida species other than C. albicans—which have intrinsic reduced susceptibility (C. glabrata) or are resistant to fluconazole (e.g., C. krusei and C. auris)—have been reported. Such infections may require alternative antifungal therapy. Resistance mechanisms have not been fully elucidated in some Candida species with intrinsic resistance (C. krusei) or emerging resistance (C. auris).

Cut-off values (according to recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST))

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, in vitro susceptibility, and clinical response, cut-off values for fluconazole against Candida species have been established. These are divided into non-species-specific cut-off values, primarily determined based on PK/PD data and independent of MIC distributions across species, and species-specific cut-off values, which are most commonly associated with human infections. These cut-off values are presented in the table below:

S – susceptible, R – resistant;

A – breakpoints not specific to a given species were established primarily based on PK/PD data and are independent of species-specific MIC distributions. They are used only for organisms lacking species-specific breakpoints;

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

* – the species C. glabrata belongs to category I. MICs against C. glabrata should be interpreted as resistant if they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is intended to prevent misclassification of "I" strains as "S". I – susceptible, increased exposure: a microorganism is classified as susceptible, increased exposure, when there is a high probability of therapeutic success due to enhanced agent exposure through adjustment of dosing regimen or increased 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 drug 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 concentration is reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 with repeated once-daily dosing. A steady-state 90% concentration is reached by day 2 of treatment when a loading dose twice the standard daily dose is administered on the first day.

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

Fluconazole penetrates well into all 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 exceeding serum levels are achieved in the skin, specifically in the stratum corneum, epidermis, dermis, and eccrine 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 in the stratum corneum 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 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 therapy ended.

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

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

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

Pharmacokinetics in Renal Impairment

In patients with severe renal impairment (CrCl < 20 mL/min), the elimination half-life increases from 30 to 98 hours, necessitating dose reduction. 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%.

Pharmacokinetics during Lactation

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

Pharmacokinetics in Children

Pharmacokinetic parameters were evaluated in 113 children across five studies: two single-dose, two multiple-dose, 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. With multiple dosing, the mean plasma elimination half-life ranged between 15 and 18 hours, and the volume of distribution was approximately 880 mL/kg. A longer half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life after intravenous single-dose administration of 3 mg/kg in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole use in neonates is limited to pharmacokinetic studies in 12 preterm infants with a gestational age of approximately 28 weeks. The median age at first dose was 24 hours (range 9–36 hours), and mean birth weight was 0.9 kg (range 0.75–1.10 kg). The study protocol was completed in 7 patients. Up to 5 intravenous fluconazole injections 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 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

Pharmacokinetics in Elderly Patients

In a study involving 22 patients (aged ≥65 years), fluconazole was administered orally at 50 mg. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after administration. Mean AUC was 76.4 ± 20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, changes in pharmacokinetics in elderly patients appear to depend on renal function parameters.

Clinical characteristics.

Indications.

Acute vaginal candidiasis when topical therapy is not appropriate.

Candidal balanitis when topical therapy is not appropriate.

Contraindications.

• Hypersensitivity to fluconazole, to other azole compounds, or to any of the excipients of the medicinal product;
• Concomitant use of fluconazole with terfenadine is contraindicated in patients receiving fluconazole repeatedly at doses of 400 mg daily or higher (based on interaction study results with repeated administration);
• Concomitant use of fluconazole with other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin); see also 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 with the following medicinal products is contraindicated

Cisapride. Cardiac events such as paroxysmal ventricular tachycardia of the "torsade de pointes" type have been reported in patients receiving fluconazole and cisapride simultaneously. In a controlled study, concomitant administration of fluconazole 200 mg once daily and cisapride 20 mg four times daily resulted in a significant increase in cisapride plasma levels and prolongation of the QTc interval. Combination therapy with fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine. Due to cases of serious cardiac arrhythmias caused by QTc interval prolongation in patients taking azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs have been conducted. In a study administering fluconazole 200 mg daily, no QTc interval prolongation was demonstrated. Another study administering fluconazole at 400 mg and 800 mg daily showed that fluconazole, when used at doses of 400 mg daily or higher, significantly increases terfenadine plasma levels upon concomitant administration. 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 with astemizole may reduce astemizole clearance. The resulting increased astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide. Concomitant use of fluconazole with pimozide may lead to inhibition of pimozide metabolism, although appropriate in vitro and in vivo studies have not been conducted. Increased pimozide plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole with pimozide is contraindicated (see section "Contraindications").

Quinidine. Concomitant use of fluconazole and quinidine may lead to inhibition of quinidine metabolism, although appropriate in vitro and in vivo studies have not been conducted. Quinidine use has been associated with QT interval prolongation and, rarely, paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole with quinidine is contraindicated (see section "Contraindications").

Erythromycin. Concomitant use of fluconazole with erythromycin may increase the risk of cardiotoxicity (QT interval prolongation and paroxysmal ventricular tachycardia of the "torsade de pointes" type), and consequently sudden coronary death. Concomitant use of fluconazole and erythromycin is contraindicated (see section "Contraindications").

Concomitant use with the following medicinal products is not recommended

Halofantrine. Fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of fluconazole and halofantrine may increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsade de pointes" type) and, consequently, lead to sudden coronary death. Use of this drug combination should be avoided (see section "Special precautions for use").

Concomitant use of fluconazole with the following medicinal products requires caution

Amiodarone. Concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. Fluconazole, especially at high doses (800 mg), should be used cautiously with amiodarone.

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

Effect of other medicinal products on fluconazole

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

Rifampicin. Concomitant use of fluconazole and rifampicin led to a 25% decrease in AUC and a 20% reduction in fluconazole elimination half-life. Therefore, for patients taking rifampicin, consideration should be given to increasing the fluconazole dose.

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

Effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of isoenzyme CYP2C19. In addition to these observed or documented interactions, there is a risk of increased concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, caution and careful patient monitoring are required when using these combinations. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after discontinuation of fluconazole due to its long elimination half-life.

Alfentanil. When fluconazole (400 mg) was administered concomitantly with alfentanil (20 μg/kg) intravenously to healthy volunteers, the AUC10 of alfentanil doubled, possibly due to CYP3A4 inhibition. Alfentanil dose adjustment may be necessary.

Amitriptyline, nortriptyline. Fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline is recommended at the start of combination therapy and after 1 week. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B. Concomitant use of fluconazole with amphotericin B in infected mice with normal and suppressed immunity demonstrated the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these study results is unknown.

Anticoagulants. During the post-marketing period, as with other azole antifungal agents, episodes of bleeding (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with increased prothrombin time have been reported in patients taking fluconazole concomitantly with warfarin. When fluconazole and warfarin were used concomitantly, a twofold prolongation of prothrombin time was observed, possibly due to inhibition of warfarin metabolism via CYP2C9. Patients receiving coumarin-type or indandione anticoagulants concomitantly with fluconazole require careful monitoring of prothrombin time. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam. Administration of fluconazole after oral administration of midazolam led to a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and midazolam 7.5 mg orally led to a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole 200 mg/day and 0.25 mg triazolam orally led to 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 when fluconazole and triazolam were used concomitantly.

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

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

Calcium channel blockers. Some calcium antagonists (nifedipine, isradipine, amlodipine, verapamil, 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. When fluconazole (200 mg daily) and celecoxib (200 mg) were used concomitantly, Cmax and AUC of celecoxib increased by 68% and 134%, respectively. When celecoxib and fluconazole are used concomitantly, a 50% reduction in celecoxib dose may be necessary.

Cyclophosphamide. Concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs can be used concomitantly, considering the risk of increased serum bilirubin and creatinine levels.

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

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

Ibrutinib. Moderate CYP3A4 inhibitors, such as fluconazole, increase ibrutinib plasma concentration and may increase the risk of toxicity. If combination therapy cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) to continue inhibitor use, and continuous clinical monitoring should be ensured.

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

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

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

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day were used concomitantly, a 1.8-fold increase in cyclosporine AUC was observed. These drugs can be used concomitantly provided cyclosporine dose is reduced depending on its concentration.

Everolimus. Although in vitro and in vivo studies have not been conducted, fluconazole may increase everolimus serum concentration due to inhibition of CYP3A4.

Sirolimus. Fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These drugs can 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 with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. With intravenous tacrolimus administration, no significant changes in pharmacokinetics were observed. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced depending on tacrolimus concentration.

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

Methadone. Fluconazole may increase methadone serum concentration. When methadone and fluconazole are used concomitantly, methadone dose adjustment may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs). When used concomitantly with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when fluconazole was used concomitantly with racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased 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 reactions and toxic effects associated with NSAIDs is recommended. NSAID dose adjustment may be necessary.

Phenytoin. Fluconazole inhibits hepatic phenytoin metabolism. Repeated concomitant administration of 200 mg fluconazole and 250 mg phenytoin intravenously increases phenytoin AUC24 by 75% and Cmin by 128%. When these drugs are used concomitantly, serum phenytoin concentration should be monitored to avoid phenytoin toxicity.

Prednisone. A case has been reported where a patient after liver transplantation developed acute adrenal insufficiency while on prednisone, occurring after discontinuation of a three-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients who have been taking fluconazole and prednisone concomitantly for a prolonged period 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. Uveitis has been reported when fluconazole and rifabutin are used concomitantly. Symptoms of rifabutin toxicity should be considered when using this drug combination.

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

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

Theophylline. In a placebo-controlled interaction study of fluconazole and theophylline, administration of fluconazole 200 mg for 14 days was found to reduce theophylline plasma clearance 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 when used concomitantly with medicinal products causing moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole). Therefore, it is recommended to reduce the tofacitinib dose to 5 mg once daily when used in combination with these drugs.

Tolvaptan. Exposure to tolvaptan significantly increases (200% in AUC; 80% in Cmax) when tolaptan, a CYP3A4 substrate, is used concomitantly with fluconazole, a moderate CYP3A4 inhibitor, increasing the risk of adverse reactions, especially significant diuresis, dehydration, and acute kidney injury. When used concomitantly, the tolaptan dose should be reduced according to its prescribing instructions, and the patient should be frequently monitored for any adverse reactions associated with tolaptan use.

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

Vitamin A. It has been reported that a patient receiving tretinoin acid (the acid form of vitamin A) concomitantly with fluconazole experienced central nervous system adverse reactions in the form of pseudotumor cerebri; this effect resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of central nervous system adverse reactions should be remembered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4). Concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers led to 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 adverse effects associated with voriconazole is recommended.

Zidovudine. Fluconazole increases zidovudine Cmax and AUC by 84% and 74%, respectively, due to a decrease in zidovudine clearance by approximately 45% upon 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 drug combination 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. Data from two pharmacokinetic studies of repeated administration of fluconazole and a combined oral contraceptive show that no effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily resulted in a 40% increase in ethinylestradiol AUC and a 24% increase in levonorgestrel AUC. This indicates that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Physicians should be aware that interaction studies with other medicinal products have not been conducted, but such interactions may occur.

Special precautions for use

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

Cryptococcosis. Evidence of fluconazole efficacy for the treatment of other forms of cryptococcosis (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, dosage recommendations for the treatment of such infections are not available.

Deep endemic mycoses. Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, dosage recommendations for the treatment of such infections are not available.

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

Renal system. Fluconazole 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 rarely observed. Adrenal insufficiency associated with concomitant treatment with prednisone is described in the section "Interaction with other medicinal products and other types of interactions".

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

Patients who develop abnormalities in liver function tests during fluconazole treatment should be closely monitored for possible development of more severe liver damage.

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

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

Fluconazole should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QT interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated.

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.

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Patients with AIDS are more prone to 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 treatment with the drug should be discontinued. If a patient with invasive/systemic fungal infection develops skin rash, careful monitoring is required, and fluconazole treatment should be discontinued in case of bullous eruptions or erythema multiforme. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported.

Hypersensitivity. Rare cases of anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. Fluconazole is also a potent inhibitor of the CYP2C19 enzyme. Patients receiving concomitant fluconazole and medicinal products with a narrow therapeutic window that are metabolized via CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

Terfenadine. Close monitoring of the patient is required when terfenadine is used concomitantly with fluconazole at doses below 400 mg per day.

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

One capsule of the medicinal product contains less than 1 mmol of sodium (23 mg), so the product 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 1 week (corresponding to 5–6 half-lives) should be observed before conception.

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 who 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, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg, compared to women who received topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses exceeding 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05 to 1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI 1.23 to 3.17) for doses exceeding 450 mg of fluconazole.

Available epidemiological studies on the risk of congenital heart defects associated with fluconazole use during pregnancy have yielded 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 use fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for more than three months for the treatment of coccidioidomycosis. The congenital malformations observed in these infants included brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radiohumeral synostosis. A causal relationship between fluconazole use and these congenital malformations has not been established.

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

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

Breastfeeding

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

Fertility

Animal studies have shown that fluconazole did not affect fertility in male and female rats.

Ability to influence reaction rate when driving or operating machinery.

Studies on the ability of fluconazole to influence reaction speed during driving or operating machinery have not been conducted.

Patients should be warned about the possibility of dizziness or seizures during fluconazole treatment and advised to refrain from driving or operating machinery if any of these symptoms occur.

Method of Administration and Dosage

Capsules should be swallowed whole. The administration of the drug is not dependent on food intake.

Adults.

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

Elderly patients.

In the absence of signs of renal impairment, the usual adult dose should be used for treatment in this patient category.

Renal impairment.

Fluconazole is primarily excreted unchanged in the urine. Dose adjustment is not required for this category of patients when the drug is administered as a single dose.

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Children.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite comprehensive data on fluconazole use in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the usual adult doses should be used.

Overdose.

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

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

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

Side effects

The most frequently reported adverse reactions (≥ 1/100 to < 1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in blood. A drug reaction with eosinophilia and systemic symptoms (DRESS) associated with fluconazole use has been reported.

The following classification was 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: anemia
Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia

Immune system disorders

Rare: anaphylaxis

Metabolism and nutrition disorders

Uncommon: decreased appetite
Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia

Psychiatric disorders

Uncommon: insomnia, somnolence

Nervous system disorders

Common: headache
Uncommon: seizures, dizziness, paraesthesia, 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

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting
Uncommon: constipation, dyspepsia, flatulence, dry mouth

Hepatobiliary disorders

Common: increased levels of ALT, AST, alkaline phosphatase in blood
Uncommon: cholestasis, jaundice, increased bilirubin levels
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury

Skin and subcutaneous tissue disorders

Common: rash
Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in children during clinical trials, except for genital candidiasis, were comparable to those in adults.

Reporting suspected adverse reactions. All suspected adverse reactions and cases of lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

1 capsule in a blister; 1 blister per carton.

Prescription status. Over-the-counter.

Manufacturer. Teva Pharmaceutical Works Private Limited Company

Manufacturer's address and location of its business operations.

Unit 1; H-4042 Debrecen, Pallagi Street 13, Hungary