Fucis tablets 100 mg blister No. 10

Instructions for Fucis tablets 100 mg blister No. 10

Composition

active ingredient: fluconazole;

1 tablet contains fluconazole 100 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, a triazole antifungal agent, is a potent and selective inhibitor of fungal enzymes required for ergosterol synthesis. 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 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 the most common Candida species (including Candida albicans, Candida parapsilosis, Candida tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, while Candida 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.

Pharmacodynamics – Pharmacokinetics

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 AUC and the dose of fluconazole (approximately 1:1). There is also a direct but insufficient relationship between the 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 may compromise efficacy in vivo and in clinical practice. Superinfection with Candida spp., other than Candida albicans, which are often insensitive to fluconazole (e.g. Candida krusei), has been reported. Alternative antifungal agents should be considered in such cases.

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 reached 0.5-1.5 hours after administration. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are reached on the second day of treatment when a loading dose of twice the usual daily dose is administered 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 studied body fluids. 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 those in serum, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum.

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 selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of CYP2C19 isoenzyme.

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.

Kidney failure

In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min), the half-life increases from 30 hours 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 intraperitoneal dialysis. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.

Elderly patients

Changes in pharmacokinetics in elderly patients depend on renal function parameters.

Indication

Treatment of diseases in adults such as:

cryptococcal meningitis; coccidioidomycosis; 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 (candidiasis caused by the use of dentures) when local dental hygiene products are ineffective; vaginal candidiasis, acute or recurrent, when local therapy is inappropriate; candidal balanitis, when local therapy is inappropriate; dermatomycoses, including athlete's foot, smooth skin mycosis, inguinal dermatomycosis; lichen multicolor and candidal skin infections, when systemic therapy is indicated; dermatophyte onychomycosis, when other drugs are inappropriate.

Prevention of diseases in adults such as:

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 recurrences of vaginal candidiasis (4 or more cases per year); Prevention of candidal infections in patients with prolonged neutropenia (e.g. patients with blood malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation).

Children

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.

The drug is used 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.

Therapy with the drug can be initiated before the results of culture and other laboratory tests are available; once the results are available, antibacterial therapy should be adjusted accordingly.

Contraindication

Hypersensitivity to fluconazole, other azole compounds or to any of the excipients of the drug; simultaneous use of fluconazole and terfenadine in patients receiving fluconazole multiple times at doses of 400 mg/day and above;

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 also 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).

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 and quinidine: Concomitant use of fluconazole and pimozide or quinidine may result in inhibition of the metabolism of pimozide or quinidine. Increased plasma concentrations of pimozide or quinidine may cause QT prolongation and, in rare cases, paroxysmal torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see Contraindications).

Erythromycin: Concomitant use of erythromycin and fluconazole may potentially lead to an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The combination of these drugs 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 increase the 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.

Effects 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.

Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. Therefore, an increase in the dose of fluconazole should be considered in patients taking rifampicin.

In a pharmacokinetic interaction study, co-administration of multiple hydrochlorothiazide with fluconazole in healthy volunteers increased fluconazole plasma concentrations by 40%. These interaction parameters do not require changes in the fluconazole dosing regimen for patients receiving concomitant diuretics.

Effect of fluconazole on other drugs

Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the CYP2C19 isoenzyme. In addition to the reported and described interactions listed below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 when used concomitantly with fluconazole. Therefore, such combinations should be used with caution; patients should be closely monitored. Due to the long half-life of fluconazole, its inhibitory effect on enzymes persists for 4-5 days (see section "Contraindications").

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.

Anticoagulants: As with other azole antifungals, bleeding events (haematoma, epistaxis, gastrointestinal haemorrhage, haematuria 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 with concomitant administration of fluconazole and triazolam.

If a patient undergoing treatment with fluconazole is to be prescribed concomitant therapy with benzodiazepines, 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.

Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole has been shown to increase serum bilirubin and creatinine levels. These drugs may be used concomitantly, taking into account the possible risk of increased serum bilirubin and creatinine concentrations.

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. If concomitant use is necessary, the patient should be closely observed 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.

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.

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.

Fluconazole has the potential to increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be necessary.

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 thought to have 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. Symptoms of rifabutin toxicity should be considered when using this combination of drugs.

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.

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): Co-administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in voriconazole Cmax and AUCτ of 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 would eliminate this effect. When voriconazole is administered after fluconazole, monitoring for adverse events associated with voriconazole should be performed.

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

Oral contraceptives: 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 doses of fluconazole are unlikely to affect the efficacy of a combined oral contraceptive.

Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator enhancer, increases ivacaftor exposure 3-fold and hydroxymethylivacaftor (M1) exposure 1.9-fold. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.

Application features

Ringworm. Fluconazole is known to be less effective than griseofulvin in treating ringworm in children, with an overall efficacy rate of less than 20%. Therefore, fluconazole should not be used to treat ringworm.

Cryptococcosis: There is insufficient evidence of the efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis), and therefore no dosage recommendations can be made for these conditions.

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

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

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although this is rare. Adrenal insufficiency associated with concomitant prednisone treatment is described in the section on Effects of fluconazole on other medicinal products 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 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 of the drug, 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, fluconazole should be discontinued immediately and a doctor should be consulted.

Cardiovascular system. Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation by inhibiting the ion current through inwardly rectifying potassium channels (Ikr). QT prolongation caused by other drugs (such as amiodarone) may be potentiated by inhibition of the cytochrome P450 enzyme CYP3A4. Very rare cases of QT prolongation and paroxysmal torsades de pointes have been reported with fluconazole. These reports have been in severely ill patients with multiple risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant use of other drugs that affect the QT interval. Patients with hypokalemia and severe heart failure are at 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 drugs that prolong the QTc interval and are metabolized by the cytochrome P450 enzyme CYP3A4 is contraindicated (see sections 4.3 and 4.5).

Halofantrine: Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section 4.5).

Dermatological reactions. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely with fluconazole. Patients with AIDS are more prone to develop severe skin reactions with many drugs. If a patient with a superficial fungal infection develops a rash that may be related to the use of fluconazole, further use of the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, his condition should be closely monitored, and in the event of the development of bullous rashes or erythema multiforme, fluconazole should be discontinued.

Hypersensitivity: Anaphylactic reactions have been reported rarely (see Contraindications).

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients should be monitored when concomitantly taking fluconazole and drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19 and CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").

Terfenadine: The patient should be carefully monitored when terfenadine and fluconazole are used concomitantly at doses less than 400 mg/day (see sections 4.3 and 4.5).

Excipients

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of fluconazole on the ability to drive or operate other mechanisms have not been conducted.

Patients should be informed about the possibility of dizziness or convulsions while using the drug. If such symptoms develop, it is not recommended to drive a car or operate other mechanisms.

Use during pregnancy or breastfeeding

Pregnancy

An observational study showed an increased risk of spontaneous abortion in women who received fluconazole during the first trimester.

Numerous congenital anomalies (including brachycephaly, auricular dysplasia, excessive anterior fontanelle enlargement, hip dysplasia, brachio-ulnar synostosis) have been reported in neonates whose mothers received high doses of fluconazole (400-800 mg/day) for at least three months or more for the treatment of coccidioidomycosis. The relationship between fluconazole use and these cases has not been established.

Animal studies have shown reproductive toxicity.

Normal doses of fluconazole and short courses of fluconazole should not be used during pregnancy unless clearly necessary.

High doses of fluconazole and/or long courses of fluconazole treatment should not be used during pregnancy, except for the treatment of potentially life-threatening infections.

Breast-feeding

Fluconazole passes into breast milk and reaches concentrations close to those in plasma (see section 5.1). Breastfeeding can be continued after a single dose of 150 mg of fluconazole.

Breastfeeding is not recommended during repeated use of fluconazole or when using high doses of fluconazole.

A decision on whether to use the drug during breastfeeding should be made taking into account the benefits of breastfeeding for the health and development of the child, the clinical need for fluconazole for the mother, and any potential adverse effects on the child from fluconazole excreted in breast milk or from the mother's health.

Fertility

Animal studies show that