Fucis tablets 150 mg blister No. 4

Instructions for Fucis tablets 150 mg blister No. 4

Composition

active ingredient: fluconazole;

1 tablet contains fluconazole 50 mg or 100 mg or 150 mg or 200 mg;

excipients: lactose monohydrate, microcrystalline cellulose, povidone K30, talc, magnesium stearate, sodium starch glycolate (type A), croscarmellose sodium.

Dosage form

Pills.

Main physicochemical properties: white, round, beveled-edge tablets with a break line on one side.

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 (ACTH) stimulation in healthy male volunteers.

An interaction study with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole did not affect the metabolism of antipyrine.

In vitro sensitivity.

Fluconazole has demonstrated antifungal activity in vitro against clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. The minimum inhibitory concentrations and the EUCAST epidemiological breakpoint (ECOFF) for fluconazole against C. guilliermondii are higher than against C. albicans.

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 animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and the efficacy against experimental models of mycoses caused by Candida species. According to clinical studies, there is a linear relationship between the 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 exhibits high MIC is less satisfactory.

Mechanism of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungals. Fluconazole exhibits high MICs against fungal strains that have one or more resistance mechanisms, which negatively impacts efficacy in vivo and in clinical practice.

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

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

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.

Based on the study of pharmacokinetic/pharmacodynamic data, in vitro susceptibility and clinical response, breakpoints for fluconazole have been established for Candida species. (EUCAST Guidance Document for Fluconazole (2020) – Version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungals, Breakpoint Tables for MIC Interpretation, Version 10.0, effective 04.02.2020). These have been divided into non-species-specific breakpoints, which are largely determined on the basis of pharmacokinetic/pharmacodynamic data and are not dependent on species-specific MIC allocation, 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;

* All C. glabrata indicators are in category I. MICs against C. glabrata should be evaluated as resistant when they exceed 16 mg/L. The susceptibility category (≤ 0.001 mg/L) is used only to prevent misclassification of I strains as S strains. I – susceptible under increased exposure: The microorganism is classified as “susceptible under increased exposure” when there is a high probability of therapeutic success because the exposure of the drug has been increased by adjusting the dosage regimen or its concentration in the focus of infection.

Pharmacokinetics

The pharmacokinetic properties of fluconazole are similar after 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 oral absorption. Peak plasma concentrations are achieved 0.5–1.5 hours after administration on an empty stomach. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are achieved by day 4–5 with multiple once-daily dosing or by day 2 with a loading dose of twice the usual daily dose on the first day.

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 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 serum levels, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum.

When using a dose of 50 mg once a 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 once a 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.

Biotransformation.

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

The long half-life of the drug from blood plasma allows for a single use of the drug for vaginal candidiasis, as well as the use of the drug once a week for other indications.

Pharmacokinetics in renal impairment.

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

Pharmacokinetics during lactation.

Fluconazole plasma and breast milk concentrations were evaluated in a pharmacokinetic study in ten lactating women who had temporarily or permanently discontinued breast-feeding their infants for 48 hours after a single 150 mg dose. Fluconazole was found in breast milk at a mean concentration approximately 98% of that observed in maternal plasma. The mean peak breast milk concentration 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 peak milk concentration 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.

Pharmacokinetic parameters in children were evaluated in 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 study in premature neonates. After administration of 2-8 mg/kg fluconazole to children aged 9 months to 15 years, an AUC of approximately 38 μg*h/ml per 1 mg/kg dose was observed. After multiple administration, the mean plasma half-life of fluconazole ranged between 15 and 18 hours, and the volume of distribution was approximately 880 ml/kg. A longer plasma half-life of fluconazole of approximately 24 hours was observed after a single dose. This is comparable to the plasma half-life of fluconazole after a single intravenous dose of 3 mg/kg to children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours), and the mean birth weight was 0.9 kg (range 0.75–1.10 kg). A maximum of 5 intravenous injections of fluconazole at a dose of 6 mg/kg were administered every 72 hours. The mean half-life was 74 hours (44–185) on the first day, then decreased to 53 hours (30–131) on the 7th day and to 47 (27–68) on the 13th day. The area under the curve (μg*h/mL) was 271 (173–385) on day 1, increasing to 490 (292–734) on day 7, then decreasing to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increasing to 1184 (510–2130) on day 7 and 1328 (1040–1680) on day 13, respectively.

Pharmacokinetics 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 half-life was 46.2 hours. These pharmacokinetic parameters are higher compared to those in healthy young 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 young volunteers. Therefore, changes in pharmacokinetics in elderly patients clearly depend on renal function parameters.

Indication

Fucis® is indicated for the treatment of the following fungal infections in adults (see section "Pharmacodynamics"):

– cryptococcal meningitis (see section “Special instructions for use”);

– coccidioidosis (see section “Special instructions for use”);

– invasive candidiasis;

– candidiasis of the mucous membranes, including oropharyngeal candidiasis and esophageal candidiasis; candiduria, chronic candidiasis of the skin and mucous membranes;

– chronic atrophic candidiasis of the oral cavity (candidiasis caused by the use of dentures) with ineffective oral hygiene or local therapy;

– vaginal candidiasis, acute or recurrent, when local therapy is not appropriate;

– candidal balanitis, when local therapy is not appropriate;

– dermatomycoses, including athlete's foot, smooth skin mycosis, inguinal dermatomycosis; lichen planus and candidal skin infections when systemic therapy is indicated;

– dermatophyte onychomycosis, when the use of other medications is not appropriate.

Fucis® is indicated for the prevention of the following diseases in adults:

– recurrence of cryptococcal meningitis in patients at high risk of its development;

– recurrence of oropharyngeal or esophageal candidiasis in HIV patients at high risk of its development;

– to reduce the frequency of recurrences of vaginal candidiasis (4 or more cases per year);

– prevention of candidal infections in patients with prolonged neutropenia (e.g. patients with malignant blood diseases receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation) (see section “Pharmacological properties. Pharmacodynamics”).

Children.

Fucis® is indicated in children for the treatment of candidiasis of the mucous membranes (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and for the prevention of candidal infections in patients with reduced immunity. The drug can be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of its development (see section "Special instructions").

The drug in tablet form can be used in this category of patients when children are able to safely swallow a tablet, which is usually possible from the age of 5.

Therapy with Fucis® may be initiated prior to the results of culture and other laboratory tests; however, once the results are available, anti-infective therapy should be adjusted accordingly.

Contraindication

– Concomitant use of fluconazole and terfenadine in patients taking fluconazole multiple times at doses of 400 mg/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 (e.g. cisapride, astemizole, pimozide, quinidine and erythromycin), see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”.

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. 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 administration of fluconazole and cisapride is contraindicated (see Contraindications).

Terfenadine: Due to cases of serious cardiac arrhythmias caused by prolongation of the QTc interval, drug-drug interaction studies have been conducted in patients receiving azole antifungals concomitantly with terfenadine. No prolongation of the QTc interval was observed with fluconazole at a dose of 200 mg/day. Fluconazole at doses of 400 mg/day or higher significantly increases plasma levels of terfenadine when these drugs are administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section 4.3). When fluconazole is administered at doses below 400 mg/day concomitantly with terfenadine, the patient should be closely monitored.

Astemizole: Concomitant use of fluconazole and astemizole 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 fluconazole and astemizole is contraindicated (see section 4.3).

Pimozide: Concomitant use of fluconazole with pimozide may result in inhibition of pimozide metabolism, although no in vitro or in vivo studies have been conducted. Increased plasma concentrations of pimozide may lead to QT prolongation and, in rare cases, torsades de pointes. Concomitant use of fluconazole with pimozide is contraindicated (see section 4.3).

Quinidine: Concomitant use of fluconazole and quinidine may result in inhibition of quinidine metabolism, although in vitro and in vivo studies have not been conducted. Quinidine has been associated with QT prolongation and, in rare cases, paroxysmal torsades de pointes. Concomitant use of fluconazole and quinidine is contraindicated (see section 4.3).

Erythromycin: Concomitant use of fluconazole with erythromycin may lead to an increased risk of cardiotoxicity (QT prolongation and torsades de pointes) and, as a result, sudden coronary death. Concomitant use of fluconazole and erythromycin is contraindicated (see section 4.3).

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

Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of CYP3A4. Concomitant use of these medicinal products may potentially lead to an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) and, consequently, sudden cardiac death. The combination of these medicinal products should be avoided (see section 4.4).

The concomitant use of fluconazole and the following drugs requires caution.

Amiodarone: Concomitant use of fluconazole with amiodarone may prolong the QT interval. Caution should be exercised when co-administering fluconazole and amiodarone, especially at high doses (800 mg).

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

Effect of other drugs on fluconazole.

Concomitant food intake, cimetidine, antacids, and radiation therapy to the entire body (in bone marrow transplantation) have no clinically significant effect on the absorption of fluconazole when administered orally.

Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple hydrochlorothiazide to healthy volunteers receiving fluconazole increased fluconazole plasma concentrations by 40%. These interaction parameters do not require changes in the fluconazole dosing regimen for patients receiving 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 co-administered with fluconazole. Therefore, such combinations should be used with caution; patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long half-life (see section "Contraindications").

Abrocitinib: Fluconazole (CYP2C19, 2C9, 3A4 inhibitor) increased the exposure of the active moiety of abrocitinib by 155%. The dose of abrocitinib should be adjusted according to the prescribing information for abrocitinib when co-administered with fluconazole.

Alfentanil: Concomitant administration of fluconazole 400 mg and alfentanil 20 mcg/kg intravenously resulted in a two-fold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates a dose adjustment of alfentanil.

Amitriptyline, nortriptyline: Fluconazole potentiates the effects of amitriptyline and nortriptyline. It is recommended to measure the concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy and 1 week after its start. If necessary, the dose of amitriptyline or nortriptyline should be adjusted.

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

Anticoagulants: As with other azole antifungals, cases of bleeding (hematoma, epistaxis, gastrointestinal bleeding, hematuria and melena) have been reported with concomitant use of fluconazole and warfarin, in association with prolonged prothrombin time. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, presumably due to inhibition of warfarin metabolism by CYP2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants or indandione. Dosage 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 concentrations and increased psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7- and 2.2-fold increase in AUC and half-life, respectively. Administration of fluconazole 200 mg/day and triazolam 0.25 mg orally resulted in a 4.4- and 2.3-fold increase in AUC and half-life, respectively. Potentiation and prolongation of the effects of triazolam were observed when fluconazole and triazolam were co-administered.

If a patient undergoing treatment with fluconazole is to be given concomitant benzodiazepine therapy, the dose of the latter should be reduced and appropriate monitoring of the patient's condition should be established.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity. The dose of carbamazepine may need to be adjusted depending on its concentration and effect.

Calcium channel blockers: Some calcium antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib: Concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased celecoxib Cmax and AUC by 68% and 134%, respectively. A halving of the celecoxib dose may be necessary when celecoxib and fluconazole are co-administered.

Fentanyl: One fatal case of fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. Fluconazole significantly slows the elimination of fentanyl. Increased fentanyl concentrations may lead to respiratory depression, so the patient should be closely monitored. 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 in a dose-dependent manner (due to decreased hepatic metabolism of the statin). If concomitant use is necessary, the patient should be closely monitored for symptoms of myopathy and rhabdomyolysis and creatine kinase levels should be monitored. In the event of a significant increase in creatine kinase levels, as well as if myopathy/rhabdomyolysis is suspected or detected, the use of HMG-CoA reductase inhibitors should be discontinued. Lower doses of HMG-CoA reductase inhibitors may be required in accordance with the instructions for medical use of statins.

Ibritinib: Moderate CYP3A4 inhibitors such as fluconazole increase ibritinib plasma concentrations and may increase the risk of toxicity. If the combination cannot be avoided, the ibritinib dose should be reduced to 280 mg once daily to allow continued use of the inhibitor and ensure ongoing clinical monitoring.

Ivacaftor (alone or in combination with drugs of the same therapeutic class): Co-administration of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR), with hydroxymethylivacaftor (M1) increased ivacaftor exposure 3-fold and hydroxymethylivacaftor (M1) exposure 1.9-fold.

The dose of ivacaftor (alone or in combination) should be reduced according to its prescribing information (alone or in combination).

Olaparib: Moderate CYP3A4 inhibitors such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If this combination cannot be avoided, the olaparib dose should be reduced to 200 mg twice daily.

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

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

Everolimus: Fluconazole may increase serum concentrations of everolimus due to inhibition of CYP3A4.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus, possibly by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These drugs can be used concomitantly, with dose adjustments of sirolimus based on concentration levels and drug effects.

Tacrolimus: Fluconazole may increase the serum concentrations of tacrolimus up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics have been observed with intravenous administration of tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced depending on tacrolimus concentrations.

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

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

Methadone: Fluconazole may increase the serum concentration of methadone. Methadone dose adjustment may be necessary when methadone and fluconazole are used concomitantly.

Non-steroidal anti-inflammatory drugs (NSAIDs): When co-administered with fluconazole, the Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when co-administered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen were increased by 15% and 82%, respectively, compared to racemic ibuprofen alone.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Simultaneous multiple administration of 200 mg of fluconazole and 250 mg of phenytoin intravenously leads to an increase in phenytoin AUC24 by 75% and Cmin by 128%. When these drugs are used simultaneously, phenytoin serum concentrations should be monitored to avoid the development of phenytoin toxicity.

Prednisone: A case report has been made of a liver transplant patient receiving prednisone who developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole. Discontinuation of fluconazole is likely to have resulted in increased CYP3A4 activity, leading to increased metabolism of prednisone. Patients receiving long-term concomitant treatment with fluconazole and prednisone should be carefully monitored for the development of adrenal insufficiency after discontinuation of fluconazole.

Rifabutin: Fluconazole increases the serum concentration of rifabutin, resulting in an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the concomitant use of fluconazole and rifabutin. When using this combination of drugs, symptoms of rifabutin toxicity should be taken into account.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of the hepatic metabolism of saquinavir by 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.

Sulfonylureas: Concomitant use of fluconazole with oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) has been shown to prolong their half-life. Frequent monitoring of blood sugar levels and appropriate dose reduction of sulfonylureas is recommended when co-administered with fluconazole.

Theophylline: 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. Therapy should be changed if signs of toxicity occur.

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

Tolvaptan: Exposure to tolvaptan (a CYP3A4 substrate) is significantly increased (200% AUC; 80% Cmax) when co-administered with fluconazole (a moderate CYP3A4 inhibitor), and the risk of adverse reactions such as increased diuresis, dehydration, and acute renal failure is increased. In case of co-administration, the dose of tolvaptan should be reduced according to its instructions and the patient should be monitored for adverse reactions.

Vinca alkaloids: Fluconazole, possibly through inhibition of CYP3A4, may cause an increase in plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: A patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole was reported to have a CNS adverse reaction in the form of pseudotumor cerebri that resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concomitant oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg