Fluconazole-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCONAZOLE-TEVA (FLUCONAZOLE-TEVA)

Composition:

Active substance: fluconazole;

1 hard capsule contains fluconazole 50 mg, or 100 mg, or 200 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, azorubine (E 122) (only for 200 mg capsules).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

Hard capsules 50 mg: hard gelatin capsules filled with white or yellowish-white homogeneous powder, with an opaque blue cap and an opaque white body;

Hard capsules 100 mg: hard gelatin capsules filled with white or yellowish-white homogeneous powder, with an opaque blue cap and an opaque white body;

Hard capsules 200 mg: hard gelatin capsules filled with white or yellowish-white homogeneous powder, with an opaque purple cap and an opaque white 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-alpha-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 to 400 mg daily did not demonstrate clinically significant effects on endogenous steroid levels or on response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Studies investigating interactions with antipyrine demonstrated that single or repeated administration of 50 mg fluconazole does 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 exhibits reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. The minimum inhibitory concentration (MIC) and epidemiological cutoff value (ECOFF) of fluconazole for C. guilliermondii are higher than for C. albicans.

Fluconazole also demonstrates 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.

Relationship between Pharmacokinetic and Pharmacodynamic Properties

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 insufficient, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Treatment is also less effective in infections caused by strains with higher fluconazole MIC values.

Mechanism 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 in vivo and clinical efficacy.

In typically susceptible Candida species, the most commonly occurring resistance mechanism involves the azole target enzymes responsible for ergosterol biosynthesis. Resistance may result from 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 certain Candida species with intrinsic resistance (C. krusei) or newly emerging species (C. auris).

Breakpoints (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, breakpoints for fluconazole against Candida species have been established. These are categorized into non-species-specific breakpoints, primarily determined based on PK/PD data and independent of MIC distributions for specific species, and species-specific breakpoints, which are most commonly associated with human infections.

These breakpoints are presented in the table below:

Antifungal agent	Species-specific breakpoints (S≤/R>), mg/l						Non-species-specific breakpointsА (S≤/R>), 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 linked to a specific 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 therapy;

* – 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 defined to prevent misclassification of "I" strains as "S" strains. I – intermediate: the microorganism is categorized as susceptible, increased exposure. A microorganism is classified as such when there is a high likelihood of therapeutic success due to increased exposure achieved by adjusting the dosing regimen or increasing the agent's concentration at the site of infection.

Pharmacokinetics.

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

Absorption. Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect absorption following oral administration. 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 concentration of 90% is reached by the second day of treatment 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. Concentrations in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, fluconazole concentrations in cerebrospinal fluid reach 80% of plasma levels.

High fluconazole concentrations in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis, and eccrine sweat. Fluconazole accumulates in the stratum corneum. After a 50 mg once-daily dose, 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 150 mg once-weekly dose, fluconazole concentration in the stratum corneum was 23.4 µg/g on day 7 and remained at 7.1 µg/g seven days after the next dose.

Fluconazole concentration in nails after 4 months of 150 mg once weekly 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 completion.

Metabolism. Fluconazole is minimally metabolized. After administration of radiolabeled fluconazole, only 11% of the dose 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 half-life allows for single-dose treatment of 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 concentrations of fluconazole were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who had temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of 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 dose of fluconazole received by the 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, corresponding to 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 in 113 children were evaluated in five studies: two single-dose studies, two multiple-dose studies, and one study in preterm neonates.

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. 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 observed 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 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 doses of fluconazole 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. 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 and older, fluconazole was administered orally at a dose of 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. Thus, pharmacokinetic changes in elderly patients appear to depend on renal function parameters.

Clinical characteristics.

Indications.

Treatment of the following diseases in adults:

• cryptococcal meningitis;
• coccidioidomycosis;
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis, esophageal candidiasis, candiduria, chronic cutaneous and mucosal candidiasis;
• chronic atrophic oral candidiasis (denture stomatitis) when oral hygiene or local therapy is ineffective;
• vaginal candidiasis (acute or recurrent) when local therapy is inappropriate;
• candidal balanitis when local therapy is inappropriate;
• dermatomycoses, including tinea pedis, tinea of smooth skin, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophytic onychomycosis when use of other medicinal products is not appropriate.

Prophylaxis of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction of the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation).

Children.

Fluconazole may be used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prophylaxis of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it.

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

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 per day or higher (based on multiple-dose interaction studies);
• 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 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 "torsades de pointes" type have been reported in patients receiving fluconazole and cisapride concomitantly. 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 plasma cisapride levels and QTc interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine. Due to cases of serious cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. A study with fluconazole 200 mg daily did not demonstrate QTc interval prolongation. Another study with fluconazole 400 mg and 800 mg daily showed that fluconazole significantly increases plasma terfenadine levels when administered at doses of 400 mg daily or higher. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used concomitantly with terfenadine at doses below 400 mg daily, 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 "torsades 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 relevant in vitro and in vivo studies have not been conducted. Increased plasma pimozide concentration may result in QT interval prolongation and, rarely, in paroxysmal ventricular tachycardia of the "torsades 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 relevant 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 "torsades 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 "torsades 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 "torsades de pointes" type) and consequently lead to sudden coronary death. 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 with caution when administered 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 resulted in a 25% decrease in AUC and a 20% reduction in fluconazole elimination half-life. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

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

Effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to these observed or documented interactions, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, caution is required and careful patient monitoring should be performed when these combinations are used. 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 intravenous alfentanil (20 mcg/kg) to healthy volunteers, the AUC of alfentanil increased twofold, possibly due to CYP3A4 inhibition. Dose adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline. Fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline is recommended at the beginning of combination therapy and after 1 week. Dose adjustment of amitriptyline/nortriptyline may be 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 findings 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 receiving fluconazole concomitantly with warfarin. Concomitant use of fluconazole and warfarin resulted in a twofold prolongation of prothrombin time, 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 midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Concomitant use of fluconazole 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 with 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 serum concentration and clinical 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. Concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg) increased Cmax and AUC of celecoxib by 68% and 134%, respectively. When celecoxib is used concomitantly with fluconazole, a 50% reduction in celecoxib dose may be necessary.

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

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

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin), increases the risk of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, careful monitoring for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels are required. If significant elevation of creatine kinase levels occurs, 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 the combination cannot be avoided, the ibrutinib dose should be reduced to 280 mg once daily (2 capsules) to continue therapy, with continuous clinical monitoring.

Ivacaftor. 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. Patients receiving moderate CYP3A inhibitors such as fluconazole and erythromycin concomitantly should have their ivacaftor dose reduced 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. Concomitant use of fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day resulted in a 1.8-fold increase in cyclosporine AUC. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus. Although in vitro and in vivo studies have not been conducted, fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

Sirolimus. Fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These drugs may be used concomitantly provided sirolimus dose is adjusted based on its concentration and clinical 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. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced based on tacrolimus concentration.

Losartan. Fluconazole inhibits the metabolism of losartan 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. Dose adjustment of methadone may be necessary when used concomitantly with fluconazole.

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, concomitant use of fluconazole with racemic ibuprofen (400 mg) increased Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer by 15% and 82%, respectively, compared to racemic ibuprofen alone.

Although specific studies have not 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. Dose adjustment of NSAIDs may be necessary.

Phenytoin. Fluconazole inhibits hepatic metabolism of phenytoin. Multiple 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 is required when these drugs are used concomitantly to avoid phenytoin toxicity.

Prednisone. A case was reported in which 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 long-term concomitant fluconazole and prednisone should be carefully monitored to prevent adrenal insufficiency after stopping fluconazole.

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

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

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

Tofacitinib. The effect of tofacitinib increases when used concomitantly with medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, the tofacitinib dose should be reduced to 5 mg once daily when used in combination with these drugs.

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

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

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

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

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4). Concomitant oral administration of voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an average increase in 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 voriconazole-associated adverse effects 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-zidovudine combination. Patients receiving this drug combination should be monitored for zidovudine-associated adverse reactions. Consideration may be given to reducing the zidovudine dose.

Azithromycin. In an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effect of azithromycin and fluconazole on each other's pharmacokinetics was evaluated after single oral doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives. Data from two multiple-dose pharmacokinetic studies of fluconazole and combined oral contraceptives show that fluconazole at a dose of 50 mg had no effect on hormone levels, whereas fluconazole at 200 mg daily increased AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that repeated use 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.

Dermatophytia. According to studies on fluconazole for the treatment of dermatophytia in children, fluconazole does not exceed griseofulvin in efficacy, and the overall effectiveness rate is less than 20%. Therefore, fluconazole 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 treating such conditions 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 treating such conditions are not available.

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

Renal system. 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 rare. Adrenal insufficiency associated with concomitant treatment with prednisone is described in the section "Interaction with other medicinal products and other forms of interaction".

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 was associated with fluconazole use, there was no clear dependence on the total daily dose of the drug, 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 progression to 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 immediately discontinued and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of the cytochrome P450 system. In the post-marketing period, very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the torsades de pointes type have been reported with fluconazole use. These reports involved patients with severe 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 arrhythmias. Concomitant use with medicinal products that prolong the QT interval and are metabolized by the cytochrome P450 CYP3A4 enzyme 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 developing severe skin reactions when taking 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, close 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 fluconazole concomitantly with drugs having a narrow therapeutic window that are metabolized via CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

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

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

One capsule of the medicinal product contains less than 1 mmol of sodium (23 mg), thus the product can be considered essentially "sodium-free".

Fluconazole-Teva 200 mg hard capsules contain azorubine, which may cause allergic reactions.

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 attempting pregnancy.

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 cumulative doses of ≤ 150 mg fluconazole in 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 increase in the risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving cumulative doses ≤ 450 mg, compared to women receiving 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 150 mg of oral 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 cardiac malformations following fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester revealed an 1.8–2-fold increased risk of cardiac malformations 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 3 months for the treatment of coccidioidomycosis. The 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 these congenital malformations has not been established.

Standard doses of fluconazole and short-term fluconazole treatment courses should not be used during pregnancy except when strictly 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 child'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 does not affect fertility in male or female rats.

Ability to influence reaction speed when driving or operating machinery.

Studies on the ability of fluconazole to affect reaction speed when 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 affected by food intake.

Dosage

The dosage should be determined according to the type and severity of the fungal infection. Treatment of infections requiring repeated administration of the drug should be continued until clinical parameters or laboratory tests confirm the absence of active fungal infection. Insufficient duration of treatment may lead to recurrence of the active infection process. For most cases of vaginal candidiasis, a single dose of the drug is sufficient.

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 of developing it: the recommended dose of the drug is 200 mg/day for an indefinite period.

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 daily dose of 800 mg may be appropriate.

Invasive candidiasis.

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

Oral mucosal candidiasis.

• 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 skin and mucosal candidiasis: 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 of developing it.

• 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 for immunocompromised patients.

Prophylaxis of candidiasis infections in patients with prolonged neutropenia.

• The recommended dose is 200–400 mg once daily. Treatment should be initiated several days before the expected onset of neutropenia and continued for 7 days after neutrophil counts rise above 1000/mm³.

Genital candidiasis.

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

Dermatomycoses.

• Tinea pedis, cutaneous mycosis, 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 regrowth on hands and great toes usually requires 3–6 months and 6–12 months, respectively. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-term chronic infections, nail appearance may sometimes remain altered.

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. The drug should be administered once daily. Capsules should be swallowed whole and taken regardless of food intake.

For children with renal function impairment, see dosage in the section «Renal function impairment». The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Infants, preschool children, and older children (from 28 days to 11 years of age)

Indications	Dosage	Recommendation
Oral mucosal candidiasis	Initial dose: 6 mg/kg; Maintenance dose: 3 mg/kg once daily	The initial dose may be administered on the first day to achieve steady-state concentration more rapidly
Invasive candidiasis Cryptococcal meningitis	6 to 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 of developing the disease	6 mg/kg once daily	Depending on the severity of the disease
Prophylaxis of candidiasis in immunocompromised patients	3 to 12 mg/kg once daily	Depending on the severity and duration of induced neutropenia (see also dosing recommendations for adults)

Adolescents (12 to 17 years of age)

Depending on body weight and pubertal development, the physician should decide which dosage (adult or pediatric) is most appropriate for the patient. Clinical data indicate that children have a higher fluconazole clearance rate than adults.

Administration of 100, 200, and 400 mg doses in adults and 3, 6, and 12 mg/kg doses in children results in comparable systemic exposure.

The safety and efficacy of fluconazole in the treatment of genital candidiasis in children have not been established. The currently available information is presented in the section “Adverse Reactions”. If urgent treatment of genital candidiasis in adolescents (12 to 17 years of age) is required, the dosage should be the same as that for adults.

Administration method

Fluconazole may be administered orally or intravenously, depending on the patient's clinical condition. When switching from intravenous to oral administration or vice versa, there is no need to change the daily dose.

Special patient groups

Elderly patients

Dosage should be adjusted according to renal function (see “Renal impairment”).

Renal impairment

Fluconazole is predominantly excreted unchanged in the urine. Dose adjustment is not required for single doses. In patients (including children) with impaired renal function requiring multiple doses of fluconazole, the initial dose should be 50 to 400 mg depending on the indication. The daily dose (depending on the indication) should be calculated according to the table below:

Creatinine clearance (ml/min) > 50 ≤ 50 (without hemodialysis) Hemodialysis

Percentage of recommended dose 100 % 50 % 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, patients should receive a dose adjusted according to creatinine clearance.

Hepatic impairment

Fluconazole should be administered with caution to patients with hepatic impairment, as there is insufficient data regarding the use of fluconazole in this patient population (see sections "Special warnings and precautions for use" and "Side effects").

Children

The capsule formulation may be administered to this patient group only when children are able to safely swallow capsules, which is generally possible at the age of 5 years.

Overdose

Cases of fluconazole overdose have been reported; hallucinations and paranoid behavior have also been reported.

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

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

Adverse Reactions

The most commonly 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. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) associated with fluconazole use have 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 based on 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 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 blood levels of ALT, AST, alkaline phosphatase
Uncommon: cholestasis, jaundice, increased bilirubin levels
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury

Skin and subcutaneous tissue disorders

Common: rash
Uncommon: 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, apart from genital candidiasis, were comparable to those in adults.

Reporting of suspected adverse reactions. Suspected adverse reactions and lack of therapeutic 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.

Hard capsules 50 mg or 100 mg: 7 or 10 capsules per blister; 1 blister per carton.

Hard capsules 200 mg: 1, 4, 7, or 10 capsules per blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

Manufacturer's address and site of operation.
Site 1; H-4042 Debrecen, Pallagi str. 13, Hungary.