Fluzamed hard capsules 150 mg blister No. 1

Instructions Fluzamed hard capsules 150 mg blister No. 1

Composition

active ingredient: fluconazole;

1 capsule contains 150 mg of fluconazole;

excipients: microcrystalline cellulose; lactose, monohydrate; magnesium stearate; sodium lauryl sulfate; gelatin capsule: black iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171), gelatin.

Dosage form

The capsules are hard.

Main physicochemical properties: hard gelatin capsules, size No. 1, cap and body of matte light green color, containing white to almost white powder.

Pharmacotherapeutic group

Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.

Pharmacological properties

Pharmacodynamics

Mechanism of action.

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is inhibition of fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. Accumulation of 14-alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.

Fluconazole 50 mg daily for 28 days had no effect on plasma testosterone levels in men or on endogenous steroid levels in women of reproductive age. Fluconazole 200-400 mg daily had no clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone stimulation in healthy male volunteers.

Interaction studies with antipyrine have shown that single or repeated administration of 50 mg fluconazole does not affect the metabolism of antipyrine.

In vitro sensitivity.

Fluconazole has demonstrated antifungal activity in vitro against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, while C. krusei is resistant to it.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mold fungi Blastomices dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

The relationship between pharmacokinetic and pharmacodynamic properties.

According to the results of animal studies, there is a correlation between the minimum inhibitory concentration and the efficacy against experimental models of mycoses caused by Candida species. According to the results of clinical studies, there is a linear relationship between the area under the pharmacokinetic curve "concentration-time" (AUC) and the dose of fluconazole (approximately 1:1). There is also a direct but insufficient relationship between AUC or dose and a positive clinical response to the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, the treatment of infections caused by strains for which fluconazole shows a high minimum inhibitory concentration is less satisfactory.

Mechanism of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole exhibits high minimum inhibitory concentrations against fungal strains that possess one or more mechanisms of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection with Candida spp., other than C. albicans, species that are often insensitive to fluconazole (e.g. C. krusei), has been reported. Alternative antifungal agents should be used in such cases.

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

Based on a review of pharmacokinetic/pharmacodynamic information, in vitro susceptibility and clinical response, breakpoints for fluconazole have been established for Candida species. These have been divided into non-species breakpoints, which are largely based on pharmacokinetic/pharmacodynamic information and are not dependent on species-specific MICs, and species-specific breakpoints, which are most commonly associated with human infections. These breakpoints are listed below.

S = sensitive;

R = resistant;

a – non-species-specific breakpoints, which were determined largely on the basis of pharmacokinetic/pharmacodynamic information and do not depend on the distribution into specific species by minimum inhibitory concentration. They were studied only in microorganisms for which there is no specific breakpoint;

- susceptibility testing is not recommended, as this species is not the target of drug therapy;

IE – there is insufficient evidence to support this species as a target for drug therapy.

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

Absorption.

Fluconazole is well absorbed after oral administration, and plasma fluconazole levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect the absorption of fluconazole after oral administration. Peak plasma concentrations (Cmax) are reached 0.5–1.5 hours after administration of fluconazole in the fasted state. Fluconazole plasma concentrations are dose-proportional. Steady-state concentrations of 90% are reached by day 4–5 of multiple once-daily fluconazole administration. Steady-state concentrations of 90% are reached by day 2 of treatment with a loading dose of twice the usual daily dose on day 1.

Distribution.

The volume of distribution is approximately equal to the total body fluid content. Plasma protein binding is low (11–12%).

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

High concentrations of fluconazole in the skin, exceeding those in plasma, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When using a dose of 50 mg 1 time per day, the concentration of fluconazole after 12 days of treatment was 73 μg / g, and 7 days after the end of treatment, the concentration was still 5.8 μg / g. When using a dose of 150 mg 1 time per week, the concentration of fluconazole on the 7th day of treatment was 23.4 μg / g; 7 days after the next dose, the concentration was still 7.1 μg / g.

The concentration of fluconazole in nails after 4 months of 150 mg once weekly was 4.05 μg/g in healthy volunteers and 1.8 μg/g in nail diseases; fluconazole was detected in nail samples 6 months after the end of therapy.

Metabolism.

Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted unchanged in the urine. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as a potent inhibitor of CYP2C19 isoenzyme.

Breeding.

The plasma half-life (t1/2) is about 30 hours. Most of fluconazole is excreted by the kidneys, with 80% of the administered dose being found in the urine unchanged. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The long t1/2 allows for a single use of fluconazole for vaginal candidiasis, as well as the use of fluconazole once a week for other indications.

Use in patients with renal failure.

In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min) t1/2 increases from 30 to 98 hours. Therefore, this category of patients requires a reduction in the dose of fluconazole. Fluconazole is removed by hemodialysis and to a lesser extent by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.

Use during breastfeeding.

Fluconazole plasma and breast milk concentrations were evaluated in a pharmacokinetic study in 10 lactating women who had temporarily or permanently discontinued breastfeeding their infants for 48 hours after a single 150 mg dose. Fluconazole was found in breast milk at a mean concentration of approximately 98% of that observed in maternal plasma. The mean Cmax in breast milk was 2.61 mg/L 5.2 hours after dosing. The daily dose of fluconazole received by the infant from breast milk (assuming an average milk intake of 150 ml/kg/day), calculated based on the average Cmax in milk of 0.39 mg/kg/day, is approximately 40% of the dose recommended for newborns (< 2 weeks of age), or 13% of the dose recommended for infants for the treatment of mucosal candidiasis.

Application to children.

Pharmacokinetic data were evaluated in 113 children in 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 study in premature infants.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age of the infant at the time of first dose was 24 hours (range 9 to 36 hours); the mean birth weight was 900 g (range 750 to 1100 g). Seven patients completed the study protocol. A maximum of 5 intravenous injections of fluconazole at a dose of 6 mg/kg were administered every 72 hours. The mean t1/2 was 74 hours (range 44–185) on day 1, then decreased to 53 hours (range 30–131) on day 7 and to 47 (range 27–68) on day 13. AUC (μg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. Volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and 1328 (1040–1680) on day 13.

Use in elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) who received 50 mg of fluconazole orally. 10 patients were taking diuretics concomitantly. Cmax was 1.54 μg/ml and was reached within 1.3 hours after fluconazole administration. The mean AUC was 76.4±20.3 μg*h/ml. The mean t1/2 was 46.2 hours. These pharmacokinetic parameters are higher compared to those in healthy younger volunteers. Concomitant use of diuretics had no significant effect on Cmax and AUC. Also, creatinine clearance (74 ml/min), the percentage of fluconazole excreted unchanged in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 ml/min/kg) in patients of this age group were lower than those in younger volunteers. Therefore, changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Indication

acute vaginal candidiasis when topical therapy is not appropriate; candidal balanitis when topical therapy is not appropriate.

Drug therapy may be initiated prior to obtaining the results of culture and other laboratory tests, but once the test results are available, anti-infective therapy should be adjusted accordingly.

Official recommendations for the appropriate use of antifungal agents should be considered.

Contraindication

Hypersensitivity to fluconazole, other azole compounds or to other excipients of the drug; simultaneous use of fluconazole and terfenadine in patients taking fluconazole multiple times at doses of 400 mg per day and above (according to the results of a multiple-dose interaction study);

Concomitant use of fluconazole and other drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme, such as cisapride, astemizole, pimozide, quinidine and erythromycin (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Interaction with other medicinal products and other types of interactions

The concomitant use of fluconazole and the following drugs is contraindicated.

Cisapride.

Cardiac adverse reactions, including torsades de pointes, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of fluconazole 200 mg once daily and cisapride 20 mg four times daily resulted in significant increases in plasma cisapride levels and QT prolongation. Concomitant use of these agents is contraindicated (see section 4.3).

Terfenadine.

Due to cases of serious cardiac arrhythmias caused by QTc prolongation, drug-drug interaction studies have been conducted in patients receiving azole antifungals concomitantly with terfenadine. One study with fluconazole 200 mg/day did not show any QTc prolongation. Another study with fluconazole 400 mg/day and 800 mg/day demonstrated that fluconazole at doses of 400 mg/day or higher significantly increased plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg/day or higher with terfenadine is contraindicated (see section 4.3). When fluconazole is administered concomitantly with terfenadine at doses below 400 mg/day, the patient should be closely monitored.

Astemizole.

Concomitant use with fluconazole may reduce the clearance of astemizole. The resulting increase in plasma concentrations of astemizole may lead to QT prolongation and, in rare cases, torsades de pointes. Concomitant use of these agents is contraindicated (see section 4.3).

Pimozide and quinidine.

Concomitant use with fluconazole may result in inhibition of the metabolism of pimozide or quinidine, although no in vitro or in vivo studies have been conducted. Increased plasma concentrations of pimozide or quinidine may prolong the QT interval and, in rare cases, lead to the development of paroxysmal torsades de pointes. Concomitant use of these agents is contraindicated (see Contraindications).

The concomitant use of erythromycin and fluconazole may lead to an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The concomitant use of these agents is contraindicated (see section "Contraindications").

The concomitant use of fluconazole and the following medicines is not recommended.

Halofantrine.

Concomitant use of fluconazole and halofantrine may lead to increased plasma concentrations of halofantrine due to inhibition of CYP3A4. The resulting increase in plasma concentrations of halofantrine may increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, consequently, sudden cardiac death. Concomitant use of these agents should be avoided (see section 4.4).

The concomitant use of fluconazole and the following medicinal products requires caution.

Amiodarone.

Concomitant use of fluconazole and amiodarone may prolong the QT interval. Concomitant use of these agents requires caution, especially when taking high doses of fluconazole (800 mg).

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

Effect of other drugs on fluconazole.

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

Rifampicin.

Concomitant use with rifampicin resulted in a 25% decrease in AUC and a 20% decrease in t1/2 of fluconazole. An increase in the dose of fluconazole should be considered when these agents are used concomitantly.

Hydrochlorothiazide.

In a pharmacokinetic interaction study, multiple simultaneous administration of hydrochlorothiazide to healthy volunteers increased the plasma concentration of fluconazole by 40%. These interaction parameters do not require changes in the dosing regimen of fluconazole in patients taking concomitant diuretics.

The effect of fluconazole on other drugs.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of the CYP2C19 isoenzyme. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 when used concomitantly with fluconazole. Therefore, such agents should be used concomitantly with fluconazole with caution and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long t1/2 (see section "Contraindications").

Alfentanil.

Co-administration of alfentanil (20 mcg/kg) to healthy volunteers resulted in a two-fold increase in the AUC10 of fluconazole (400 mg), possibly due to inhibition of CYP3A4. Alfentanil dose adjustment may be necessary when these agents are co-administered.

Amitriptyline, nortriptyline.

Concomitant use with fluconazole has been shown to potentiate the effects of amitriptyline or nortriptyline. In the case of concomitant use of these agents, it is recommended to measure the concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy and after 1 week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B.

Concomitant administration of fluconazole and amphotericin B to infected mice with normal immunity and infected mice with reduced immunity yielded the following results: a small additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism of these agents in systemic Aspergillus fumigatus infection. The clinical significance of the results obtained in these studies is unknown.

Anticoagulants.

As with other azole antifungals, bleeding events (hematomas, epistaxis, gastrointestinal bleeding, haematuria and melena) in association with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, probably due to inhibition of warfarin metabolism by CYP2C9. Prothrombin time should be closely monitored when fluconazole is coumarin anticoagulants or indanedione are administered concomitantly. Dose adjustment of anticoagulants may be necessary.

Concomitant use with fluconazole resulted in a significant increase in the concentration of oral midazolam and increased psychomotor effects. Concomitant use of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally resulted in an increase in the AUC and t1/2 of midazolam by 3.7 and 2.2 times, respectively. Concomitant use of fluconazole at a dose of 200 mg per day and 0.25 mg orally resulted in an increase in the AUC and t1/2 of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of the effects of triazolam were observed with the simultaneous use of fluconazole and triazolam. In the case of concomitant use of fluconazole with benzodiazepines, the dose of benzodiazepines should be reduced and appropriate monitoring of the patient's condition should be established.

Carbamazepine.

Concomitant use with fluconazole inhibits the metabolism of carbamazepine and causes an increase in carbamazepine plasma levels by 30%. There is a risk of carbamazepine toxicity. In the case of simultaneous use of these agents, it may be necessary to adjust the dose of carbamazepine depending on its concentration and effects.

Calcium channel blockers.

Some calcium antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase the systemic exposure of calcium channel blockers. Careful monitoring for adverse reactions is recommended when these agents are used concomitantly.

Celecoxib.

Concomitant use with fluconazole (200 mg daily) increased the Cmax and AUC of celecoxib (200 mg) by 68% and 134%, respectively. A 2-fold reduction in the dose of celecoxib may be necessary when these agents are used concomitantly.

Cyclophosphamide.

Concomitant use of cyclophosphamide and fluconazole leads to an increase in plasma bilirubin and creatinine levels. These agents can be used simultaneously, given the risk of increasing plasma bilirubin and creatinine concentrations.

Fentanyl.

A fatal case of fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. In addition, a study in healthy volunteers demonstrated that concomitant use with fluconazole significantly delayed the elimination of fentanyl. Increased fentanyl concentrations may lead to respiratory depression. Patients should be closely monitored when these agents are used concomitantly. Fentanyl dosage 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 agents is necessary, the patient should be closely monitored for symptoms of myopathy and rhabdomyolysis and plasma creatine kinase levels should be monitored. In the event of a significant increase in creatine kinase levels, as well as when myopathy/rhabdomyolysis is diagnosed or suspected, the use of HMG-CoA reductase inhibitors should be discontinued.

Olaparib.

Concomitant use with moderate CYP3A4 inhibitors such as fluconazole increases olaparib plasma concentrations. Concomitant use of these agents is not recommended. If this combination cannot be avoided, olaparib should be limited to 200 mg twice daily.

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

Cyclosporine.

Concomitant use with fluconazole significantly increases the concentration and AUC of cyclosporine. When fluconazole 200 mg per day was administered simultaneously with cyclosporine 2.7 mg/kg/day, an increase in cyclosporine AUC by 1.8 times was observed. These agents can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration.

Everolimus.

Although in vitro and in vivo studies have not been performed, it is known that fluconazole may increase everolimus plasma concentrations through inhibition of CYP3A4.

Sirolimus.

Concomitant use with fluconazole increases sirolimus plasma concentrations, likely by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These agents can be used concomitantly, with dose adjustments of sirolimus based on serum concentrations and effects.

Tacrolimus.

Concomitant use with fluconazole may increase the plasma concentration of tacrolimus up to 5-fold compared to oral tacrolimus due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics have been observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced depending on tacrolimus concentration when these agents are used concomitantly.

Losartan.

Concomitant use with fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism of losartan. In the case of concomitant use of these agents, continuous monitoring of blood pressure in patients is recommended.

Methadone.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Concomitant use with fluconazole increased the Cmax and AUC of flurbiprofen by 23% and 81%, respectively, compared with flurbiprofen alone. Similarly, when fluconazole was co-administered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared with racemic ibuprofen alone. Although no specific studies have been conducted, fluconazole may increase the systemic exposure of other NSAIDs metabolised by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for NSAID-related adverse reactions should be performed when these agents are co-administered. Dose adjustment of the NSAID may be necessary.

Phenytoin.

Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous multiple administration of fluconazole at a dose of 200 mg and intravenous phenytoin at a dose of 250 mg leads to an increase in phenytoin AUC24 by 75% and Cmin by 128%. In case of simultaneous use of these agents, phenytoin plasma concentrations should be monitored to avoid the development of its toxic effects.

Prednisone.

A case has been reported in a liver transplant patient who developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole while receiving prednisone. Discontinuation of fluconazole likely resulted in increased CYP3A4 activity, leading to increased metabolism of prednisone. Patients should be closely monitored for the development of adrenal insufficiency after discontinuation of fluconazole if these agents are used concomitantly for long periods.

Rifabutin.

Concomitant use with fluconazole increases the concentration of rifabutin in the blood plasma, which leads to an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the simultaneous use of fluconazole and rifabutin. In the case of simultaneous use of these agents, symptoms of rifabutin toxicity should be taken into account.

Saquinavir.

Concomitant use with fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by the enzyme CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may therefore be more pronounced. Saquinavir dose adjustment may be necessary when these agents are used concomitantly.

Sulfonylurea derivatives.

Concomitant use with fluconazole prolongs the t1/2 of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) in healthy volunteers. Frequent monitoring of blood sugar levels is recommended during concomitant use and the dose of the sulfonylurea should be reduced accordingly.

Theophylline.

In a placebo-controlled drug interaction study, fluconazole 200 mg for 14 days decreased the mean plasma clearance of theophylline by 18%. Patients receiving high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity when these agents are coadministered. Therapy should be changed if signs of toxicity occur.

Tofacitinib.

Tofacitinib exposure is increased when co-administered with medicinal products that result in moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g. fluconazole). In case of co-administration with such medicinal products, it is recommended to reduce the dose of tofacitinib to 5 mg once daily.

Periwinkle alkaloids.

Although no relevant studies have been conducted, fluconazole, probably through inhibition of CYP3A4, may cause an increase in plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to the development of neurotoxic effects.

Vitamin A.

A patient receiving all-trans retinoic acid (an acid form of vitamin A) and fluconazole concomitantly has been reported to have experienced a central nervous system (CNS) adverse reaction in the form of pseudotumor cerebri; this effect resolved after discontinuation of fluconazole. These agents may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Co-administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an increase in voriconazole Cmax and AUCτ by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether reducing the dose and/or frequency of voriconazole or fluconazole would eliminate this effect. If voriconazole is administered after fluconazole, monitoring for adverse reactions associated with voriconazole should be performed.

Concomitant use with fluconazole increased the Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in zidovudine clearance by approximately 45% when administered orally. The t1/2 of zidovudine was also prolonged by approximately 128% after the combination of fluconazole and zidovudine. In the case of concomitant use of these agents, monitoring for adverse reactions associated with the use of zidovudine should be carried out. A reduction in the dose of zidovudine may be considered.

Azithromycin.

No significant pharmacokinetic interactions were observed with simultaneous oral single administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.

Oral contraceptives.

Two pharmacokinetic studies of multiple administration of fluconazole and a combined oral contraceptive have been conducted. Fluconazole 50 mg had no effect on hormone levels, while fluconazole 200 mg daily increased the AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that multiple administration of fluconazole at these doses is unlikely to affect the efficacy of a combined oral contraceptive.

Ivacaftor.

Co-administration with fluconazole increases the exposure of ivacaftor (a cystic fibrosis transmembrane conductance regulator enhancer) by 3-fold and hydroxymethylivacaftor (M1) by 1.9-fold. When moderate CYP3A inhibitors such as fluconazole and erythromycin are co-administered with ivacaftor, a dose reduction to 150 mg once daily is recommended.

Application features

Use for dermatophytosis.

According to the results of a study of fluconazole for the treatment of dermatophytosis in children, fluconazole is not superior to griseofulvin in terms of efficacy, with an overall efficacy rate of less than 20%. Therefore, the drug should not be used for the treatment of dermatophytosis.

Use in cryptococcosis.

There is insufficient evidence of the effectiveness of fluconazole for the treatment of cryptococcosis of other locations (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis), therefore there are no recommendations for the dosage regimen of the drug for the treatment of such diseases.

Use in deep endemic mycoses.

There is insufficient evidence of the effectiveness of fluconazole for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, therefore there are no recommendations for the dosage regimen of the drug for the treatment of such diseases.

Effect on the kidneys.

The drug should be used with caution in patients with impaired renal function (see section "Method of administration and dosage").

Risk of adrenal insufficiency.

Ketoconazole causes adrenal insufficiency, which may also be the case with fluconazole, although this is rare. Adrenal insufficiency associated with concomitant treatment with prednisone is described in the section "Interaction with other medicinal products and other forms of interaction".

Effect on the liver.

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 fatalities, mainly in patients with severe underlying diseases. In cases where hepatotoxicity has been associated with the use of fluconazole, there has been no clear relationship between the total daily dose, duration of therapy, gender or age of the patient. Usually, hepatotoxicity caused by fluconazole is reversible and its manifestations disappear after discontinuation of therapy.

Patients who develop abnormal liver function tests while taking fluconazole should be closely monitored for the development of more severe liver damage.

Patients should be informed of symptoms that may indicate serious liver effects (severe asthenia, anorexia, persistent nausea, vomiting and jaundice). In such cases, the use of the medicinal product should be discontinued immediately and a doctor should be consulted.

Effect on the cardiovascular system.

Some azoles, including fluconazole, are associated with prolongation of the interstitial nephritis.